Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors.

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Guofeng Qian

Full Text Available Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat, whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and

Gli2 activator function in preosteoblasts is sufficient to mediate Ihh-dependent osteoblast differentiation, whereas the repressor function of Gli2 is dispensable for endochondral ossification.

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Kesper, Dörthe Andrea; Didt-Koziel, Lydia; Vortkamp, Andrea

2010-06-01

Signaling of Indian hedgehog (Ihh), one of the key regulators of endochondral ossification is mediated by transcription factors of the Gli family, Gli1, Gli2, and Gli3. Gli3 and to a lesser extent Gli2 can be proteolytically processed into short repressor proteins. Upon Ihh signaling, processing is inhibited and the full-length proteins function as activators of transcription. Gli3 has been shown to mainly act as a repressor of Ihh target genes in chondrocytes, but the role of other Gli isoforms is less clear. Analyzing mouse mutants deficient for Ihh;Gli2 or Gli3;Gli2, we show here that the Gli2 repressor has no detectable function in chondrocyte or osteoblast differentiation. Instead, Gli2 seems to act as an activator to fully induce the expression of Ihh target genes in skeletal tissues. Furthermore, we show that, in the absence of Gli3, the activator function of Gli2 is sufficient to induce Ihh-dependent osteoblast differentiation.

FGFR3 mutation causes abnormal membranous ossification in achondroplasia.

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Di Rocco, Federico; Biosse Duplan, Martin; Heuzé, Yann; Kaci, Nabil; Komla-Ebri, Davide; Munnich, Arnold; Mugniery, Emilie; Benoist-Lasselin, Catherine; Legeai-Mallet, Laurence

2014-06-01

FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.

Dlx5 Is a cell autonomous regulator of chondrocyte hypertrophy in mice and functionally substitutes for Dlx6 during endochondral ossification.

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Hui Zhu

Full Text Available The axial and appendicular skeleton of vertebrates develops by endochondral ossification, in which skeletogenic tissue is initially cartilaginous and the differentiation of chondrocytes via the hypertrophic pathway precedes the differentiation of osteoblasts and the deposition of a definitive bone matrix. Results from both loss-of-function and misexpression studies have implicated the related homeobox genes Dlx5 and Dlx6 as partially redundant positive regulators of chondrocyte hypertrophy. However, experimental perturbations of Dlx expression have either not been cell type specific or have been done in the context of endogenous Dlx5 expression. Thus, it has not been possible to conclude whether the effects on chondrocyte differentiation are cell autonomous or whether they are mediated by Dlx expression in adjacent tissues, notably the perichondrium. To address this question we first engineered transgenic mice in which Dlx5 expression was specifically restricted to immature and differentiating chondrocytes and not the perichondrium. Col2a1-Dlx5 transgenic embryos and neonates displayed accelerated chondrocyte hypertrophy and mineralization throughout the endochondral skeleton. Furthermore, this transgene specifically rescued defects of chondrocyte differentiation characteristic of the Dlx5/6 null phenotype. Based on these results, we conclude that the role of Dlx5 in the hypertrophic pathway is cell autonomous. We further conclude that Dlx5 and Dlx6 are functionally equivalent in the endochondral skeleton, in that the requirement for Dlx5 and Dlx6 function during chondrocyte hypertrophy can be satisfied with Dlx5 alone.

Reappraisal of mesenchymal chondrosarcoma: novel morphologic observations of the hyaline cartilage and endochondral ossification and beta-catenin, Sox9, and osteocalcin immunostaining of 22 cases.

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Fanburg-Smith, Julie C; Auerbach, Aaron; Marwaha, Jayson S; Wang, Zengfeng; Rushing, Elisabeth J

2010-05-01

Mesenchymal chondrosarcoma, a rare malignant round cell and hyaline cartilage tumor, is most commonly intraosseous but can occur in extraskeletal sites. We intensively observed the morphology and applied Sox9 (master regulator of chondrogenesis), beta-catenin (involved in bone formation, thought to inhibit chondrogenesis in a Sox9-dependent manner), and osteocalcin (a marker for osteoblastic phenotype) to 22 central nervous system and musculoskeletal mesenchymal chondrosarcoma. Cases of mesenchymal chondrosarcoma were retrieved and reviewed from our files. Immunohistochemistry and follow-up were obtained on mesenchymal chondrosarcoma and tumor controls. Twenty-two mesenchymal chondrosarcomas included 5 central nervous system (all female; mean age, 30.2; mean size, 7.8 cm; in frontal lobe [n = 4] and spinal cord [n = 1]) and 17 musculoskeletal (female-male ratio, 11:6; mean age, 31.1; mean size, 6.2 cm; 3 each of humerus and vertebrae; 2 each of pelvis, rib, tibia, neck soft tissue; one each of femur, unspecified bone, and elbow soft tissue). The hyaline cartilage in most tumors revealed a consistent linear progression of chondrocyte morphology, from resting to proliferating to hypertrophic chondrocytes. Sixty-seven percent of cases demonstrated cell death and acquired osteoblastic phenotype, cells positive for osteocalcin at the site of endochondral ossification. Small round cells of mesenchymal chondrosarcoma were negative for osteocalcin. SOX9 was positive in both components of 21 of 22 cases of mesenchymal chondrosarcoma. beta-Catenin highlighted rare nuclei at the interface between round cells and hyaline cartilage in 35% cases. Control skull and central nervous system cases were compared, including chondrosarcomas and small cell osteosarcoma, the latter positive for osteocalcin in small cells. Mesenchymal chondrosarcoma demonstrates centrally located hyaline cartilage with a linear progression of chondrocytes from resting to proliferative to hypertrophic

Endochondral Growth Defect and Deployment of Transient Chondrocyte Behaviors Underlie Osteoarthritis Onset in a Natural Murine Model

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Staines, K. A.; Madi, K.; Mirczuk, S. M.; Parker, S.; Burleigh, A.; Poulet, B.; Hopkinson, M.; Bodey, A. J.; Fowkes, R. C.; Farquharson, C.; Lee, P. D.

2016-01-01

Objective To explore whether aberrant transient chondrocyte behaviors occur in the joints of STR/Ort mice (which spontaneously develop osteoarthritis [OA]) and whether they are attributable to an endochondral growth defect. Methods Knee joints from STR/Ort mice with advanced OA and age‐matched CBA (control) mice were examined by Affymetrix microarray profiling, multiplex polymerase chain reaction (PCR) analysis, and immunohistochemical labeling of endochondral markers, including sclerostin and MEPE. The endochondral phenotype of STR/Ort mice was analyzed by histologic examination, micro–computed tomography, and ex vivo organ culture. A novel protocol for quantifying bony bridges across the murine epiphysis (growth plate fusion) using synchrotron x‐ray computed microtomography was developed and applied. Results Meta‐analysis of transcription profiles showed significant elevation in functions linked with endochondral ossification in STR/Ort mice (compared to CBA mice; P mice. Our novel synchrotron radiation microtomography method showed increased numbers (P mice compared to age‐matched CBA mice. Conclusion Taken together, our data support the notion of an inherent endochondral defect that is linked to growth dynamics and subject to regulation by the MEPE/sclerostin axis and may represent an underlying mechanism of pathologic ossification in OA. PMID:26605758

Delayed endochondral ossification in early medial coronoid disease (MCD): a morphological and immunohistochemical evaluation in growing Labrador retrievers.

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Lau, S F; Hazewinkel, H A W; Grinwis, G C M; Wolschrijn, C F; Siebelt, M; Vernooij, J C M; Voorhout, G; Tryfonidou, M A

2013-09-01

Medial coronoid disease (MCD) is a common joint disease of dogs. It has a multifactorial aetiology, but the relationship between known causal factors and the disease has yet to be elucidated. As most of the published literature is clinical and it reports changes associated with advanced disease, it is not known whether the changes reflect the cause or consequences of the condition. The aim of this study was to investigate early micromorphological changes occurring in articular cartilage and to describe the postnatal development of the medial coronoid process (MCP) before MCD develops. Three litters of MCD-prone young Labrador retrievers were purpose-bred from a dam and two sires with MCD. Comparisons of the micromorphological appearance of the MCP in MCD-negative and MCD-positive joints demonstrated that MCD was initially associated with a disturbance of endochondral ossification, namely a delay in the calcification of the calcifying zone, without concurrent abnormalities in the superficial layers of the joint cartilage. Cartilage canals containing patent blood vessels were only detected in dogs <12 weeks old, but the role of these channels in impaired ossification requires further investigation. Retained hyaline cartilage might ossify as the disease progresses, but weak areas can develop into cracks between the retained cartilage and the subchondral bone, leading to cleft formation and fragmentation of the MCP. Copyright © 2013 Elsevier Ltd. All rights reserved.

Osteogenic Potential of Caspases Related to Endochondral Ossification

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Janečková, E.; Bíliková, P.; Matalová, Eva

2018-01-01

Roč. 66, č. 1 (2018), s. 47-58 ISSN 0022-1554 Institutional support: RVO:67985904 Keywords : caspases * endochronal ossification * growth plate Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Developmental biology Impact factor: 2.511, year: 2016

Clock Genes Influence Gene Expression in Growth Plate and Endochondral Ossification in Mice*

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Takarada, Takeshi; Kodama, Ayumi; Hotta, Shogo; Mieda, Michihiro; Shimba, Shigeki; Hinoi, Eiichi; Yoneda, Yukio

2012-01-01

We have previously shown transient promotion by parathyroid hormone of Period-1 (Per1) expression in cultured chondrocytes. Here we show the modulation by clock genes of chondrogenic differentiation through gene transactivation of the master regulator of chondrogenesis Indian hedgehog (IHH) in chondrocytes of the growth plate. Several clock genes were expressed with oscillatory rhythmicity in cultured chondrocytes and rib growth plate in mice, whereas chondrogenesis was markedly inhibited in stable transfectants of Per1 in chondrocytic ATDC5 cells and in rib growth plate chondrocytes from mice deficient of brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL1). Ihh promoter activity was regulated by different clock gene products, with clear circadian rhythmicity in expression profiles of Ihh in the growth plate. In BMAL1-null mice, a predominant decrease was seen in Ihh expression in the growth plate with a smaller body size than in wild-type mice. BMAL1 deficit led to disruption of the rhythmic expression profiles of both Per1 and Ihh in the growth plate. A clear rhythmicity was seen with Ihh expression in ATDC5 cells exposed to dexamethasone. In young mice defective of BMAL1 exclusively in chondrocytes, similar abnormalities were found in bone growth and Ihh expression. These results suggest that endochondral ossification is under the regulation of particular clock gene products expressed in chondrocytes during postnatal skeletogenesis through a mechanism relevant to the rhythmic Ihh expression. PMID:22936800

An unusual form of spondyloepiphyseal dysplasia, with advanced carpal and spinal end-plate ossification mimicking COMP-mutation-like multiple epiphyseal dysplasia

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Pazzaglia, Ugo E.; Zarattini, Guido [University of Brescia Medical School, Department of Orthopaedics and Traumatology, Brescia (Italy); Beluffi, Giampiero [Fondazione IRCCS Policlinico S. Matteo, Section of Paediatric Radiology, Department of Radiodiagnosis, Pavia (Italy)

2008-07-15

We present a child with irregular ossification of tubular bone epiphyses, short bones, and spine. The radiographic evolution of bones undergoing endochondral ossification was followed from the age of 1 year 9 months to 6 years. The unusual features demonstrated in this child made classification difficult: pseudoachondroplasia was excluded because no mutations of the COMP gene were found. Considering the evolution of the radiographic appearances, the most likely diagnosis would seem to be an unusual form of spondyloepiphyseal dysplasia, mimicking some aspects of multiple epiphyseal dysplasia. Endochondral ossification was diffusely altered with a mixture of epiphyseal ossification delay associated with acceleration and early fusion. This case was a unique presentation within the family, suggesting a mutation in the affected child. (orig.)

An unusual form of spondyloepiphyseal dysplasia, with advanced carpal and spinal end-plate ossification mimicking COMP-mutation-like multiple epiphyseal dysplasia

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Pazzaglia, Ugo E.; Zarattini, Guido; Beluffi, Giampiero

2008-01-01

We present a child with irregular ossification of tubular bone epiphyses, short bones, and spine. The radiographic evolution of bones undergoing endochondral ossification was followed from the age of 1 year 9 months to 6 years. The unusual features demonstrated in this child made classification difficult: pseudoachondroplasia was excluded because no mutations of the COMP gene were found. Considering the evolution of the radiographic appearances, the most likely diagnosis would seem to be an unusual form of spondyloepiphyseal dysplasia, mimicking some aspects of multiple epiphyseal dysplasia. Endochondral ossification was diffusely altered with a mixture of epiphyseal ossification delay associated with acceleration and early fusion. This case was a unique presentation within the family, suggesting a mutation in the affected child. (orig.)

Endochondral vs. intramembranous demineralized bone matrices as implants for osseous defects.

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Nidoli, M C; Nielsen, F F; Melsen, B

1999-05-01

This study focuses on the difference in regenerative capacity between endochondral and intramembranous demineralized bone matrices (DBMs) when implanted into bony defects. It also focuses on the possible influence of the type of skeletal recipient site (orthotopic or heterotopic). Of 34 Wistar rats, 10 served as a source of DBM, and 24 were divided into two groups of 12 animals. In group A identical defects were produced in the parietal bones, whereas in group B the defects were produced in each radius. The right defects were implanted with endochondral DBM and the left defects were implanted with intramembranous DBM. Descriptive and/or histomorphometric analyses were performed by means of light and polarized microscopy, and radiography (group B). Right and left data were compared to disclose differences in bone-healing capacity. The quantitative results demonstrated that endochondral DBM displays a greater regenerative capacity than intramembranous DBM when implanted heterotopically. The different clinical performances of endochondral and intramembranous bone grafts might be explained on the basis of the mechanical rather than the osteoinductive principle. The qualitative results suggest that the type of bone deposition induced by the DBMs is not related to the type of implanted DBM. Recipient site characteristics and/or environmental factors seem decisive in the occurrence of either types of ossification.

Comparative studies on the ossification in several experimental animals

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Matsuoka, Osamu; Fukuda, Shun

1978-01-01

For estimating the risk of the bone seeking radionuclides in man, it is necessary to extrapolate the data of experimental animals to those of man. Detailed information on the biological stages of development, especially on bone growth of several experimental animals and of man is required for better extrapolation. Multi-species comparison of bone growth and ossification was carried out in several mammalian species such as mouse, rat, dog and monkey. The appearance, ossifying process and fusion of the secondary ossification centers in extremities were selected as indicators of the biological stage of bone. The observation of the secondary ossification centers was made by radiography. The maturity process of the secondary ossification centers in each animal was illustrated. The ossifying process of the secondary ossification center could be divided into the following three categories; (1) the acute ossification observed in mouse, rat, dog and monkey (2) the delayed ossification observed in mouse, rat, dog and monkey, (3) the incomplete ossification without complete fusion which is specific in mouse and rat, appeared and continued up to at least 27 weeks in mouse and up to 134 weeks in rat. The results of the study suggested that a mouse 17 weeks old, a rat 17 - 21 weeks old, a dog (beagle) 14 months old and a monkey about 6 years old may correspond to a man about 20 years old. (author)

Roles of Chondrocytes in Endochondral Bone Formation and Fracture Repair

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Hinton, R.J.; Jing, Y.; Jing, J.; Feng, J.Q.

2016-01-01

The formation of the mandibular condylar cartilage (MCC) and its subchondral bone is an important but understudied topic in dental research. The current concept regarding endochondral bone formation postulates that most hypertrophic chondrocytes undergo programmed cell death prior to bone formation. Under this paradigm, the MCC and its underlying bone are thought to result from 2 closely linked but separate processes: chondrogenesis and osteogenesis. However, recent investigations using cell lineage tracing techniques have demonstrated that many, perhaps the majority, of bone cells are derived via direct transformation from chondrocytes. In this review, the authors will briefly discuss the history of this idea and describe recent studies that clearly demonstrate that the direct transformation of chondrocytes into bone cells is common in both long bone and mandibular condyle development and during bone fracture repair. The authors will also provide new evidence of a distinct difference in ossification orientation in the condylar ramus (1 ossification center) versus long bone ossification formation (2 ossification centers). Based on our recent findings and those of other laboratories, we propose a new model that contrasts the mode of bone formation in much of the mandibular ramus (chondrocyte-derived) with intramembranous bone formation of the mandibular body (non-chondrocyte-derived). PMID:27664203

Endochondral Ossification Is Accelerated in Cholinesterase-Deficient Mice and in Avian Mesenchymal Micromass Cultures.

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Janine Spieker

Full Text Available Most components of the cholinergic system are detected in skeletogenic cell types in vitro, yet the function of this system in skeletogenesis remains unclear. Here, we analyzed endochondral ossification in mutant murine fetuses, in which genes of the rate-limiting cholinergic enzymes acetyl- (AChE, or butyrylcholinesterase (BChE, or both were deleted (called here A-B+, A+B-, A-B-, respectively. In all mutant embryos bone growth and cartilage remodeling into mineralizing bone were accelerated, as revealed by Alcian blue (A-blu and Alizarin red (A-red staining. In A+B- and A-B- onset of mineralization was observed before E13.5, about 2 days earlier than in wild type and A-B+ mice. In all mutants between E18.5 to birth A-blu staining disappeared from epiphyses prematurely. Instead, A-blu+ cells were dislocated into diaphyses, most pronounced so in A-B- mutants, indicating additive effects of both missing ChEs in A-B- mutant mice. The remodeling effects were supported by in situ hybridization (ISH experiments performed on cryosections from A-B- mice, in which Ihh, Runx2, MMP-13, ALP, Col-II and Col-X were considerably decreased, or had disappeared between E18.5 and P0. With a second approach, we applied an improved in vitro micromass model from chicken limb buds that allowed histological distinction between areas of cartilage, apoptosis and mineralization. When treated with the AChE inhibitor BW284c51, or with nicotine, there was decrease in cartilage and accelerated mineralization, suggesting that these effects were mediated through nicotinic receptors (α7-nAChR. We conclude that due to absence of either one or both cholinesterases in KO mice, or inhibition of AChE in chicken micromass cultures, there is increase in cholinergic signalling, which leads to increased chondroblast production and premature mineralization, at the expense of incomplete chondrogenic differentiation. This emphasizes the importance of cholinergic signalling in cartilage and

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

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Carpio, Lomeli R.; Bradley, Elizabeth W.; McGee-Lawrence, Meghan E.; Weivoda, Megan M.; Poston, Daniel D.; Dudakovic, Amel; Xu, Ming; Tchkonia, Tamar; Kirkland, James L.; van Wijnen, Andre J.; Oursler, Merry Jo; Westendorf, Jennifer J.

2017-01-01

Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)–expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)–JAK–STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development. PMID

Endochondral gigantism: a newly recognized skeletal dysplasia with pre- and postnatal overgrowth and endocrine abnormalities.

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Schmidt, Heinrich; Kammer, Birgit; Grasser, Monika; Enders, Angelika; Rost, Imma; Kiess, Wieland

2007-08-15

We report on a 3-year-old male, born at 34 weeks of gestation, with marked pre- and postnatal overgrowth, birth weight of 6,600 g, length of 61 cm, and head circumference of 38.5 cm. A striking phenotype was recorded at birth, which became more evident during the follow-up period. He had macrobrachycephaly, facial abnormalities, small thoracic cage, long trunk, deformed spine, rhizomelia, large hands and feets, absent subcutaneous fat, small umbilical hernia, inguinal hernias, and large joints with mild contractures. Hypoglycemic episodes and obstructive apnea complicated the neonatal period. During follow-up, overgrowth continued with a height of 146 cm (+11.65 SDS) and a weight of 39 kg (BMI 18.3 kg/m(2)) at 3.5 years. Endocrinological work-up disclosed extremely low levels of growth hormone, insulin-like growth factors, and insulin. What makes our patient unique is the association of marked prenatal overgrowth; unusual phenotype; skeletal dysplasia caused by accelerated endochondral ossification resulting in cartilage hyperplasia of the skull base and spine, and postnatal gigantism; and complete absence of subcutaneous fat. Other well-known overgrowth syndromes were excluded. We hypothesize that autocrine/paracrine growth factors could be the cause of excessive endochondral ossification. Alternately, activating mutations in transcription factors involved in both growth and endocrine/metabolic homeostasis could be responsible for this unusual phenotype. (c) 2007 Wiley-Liss, Inc.

3D printed microchannel networks to direct vascularisation during endochondral bone repair.

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Daly, Andrew C; Pitacco, Pierluca; Nulty, Jessica; Cunniffe, Gráinne M; Kelly, Daniel J

2018-04-01

Bone tissue engineering strategies that recapitulate the developmental process of endochondral ossification offer a promising route to bone repair. Clinical translation of such endochondral tissue engineering strategies will require overcoming a number of challenges, including the engineering of large and often anatomically complex cartilage grafts, as well as the persistence of core regions of avascular cartilage following their implantation into large bone defects. Here 3D printing technology is utilized to develop a versatile and scalable approach to guide vascularisation during endochondral bone repair. First, a sacrificial pluronic ink was used to 3D print interconnected microchannel networks in a mesenchymal stem cell (MSC) laden gelatin-methacryloyl (GelMA) hydrogel. These constructs (with and without microchannels) were next chondrogenically primed in vitro and then implanted into critically sized femoral bone defects in rats. The solid and microchanneled cartilage templates enhanced bone repair compared to untreated controls, with the solid cartilage templates (without microchannels) supporting the highest levels of total bone formation. However, the inclusion of 3D printed microchannels was found to promote osteoclast/immune cell invasion, hydrogel degradation, and vascularisation following implantation. In addition, the endochondral bone tissue engineering strategy was found to support comparable levels of bone healing to BMP-2 delivery, whilst promoting lower levels of heterotopic bone formation, with the microchanneled templates supporting the lowest levels of heterotopic bone formation. Taken together, these results demonstrate that 3D printed hypertrophic cartilage grafts represent a promising approach for the repair of complex bone fractures, particularly for larger defects where vascularisation will be a key challenge. Copyright © 2018 Elsevier Ltd. All rights reserved.

Interleukin-1β modulates endochondral ossification by human adult bone marrow stromal cells

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M Mumme

2012-09-01

Full Text Available Inflammatory cytokines present in the milieu of the fracture site are important modulators of bone healing. Here we investigated the effects of interleukin-1β (IL-1β on the main events of endochondral bone formation by human bone marrow mesenchymal stromal cells (BM-MSC, namely cell proliferation, differentiation and maturation/remodelling of the resulting hypertrophic cartilage. Low doses of IL-1β (50 pg/mL enhanced colony-forming units-fibroblastic (CFU-f and -osteoblastic (CFU-o number (up to 1.5-fold and size (1.2-fold in the absence of further supplements and glycosaminoglycan accumulation (1.4-fold upon BM-MSC chondrogenic induction. In osteogenically cultured BM-MSC, IL-1β enhanced calcium deposition (62.2-fold and BMP-2 mRNA expression by differential activation of NF-κB and ERK signalling. IL-1β-treatment of BM-MSC generated cartilage resulted in higher production of MMP-13 (14.0-fold in vitro, mirrored by an increased accumulation of the cryptic cleaved fragment of aggrecan, and more efficient cartilage remodelling/resorption after 5 weeks in vivo (i.e., more TRAP positive cells and bone marrow, less cartilaginous areas, resulting in the formation of mature bone and bone marrow after 12 weeks. In conclusion, IL-1β finely modulates early and late events of the endochondral bone formation by BM-MSC. Controlling the inflammatory environment could enhance the success of therapeutic approaches for the treatment of fractures by resident MSC and as well as improve the engineering of implantable tissues.

Endochondral fracture healing with external fixation in the Sost knockout mouse results in earlier fibrocartilage callus removal and increased bone volume fraction and strength.

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Morse, A; Yu, N Y C; Peacock, L; Mikulec, K; Kramer, I; Kneissel, M; McDonald, M M; Little, D G

2015-02-01

Sclerostin deficiency, via genetic knockout or anti-Sclerostin antibody treatment, has been shown to cause increased bone volume, density and strength of calluses following endochondral bone healing. However, there is limited data on the effect of Sclerostin deficiency on the formative early stage of fibrocartilage (non-bony tissue) formation and removal. In this study we extensively investigate the early fibrocartilage callus. Closed tibial fractures were performed on Sost(-/-) mice and age-matched wild type (C57Bl/6J) controls and assessed at multiple early time points (7, 10 and 14days), as well as at 28days post-fracture after bony union. External fixation was utilized, avoiding internal pinning and minimizing differences in stability stiffness, a variable that has confounded previous research in this area. Normal endochondral ossification progressed in wild type and Sost(-/-) mice with equivalent volumes of fibrocartilage formed at early day 7 and day 10 time points, and bony union in both genotypes by day 28. There were no significant differences in rate of bony union; however there were significant increases in fibrocartilage removal from the Sost(-/-) fracture calluses at day 14 suggesting earlier progression of endochondral healing. Earlier bone formation was seen in Sost(-/-) calluses over wild type with greater bone volume at day 10 (221%, p<0.01). The resultant Sost(-/-) united bony calluses at day 28 had increased bone volume fraction compared to wild type calluses (24%, p<0.05), and the strength of the fractured Sost(-/-) tibiae was greater than that that of wild type fractured tibiae. In summary, bony union was not altered by Sclerostin deficiency in externally-fixed closed tibial fractures, but fibrocartilage removal was enhanced and the resultant united bony calluses had increased bone fraction and increased strength. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation.

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Mak, Kingston Kinglun; Chen, Miao-Hsueh; Day, Timothy F; Chuang, Pao-Tien; Yang, Yingzi

2006-09-01

Both the Wnt/beta-catenin and Ihh signaling pathways play essential roles in crucial aspects of endochondral ossification: osteoblast differentiation, chondrocyte proliferation and hypertrophy. To understand the genetic interaction between these two signaling pathways, we have inactivated the beta-catenin gene and upregulated Ihh signaling simultaneously in the same cells during endochondral skeletal development using beta-catenin and patched 1 floxed alleles. We uncovered previously unexpected roles of Ihh signaling in synovial joint formation and the essential function of Wnt/beta-catenin signaling in regulating chondrocyte survival. More importantly, we found that Wnt and Ihh signaling interact with each other in distinct ways to control osteoblast differentiation, chondrocyte proliferation, hypertrophy, survival and synovial joint formation in the developing endochondral bone. Beta-catenin is required downstream of Ihh signaling and osterix expression for osteoblast differentiation. But in chondrocyte survival, beta-catenin is required upstream of Ihh signaling to inhibit chondrocyte apoptosis. In addition, Ihh signaling can inhibit chondrocyte hypertrophy and synovial joint formation independently of beta-catenin. However, there is a strong synergistic interaction between Wnt/beta-catenin and Ihh signaling in regulating synovial joint formation.

The transcription factor Lc-Maf participates in Col27a1 regulation during chondrocyte maturation

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Mayo, Jaime L.; Holden, Devin N. [Department of Microbiology and Molecular Biology, Brigham Young University, 591 WIDB, Provo, UT 84602 (United States); Barrow, Jeffery R. [Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602 (United States); Bridgewater, Laura C., E-mail: laura_bridgewater@byu.edu [Department of Microbiology and Molecular Biology, Brigham Young University, 591 WIDB, Provo, UT 84602 (United States)

2009-08-01

The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with an Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.

Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor.

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Panda, Dibyendu Kumar; Goltzman, David; Karaplis, Andrew C

2012-12-15

The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and β-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition.

Wnt7b can replace Ihh to induce hypertrophic cartilage vascularization but not osteoblast differentiation during endochondral bone development.

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Joeng, Kyu Sang; Long, Fanxin

2014-01-01

Indian hedgehog (Ihh) is an essential signal that regulates endochondral bone development. We have previously shown that Wnt7b promotes osteoblast differentiation during mouse embryogenesis, and that its expression in the perichondrium is dependent on Ihh signaling. To test the hypothesis that Wnt7b may mediate some aspects of Ihh function during endochondral bone development, we activated Wnt7b expression from the R26-Wnt7b allele with Col2-Cre in the Ihh(-/-) mouse. Artificial expression of Wnt7b rescued vascularization of the hypertrophic cartilage in the Ihh(-/-) mouse, but failed to restore orthotopic osteoblast differentiation in the perichondrium. Similarly, Wnt7b did not recover Ihh-dependent perichondral bone formation in the Ihh(-/-); Gli3(-/-) embryo. Interestingly, Wnt7b induced bone formation at the diaphyseal region of long bones in the absence of Ihh, possibly due to increased vascularization in the area. Thus, Ihh-dependent expression of Wnt7b in the perichondrium may contribute to vascularization of the hypertrophic cartilage during endochondral bone development.

Intramembranous ossification of scleral ossicles in Chelydra serpentina.

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Franz-Odendaal, Tamara A

2006-01-01

Scleral ossicles are present in many reptiles, including turtles and birds. In both groups the sclerotic ring situated in the eye is composed of a number of imbricating scleral ossicles or plates. Despite this gross morphological similarity, Andrews (1996. An endochondral rather than a dermal origin for scleral ossicles in Cryptodiran turtles. J. Herpetol. 30, 257-260) reported that the scleral ossicles of turtles develop endochondrally unlike those in birds, which develop intramembranously after a complex epithelial-mesenchymal inductive event. This study re-explores one of the species examined by Andrews in order to determine the mode of ossification of scleral ossicles in turtles. A growth series of Chelydra serpentina embryos, including the stages examined by Andrews, were examined by staining separately for cartilage and bone. Results clearly contradict Andrews (1996) and show that the scleral ossicles of Chelydra serpentina develop similarly to those in birds. That is, they develop intramembranously without a cartilage precursor and are likely induced by transient scleral papillae. The sequence of scleral papillae development is broadly similar, but the papillae themselves are not as distinct as those seen in chicken embryos. This study has important consequences for understanding the homology of scleral ossicles among tetrapods.

Androgen-dependent and independent process of bone formation in the distal segment of Os penis in the rat.

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Murakami, R; Izumi, K; Yamaoka, I

1995-11-01

The distal segment of the os penis of the rat develops as a fibrocartilage which is replaced with non-lamellar bone by endochondral ossification after puberty. Development of the fibrocartilage and its calcification have been shown to be induced by androgens, but androgen-dependency of the endochondral ossification has not been studied in detail. In the present study, immature male rats of various ages were castrated and the ossification of the fibrocartilage of os penis was examined. In rats castrated at 6 weeks, when the fibrocartilage was scarcely calcified, ossification did not occur even at 24 weeks. When the castrated rats were treated with testosterone, ossification started before 12 weeks of age. In rats castrated at 8 weeks, when the fibrocartilage was heavily calcified, endochondral ossification was observed in some of the animals (5/7) at 24 weeks of age. The results of this study indicate that once the fibrocartilage is calcified, the endochondral ossification can take place without androgen, although the androgen can promote the process of ossification.

Abnormal bone formation induced by implantation of osteosarcoma-derived bone-inducing substance in the X-linked hypophosphatemic mouse

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Yoshikawa, H.; Masuhara, K.; Takaoka, K.; Ono, K.; Tanaka, H.; Seino, Y.

1985-01-01

The X-linked hypophosphatemic mouse (Hyp) has been proposed as a model for the human familial hypophosphatemia (the most common form of vitamin D-resistant rickets). An osteosarcoma-derived bone-inducing substance was subcutaneously implanted into the Hyp mouse. The implant was consistently replaced by cartilage tissue at 2 weeks after implantation. The cartilage matrix seemed to be normal, according to the histological examination, and 35sulphur ( 35 S) uptake was also normal. Up to 4 weeks after implantation the cartilage matrix was completely replaced by unmineralized bone matrix and hematopoietic bone marrow. Osteoid tissue arising from the implantation of bone inducing substance in the Hyp mouse showed no radiologic or histologic sign of calcification. These findings suggest that the abnormalities of endochondral ossification in the Hyp mouse might be characterized by the failure of mineralization in cartilage and bone matrix. Analysis of the effects of bone-inducing substance on the Hyp mouse may help to give greater insight into the mechanism and treatment of human familial hypophosphatemia

The chondrocytic journey in endochondral bone growth and skeletal dysplasia.

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Yeung Tsang, Kwok; Wa Tsang, Shun; Chan, Danny; Cheah, Kathryn S E

2014-03-01

The endochondral bones of the skeleton develop from a cartilage template and grow via a process involving a cascade of chondrocyte differentiation steps culminating in formation of a growth plate and the replacement of cartilage by bone. This process of endochondral ossification, driven by the generation of chondrocytes and their subsequent proliferation, differentiation, and production of extracellular matrix constitute a journey, deviation from which inevitably disrupts bone growth and development, and is the basis of human skeletal dysplasias with a wide range of phenotypic severity, from perinatal lethality to progressively deforming. This highly coordinated journey of chondrocyte specification and fate determination is controlled by a myriad of intrinsic and extrinsic factors. SOX9 is the master transcription factor that, in concert with varying partners along the way, directs the different phases of the journey from mesenchymal condensation, chondrogenesis, differentiation, proliferation, and maturation. Extracellular signals, including bone morphogenetic proteins, wingless-related MMTV integration site (WNT), fibroblast growth factor, Indian hedgehog, and parathyroid hormone-related peptide, are all indispensable for growth plate chondrocytes to align and organize into the appropriate columnar architecture and controls their maturation and transition to hypertrophy. Chondrocyte hypertrophy, marked by dramatic volume increase in phases, is controlled by transcription factors SOX9, Runt-related transcription factor, and FOXA2. Hypertrophic chondrocytes mediate the cartilage to bone transition and concomitantly face a live-or-die situation, a subject of much debate. We review recent insights into the coordination of the phases of the chondrocyte journey, and highlight the need for a systems level understanding of the regulatory networks that will facilitate the development of therapeutic approaches for skeletal dysplasia. Copyright © 2014 Wiley Periodicals

Heterotopic ossification revisited.

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Mavrogenis, Andreas F; Soucacos, Panayotis N; Papagelopoulos, Panayiotis J

2011-03-11

Heterotopic ossification is the abnormal formation of mature lamellar bone within extraskeletal soft tissues where bone does not exist. Heterotopic ossification has been classified into posttraumatic, nontraumatic or neurogenic, and myositis ossificans progressiva or fibrodysplasia ossificans progressive. The pathophysiology is unknown. Anatomically, heterotopic ossification occurs outside the joint capsule without disrupting it. The new bone can be contiguous with the skeleton but generally does not involve the periosteum. Three-phase technetium-99m (99mTc) methylene diphosphonate bone scan is the most sensitive imaging modality for early detection and assessing the maturity of heterotopic ossification. Nonsurgical treatment with indomethacin and radiation therapy is appropriate for prophylaxis or early treatment of heterotopic ossification. Although bisphosphonates are effective prophylaxis if initiated shortly after the trauma, mineralization of the bone matrix resumes after drug discontinuation. During the acute inflammatory stage, the patient should rest the involved joint in a functional position; once acute inflammatory signs subside, passive range of motion exercises and continued mobilization are indicated. Surgical indications for excision of heterotopic ossification include improvement of function, standing posture, sitting or ambulation, independent dressing, feeding and hygiene, and repeated pressure sores from underlying bone mass. The optimal timing of surgery has been suggested to be a delay of 12 to 18 months until radiographic evidence of heterotopic ossification maturation and maximal recovery after neurological injury. The ideal candidate for surgical treatment before 18 months should have no joint pain or swelling, a normal alkaline phosphatase level, and 3-phase bone scan indicating mature heterotopic ossification. Copyright 2011, SLACK Incorporated.

Role of c-Myb in chondrogenesis.

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Oralová, V; Matalová, E; Janečková, E; Drobná Krejčí, E; Knopfová, L; Šnajdr, P; Tucker, A S; Veselá, I; Šmarda, J; Buchtová, M

2015-07-01

The Myb locus encodes the c-Myb transcription factor involved in controlling a broad variety of cellular processes. Recently, it has been shown that c-Myb may play a specific role in hard tissue formation; however, all of these results were gathered from an analysis of intramembranous ossification. To investigate a possible role of c-Myb in endochondral ossification, we carried out our study on the long bones of mouse limbs during embryonic development. Firstly, the c-myb expression pattern was analyzed by in situ hybridization during endochondral ossification of long bones. c-myb positive areas were found in proliferating as well as hypertrophic zones of the growth plate. At early embryonic stages, localized expression was also observed in the perichondrium and interdigital areas. The c-Myb protein was found in proliferating chondrocytes and in the perichondrium of the forelimb bones (E14.5-E17.5). Furthermore, protein was detected in pre-hypertrophic as well as hypertrophic chondrocytes. Gain-of-function and loss-of-function approaches were used to test the effect of altered c-myb expression on chondrogenesis in micromass cultures established from forelimb buds of mouse embryos. A loss-of-function approach using c-myb specific siRNA decreased nodule formation, as well as downregulated the level of Sox9 expression, a major marker of chondrogenesis. Transient c-myb overexpression markedly increased the formation of cartilage nodules and the production of extracellular matrix as detected by intense staining with Alcian blue. Moreover, the expression of early chondrogenic genes such as Sox9, Col2a1 and activity of a Col2-LUC reporter were increased in the cells overexpressing c-myb while late chondrogenic markers such as Col10a1 and Mmp13 were not significantly changed or were downregulated. Taken together, the results of this study demonstrate that the c-Myb transcription factor is involved in the regulation and promotion of endochondral bone formation. Copyright �

Heterotopic ossifications in a mouse model of albright hereditary osteodystrophy.

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David L Huso

Full Text Available Albright hereditary osteodystrophy (AHO is characterized by short stature, brachydactyly, and often heterotopic ossifications that are typically subcutaneous. Subcutaneous ossifications (SCO cause considerable morbidity in AHO with no effective treatment. AHO is caused by heterozygous inactivating mutations in those GNAS exons encoding the α-subunit of the stimulatory G protein (Gα(s. When inherited maternally, these mutations are associated with obesity, cognitive impairment, and resistance to certain hormones that mediate their actions through G protein-coupled receptors, a condition termed pseudohypoparathyroidism type 1a (PHP1a. When inherited paternally, GNAS mutations cause only AHO but not hormonal resistance, termed pseudopseudohypoparathyroidism (PPHP. Mice with targeted disruption of exon 1 of Gnas (Gnas(E1-/+ replicate human PHP1a or PPHP phenotypically and hormonally. However, SCO have not yet been reported in Gnas(E1+/- mice, at least not those that had been analyzed by us up to 3 months of age. Here we now show that Gnas(E1-/+ animals develop SCO over time. The ossified lesions increase in number and size and are uniformly detected in adult mice by one year of age. They are located in both the dermis, often in perifollicular areas, and the subcutis. These lesions are particularly prominent in skin prone to injury or pressure. The SCO comprise mature bone with evidence of mineral deposition and bone marrow elements. Superficial localization was confirmed by radiographic and computerized tomographic imaging. In situ hybridization of SCO lesions were positive for both osteonectin and osteopontin. Notably, the ossifications were much more extensive in males than females. Because Gnas(E1-/+ mice develop SCO features that are similar to those observed in AHO patients, these animals provide a model system suitable for investigating pathogenic mechanisms involved in SCO formation and for developing novel therapeutics for heterotopic bone

Altering the architecture of tissue engineered hypertrophic cartilaginous grafts facilitates vascularisation and accelerates mineralisation.

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Eamon J Sheehy

Full Text Available Cartilaginous tissues engineered using mesenchymal stem cells (MSCs can be leveraged to generate bone in vivo by executing an endochondral program, leading to increased interest in the use of such hypertrophic grafts for the regeneration of osseous defects. During normal skeletogenesis, canals within the developing hypertrophic cartilage play a key role in facilitating endochondral ossification. Inspired by this developmental feature, the objective of this study was to promote endochondral ossification of an engineered cartilaginous construct through modification of scaffold architecture. Our hypothesis was that the introduction of channels into MSC-seeded hydrogels would firstly facilitate the in vitro development of scaled-up hypertrophic cartilaginous tissues, and secondly would accelerate vascularisation and mineralisation of the graft in vivo. MSCs were encapsulated into hydrogels containing either an array of micro-channels, or into non-channelled 'solid' controls, and maintained in culture conditions known to promote a hypertrophic cartilaginous phenotype. Solid constructs accumulated significantly more sGAG and collagen in vitro, while channelled constructs accumulated significantly more calcium. In vivo, the channels acted as conduits for vascularisation and accelerated mineralisation of the engineered graft. Cartilaginous tissue within the channels underwent endochondral ossification, producing lamellar bone surrounding a hematopoietic marrow component. This study highlights the potential of utilising engineering methodologies, inspired by developmental skeletal processes, in order to enhance endochondral bone regeneration strategies.

Altering the architecture of tissue engineered hypertrophic cartilaginous grafts facilitates vascularisation and accelerates mineralisation.

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Sheehy, Eamon J; Vinardell, Tatiana; Toner, Mary E; Buckley, Conor T; Kelly, Daniel J

2014-01-01

Cartilaginous tissues engineered using mesenchymal stem cells (MSCs) can be leveraged to generate bone in vivo by executing an endochondral program, leading to increased interest in the use of such hypertrophic grafts for the regeneration of osseous defects. During normal skeletogenesis, canals within the developing hypertrophic cartilage play a key role in facilitating endochondral ossification. Inspired by this developmental feature, the objective of this study was to promote endochondral ossification of an engineered cartilaginous construct through modification of scaffold architecture. Our hypothesis was that the introduction of channels into MSC-seeded hydrogels would firstly facilitate the in vitro development of scaled-up hypertrophic cartilaginous tissues, and secondly would accelerate vascularisation and mineralisation of the graft in vivo. MSCs were encapsulated into hydrogels containing either an array of micro-channels, or into non-channelled 'solid' controls, and maintained in culture conditions known to promote a hypertrophic cartilaginous phenotype. Solid constructs accumulated significantly more sGAG and collagen in vitro, while channelled constructs accumulated significantly more calcium. In vivo, the channels acted as conduits for vascularisation and accelerated mineralisation of the engineered graft. Cartilaginous tissue within the channels underwent endochondral ossification, producing lamellar bone surrounding a hematopoietic marrow component. This study highlights the potential of utilising engineering methodologies, inspired by developmental skeletal processes, in order to enhance endochondral bone regeneration strategies.

Discoidin domain receptor 2 (DDR2) regulates proliferation of endochondral cells in mice

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Kawai, Ikuma; Hisaki, Tomoka; Sugiura, Koji; Naito, Kunihiko; Kano, Kiyoshi

2012-01-01

Highlights: ► Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase. ► DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. ► We produced in vitro and in vivo model to better understand the role of DDR2. ► DDR2 might play an inhibitory role in the proliferation of chondrocyte. -- Abstract: Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens. DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. The decrement of endogenous DDR2 represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells, but the functions of DDR2 in chondrogenic cellular proliferation remain unclear. To better understand the role of DDR2 signaling in cellular proliferation in endochondral ossification, we inhibited Ddr2 expression via the inhibitory effect of miRNA on Ddr2 mRNA (miDdr2) and analyzed the cellular proliferation and differentiation in the prechondrocyte ATDC5 cell lines. To investigate DDR2’s molecular role in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of truncated, kinase dead (KD) DDR2 protein is induced, and evaluated the DDR2 function in cellular proliferation in chondrocytes. Although the miDdr2-transfected ATDC5 cell lines retained normal differentiation ability, DDR2 reduction finally promoted cellular proliferation in proportion to the decreasing ratio of Ddr2 expression, and it also promoted earlier differentiation to cartilage cells by insulin induction. The layer of hypertrophic chondrocytes in KD Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates. Taken together, our data demonstrated that DDR2 might play a local and essential role in the

Discoidin domain receptor 2 (DDR2) regulates proliferation of endochondral cells in mice

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Kawai, Ikuma; Hisaki, Tomoka; Sugiura, Koji; Naito, Kunihiko [Laboratory of Applied Genetics, Graduate School of Agricultural and Life Science, University of Tokyo, Tokyo 113-8657 (Japan); Kano, Kiyoshi, E-mail: kanokiyo@yamaguchi-u.ac.jp [Laboratory of Developmental Biology, Joint Faculty of Veterinary Medicine, Yamaguchi University, Yamaguchi 753-8515, Japan. (Japan); Biomedical Science Center for Translational Research (BSCTR), The United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi 753-8515 (Japan)

2012-10-26

Highlights: Black-Right-Pointing-Pointer Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase. Black-Right-Pointing-Pointer DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. Black-Right-Pointing-Pointer We produced in vitro and in vivo model to better understand the role of DDR2. Black-Right-Pointing-Pointer DDR2 might play an inhibitory role in the proliferation of chondrocyte. -- Abstract: Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens. DDR2 regulates cell proliferation, cell adhesion, migration, and extracellular matrix remodeling. The decrement of endogenous DDR2 represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells, but the functions of DDR2 in chondrogenic cellular proliferation remain unclear. To better understand the role of DDR2 signaling in cellular proliferation in endochondral ossification, we inhibited Ddr2 expression via the inhibitory effect of miRNA on Ddr2 mRNA (miDdr2) and analyzed the cellular proliferation and differentiation in the prechondrocyte ATDC5 cell lines. To investigate DDR2's molecular role in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of truncated, kinase dead (KD) DDR2 protein is induced, and evaluated the DDR2 function in cellular proliferation in chondrocytes. Although the miDdr2-transfected ATDC5 cell lines retained normal differentiation ability, DDR2 reduction finally promoted cellular proliferation in proportion to the decreasing ratio of Ddr2 expression, and it also promoted earlier differentiation to cartilage cells by insulin induction. The layer of hypertrophic chondrocytes in KD Ddr2 transgenic mice was not significantly thicker than that of normal littermates, but the layer of proliferative chondrocytes in KD-Ddr2 transgenic mice was significantly thicker than that of normal littermates

Spongiosa Primary Development: A Biochemical Hypothesis by Turing Patterns Formations

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Oscar Rodrigo López-Vaca

2012-01-01

Full Text Available We propose a biochemical model describing the formation of primary spongiosa architecture through a bioregulatory model by metalloproteinase 13 (MMP13 and vascular endothelial growth factor (VEGF. It is assumed that MMP13 regulates cartilage degradation and the VEGF allows vascularization and advances in the ossification front through the presence of osteoblasts. The coupling of this set of molecules is represented by reaction-diffusion equations with parameters in the Turing space, creating a stable spatiotemporal pattern that leads to the formation of the trabeculae present in the spongy tissue. Experimental evidence has shown that the MMP13 regulates VEGF formation, and it is assumed that VEGF negatively regulates MMP13 formation. Thus, the patterns obtained by ossification may represent the primary spongiosa formation during endochondral ossification. Moreover, for the numerical solution, we used the finite element method with the Newton-Raphson method to approximate partial differential nonlinear equations. Ossification patterns obtained may represent the primary spongiosa formation during endochondral ossification.

Dwarfism and early death in mice lacking C-type natriuretic peptide

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Chusho, Hideki; Tamura, Naohisa; Ogawa, Yoshihiro; Yasoda, Akihiro; Suda, Michio; Miyazawa, Takashi; Nakamura, Kenji; Nakao, Kazuki; Kurihara, Tatsuya; Komatsu, Yasato; Itoh, Hiroshi; Tanaka, Kiyoshi; Saito, Yoshihiko; Katsuki, Motoya; Nakao, Kazuwa

2001-01-01

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo, we generated mice with targeted disruption of CNP (Nppc−/− mice). The Nppc−/− mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc−/− mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia. PMID:11259675

In-vivo generation of bone via endochondral ossification by in-vitro chondrogenic priming of adult human and rat mesenchymal stem cells

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Farrell, Eric

2011-01-31

Abstract Background Bone grafts are required to repair large bone defects after tumour resection or large trauma. The availability of patients\\' own bone tissue that can be used for these procedures is limited. Thus far bone tissue engineering has not lead to an implant which could be used as alternative in bone replacement surgery. This is mainly due to problems of vascularisation of the implanted tissues leading to core necrosis and implant failure. Recently it was discovered that embryonic stem cells can form bone via the endochondral pathway, thereby turning in-vitro created cartilage into bone in-vivo. In this study we investigated the potential of human adult mesenchymal stem cells to form bone via the endochondral pathway. Methods MSCs were cultured for 28 days in chondrogenic, osteogenic or control medium prior to implantation. To further optimise this process we induced mineralisation in the chondrogenic constructs before implantation by changing to osteogenic medium during the last 7 days of culture. Results After 8 weeks of subcutaneous implantation in mice, bone and bone marrow formation was observed in 8 of 9 constructs cultured in chondrogenic medium. No bone was observed in any samples cultured in osteogenic medium. Switch to osteogenic medium for 7 days prevented formation of bone in-vivo. Addition of β-glycerophosphate to chondrogenic medium during the last 7 days in culture induced mineralisation of the matrix and still enabled formation of bone and marrow in both human and rat MSC cultures. To determine whether bone was formed by the host or by the implanted tissue we used an immunocompetent transgenic rat model. Thereby we found that osteoblasts in the bone were almost entirely of host origin but the osteocytes are of both host and donor origin. Conclusions The preliminary data presented in this manuscript demonstrates that chondrogenic priming of MSCs leads to bone formation in vivo using both human and rat cells. Furthermore, addition of �

Costochondral ossification pattern. Analysis by 3-dimensional CT image

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Ma, Hailong; Nakatani, Kimiko

2005-01-01

We reviewed about an ossification pattern of costal cartilage with using three dimensional images made from computed tomography. We analyzed ossification of 16 costal cartilages in each case. We classified ossification pattern into eight groups by its configuration in one hundred cases. The sexual specificity of ossification pattern was revealed, and we can determinate sex in 82%. It was also revealed that ossification grows with increasing age. Finally, the knowledge of costochondral ossification pattern must help in case of reading chest radiographs. (author)

Hypoxia inhibits hypertrophic differentiation and endochondral ossification in explanted tibiae.

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Jeroen C H Leijten

Full Text Available Hypertrophic differentiation of growth plate chondrocytes induces angiogenesis which alleviates hypoxia normally present in cartilage. In the current study, we aim to determine whether alleviation of hypoxia is merely a downstream effect of hypertrophic differentiation as previously described or whether alleviation of hypoxia and consequent changes in oxygen tension mediated signaling events also plays an active role in regulating the hypertrophic differentiation process itself.Fetal mouse tibiae (E17.5 explants were cultured up to 21 days under normoxic or hypoxic conditions (21% and 2.5% oxygen respectively. Tibiae were analyzed on growth kinetics, histology, gene expression and protein secretion.The oxygen level had a strong influence on the development of explanted fetal tibiae. Compared to hypoxia, normoxia increased the length of the tibiae, length of the hypertrophic zone, calcification of the cartilage and mRNA levels of hypertrophic differentiation-related genes e.g. MMP9, MMP13, RUNX2, COL10A1 and ALPL. Compared to normoxia, hypoxia increased the size of the cartilaginous epiphysis, length of the resting zone, calcification of the bone and mRNA levels of hyaline cartilage-related genes e.g. ACAN, COL2A1 and SOX9. Additionally, hypoxia enhanced the mRNA and protein expression of the secreted articular cartilage markers GREM1, FRZB and DKK1, which are able to inhibit hypertrophic differentiation.Collectively our data suggests that oxygen levels play an active role in the regulation of hypertrophic differentiation of hyaline chondrocytes. Normoxia stimulates hypertrophic differentiation evidenced by the expression of hypertrophic differentiation related genes. In contrast, hypoxia suppresses hypertrophic differentiation of chondrocytes, which might be at least partially explained by the induction of GREM1, FRZB and DKK1 expression.

Normal proliferation and differentiation of Hoxc-8 transgenic chondrocytes in vitro

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Mello Maria

2003-04-01

Full Text Available Abstract Background Hox genes encode transcription factors that are involved in pattern formation in the skeleton, and recent evidence suggests that they also play a role in the regulation of endochondral ossification. To analyze the role of Hoxc-8 in this process in more detail, we applied in vitro culture systems, using high density cultures of primary chondrocytes from neonatal mouse ribs. Results Cultured cells were characterized on the basis of morphology (light microscopy and production of cartilage-specific extracellular matrix (sulfated proteoglycans and type II Collagen. Hypertrophy was demonstrated by increase in cell size, alkaline phosphatase activity and type X Collagen immunohistochemistry. Proliferation was assessed by BrdU uptake and flow cytometry. Unexpectedly, chondrocytes from Hoxc-8 transgenic mice, which exhibit delayed cartilage maturation in vivo 1, were able to proliferate and differentiate normally in our culture systems. This was the case even though freshly isolated Hoxc-8 transgenic chondrocytes exhibited significant molecular differences as measured by real-time quantitative PCR. Conclusions The results demonstrate that primary rib chondrocytes behave similar to published reports for chondrocytes from other sources, validating in vitro approaches for studies of Hox genes in the regulation of endochondral ossification. Our analysis of cartilage-producing cells from Hoxc-8 transgenic mice provides evidence that the cellular phenotype induced by Hoxc-8 overexpression in vivo is reversible in vitro.

Histomorphometric Parameters of the Growth Plate and Trabecular Bone in Wild-Type and Trefoil Factor Family 3 (Tff3)-Deficient Mice Analyzed by Free and Open-Source Image Processing Software.

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Bijelić, Nikola; Belovari, Tatjana; Stolnik, Dunja; Lovrić, Ivana; Baus Lončar, Mirela

2017-08-01

Trefoil factor family 3 (Tff3) peptide is present during intrauterine endochondral ossification in mice, and its deficiency affects cancellous bone quality in secondary ossification centers of mouse tibiae. The aim of this study was to quantitatively analyze parameters describing the growth plate and primary ossification centers in tibiae of 1-month-old wild-type and Tff3 knock-out mice (n=5 per genotype) by using free and open-source software. Digital photographs of the growth plates and trabecular bone were processed by open-source computer programs GIMP and FIJI. Histomorphometric parameters were calculated using measurements made with FIJI. Tff3 knock-out mice had significantly smaller trabecular number and significantly larger trabecular separation. Trabecular bone volume, trabecular bone surface, and trabecular thickness showed no significant difference between the two groups. Although such histomorphological differences were found in the cancellous bone structure, no significant differences were found in the epiphyseal plate histomorphology. Tff3 peptide probably has an effect on the formation and quality of the cancellous bone in the primary ossification centers, but not through disrupting the epiphyseal plate morphology. This work emphasizes the benefits of using free and open-source programs for morphological studies in life sciences.

bridging glenohumeral heterotopic ossification at the kenyatta ...

African Journals Online (AJOL)

dislocations (4,11) and at the knee after total knee arthroplasty (1). At the shoulder, heterotopic ossification is considered rare (6,7,13-15). Nevertheless heterotopic ossification at the shoulder has been reported after encephalitis (16), bilateral.

Primary palpebral and orbital ossification in pseudo-pseudohypoparathyroidism

DEFF Research Database (Denmark)

Klauber, S.; Heegaard, S.; Prause, J.U.

2002-01-01

ophthalmology, Albright's heriditary osteodystrophy, ossification, pseudo-pseudohypoparathyroidism, pseodohypoparathyroidism, hypothyroidism, GNAS1 gene, history, eyelid, orbit......ophthalmology, Albright's heriditary osteodystrophy, ossification, pseudo-pseudohypoparathyroidism, pseodohypoparathyroidism, hypothyroidism, GNAS1 gene, history, eyelid, orbit...

Indian hedgehog signaling promotes chondrocyte differentiation in enchondral ossification in human cervical ossification of the posterior longitudinal ligament.

Science.gov (United States)

Sugita, Daisuke; Yayama, Takafumi; Uchida, Kenzo; Kokubo, Yasuo; Nakajima, Hideaki; Yamagishi, Atsushi; Takeura, Naoto; Baba, Hisatoshi

2013-10-15

Histological, immunohistochemical, and immunoblot analyses of the expression of Indian hedgehog (Ihh) signaling in human cervical ossification of the posterior longitudinal ligament (OPLL). To examine the hypothesis that Ihh signaling in correlation with Sox9 and parathyroid-related peptide hormone (PTHrP) facilitates chondrocyte differentiation in enchondral ossification process in human cervical OPLL. In enchondral ossification, certain transcriptional factors regulate cell differentiation. OPLL is characterized by overexpression of these factors and disturbance of the normal cell differentiation process. Ihh signaling is essential for enchondral ossification, especially in chondrocyte hypertrophy. Samples of ossified ligaments were harvested from 45 patients who underwent anterior cervical decompressive surgery for symptomatic OPLL, and 6 control samples from patients with cervical spondylotic myelopathy/radiculopathy without OPLL. The harvested sections were stained with hematoxylin-eosin and toluidine blue, examined by transmission electron microscopy, and immunohistochemically stained for Ihh, PTHrP, Sox9, type X, XI collagen, and alkaline phosphatase. Immunoblot analysis was performed in cultured cells derived from the posterior longitudinal ligaments in the vicinity of the ossified plaque and examined for the expression of these factors. The ossification front in OPLL contained chondrocytes at various differentiation stages, including proliferating chondrocytes in fibrocartilaginous area, hypertrophic chondrocytes around the calcification front, and apoptotic chondrocytes near the ossified area. Immunoreactivity for Ihh and Sox9 was evident in proliferating chondrocytes and was strongly positive for PTHrP in hypertrophic chondrocytes. Mesenchymal cells with blood vessel formation were positive for Ihh, PTHrP, and Sox9. Cultured cells from OPLL tissues expressed significantly higher levels of Ihh, PTHrP, and Sox9 than those in non-OPLL cells. Our results

Heterotopic mesenteric and abdominal wall ossification – Two case reports in one institution

OpenAIRE

Cátia Ferreira; Carina Gomes; Ana Melo; Nádia Tenreiro; Bruno Pinto; Herculano Moreira; Artur Ribeiro; Paulo Avelar

2017-01-01

Introduction: Heterotopic ossification occurs when bone develops in tissues which usually don’t undergo ossification. Heterotopic mesenteric ossification, also known as intra-abdominal myositis ossificans, is a rare and benign form of ossification, usually related with previous abdominal surgery or trauma. Presentation of cases: We report two cases of heterotopic ossification both after multiple abdominal surgeries, with intraoperative findings of mesenteric and abdominal wall ossification...

Idiopathic Pulmonary Calcification and Ossification in an Elderly ...

African Journals Online (AJOL)

Histology of tissue from autopsy showed intraparenchymal pulmonary calcification and ossification with marrow elements. Idiopathic pulmonary calcification and ossification is rare. At autopsy, she was also found to have had bilateral subarachnoid haemorrhage (SAH), a diagnosis missed during clinical evaluation.

Cochlear ossification in patients with profound hearing loss following bacterial meningitis

DEFF Research Database (Denmark)

Caye-Thomasen, Per; Dam, Mikkel Seidelin; Omland, Silje Haukali

2012-01-01

Cochlear ossification following bacterial meningitis is related to causative pathogen, but not age at disease or time point of evaluation. However, progression may occur over time, especially in case of primary signs of ossification.......Cochlear ossification following bacterial meningitis is related to causative pathogen, but not age at disease or time point of evaluation. However, progression may occur over time, especially in case of primary signs of ossification....

Study on the nuchal ligament ossification on lateral cephalometric radiograph

International Nuclear Information System (INIS)

An, Chang Hyeon

2009-01-01

The purpose of this study was to assess the prevalence and radiographic characteristics of the nuchal ligament ossification on lateral cephalometric radiographs in Koreans. I review and interpreted the lateral cephalometric radiographs from 4,558 patients (1,857 males and 2,701 females, age range from 2 to 79 years) who visited the Kyungpook National University Dental Hospital from January 1, 2008 to February 3, 2009. I grouped the shapes of nuchal ligament ossification as round, rod-like, and segmented shape. And localized the ossification as the involvement of anterior cervical vertebral body. The data were analyzed by using chi-squared test with two-tailed and at a 5% significance level. Among those who showed the nuchal ligament ossification, the mean age of the 143 males was 51.1 and that of the 97 females was 48.0 years. It was not observed completely below teens, and was observed 1% in twenties, 6.1% in thirties, 18.6% in forties, and 26.3% over fifties. It was significantly prevalent in older age group (P<0.01) and in males than females among the same age group (P<0.05). The shapes of nuchal ligament ossification were as follows in order of frequency : rod-like (49.2%), round (30.4%), and segmented (20.4%). The highest involvement of ossification was found at the level of C5 (67.9%), C4 (29.2%), C6 (22.9%), C3 (3.3%), C7 (2.9%), C2 (0.8%), and C1 (0.4%). The nuchal ligament ossifications on lateral cephalometric radiographs were showed as round, rodlike, or segmented shape. The nuchal ligament ossification is often observed after the age of 40 and is observed more frequently in males than females. The highest shape of nuchal ligament ossification was rod-like shape and the highest involvement of cervical spine was C5.

Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton.

Science.gov (United States)

Long, Fanxin; Chung, Ung-il; Ohba, Shinsuke; McMahon, Jill; Kronenberg, Henry M; McMahon, Andrew P

2004-03-01

Indian hedgehog (Ihh) is indispensable for development of the osteoblast lineage in the endochondral skeleton. In order to determine whether Ihh is directly required for osteoblast differentiation, we have genetically manipulated smoothened (Smo), which encodes a transmembrane protein that is essential for transducing all Hedgehog (Hh) signals. Removal of Smo from perichondrial cells by the Cre-LoxP approach prevents formation of a normal bone collar and also abolishes development of the primary spongiosa. Analysis of chimeric embryos composed of wild-type and Smo(n/n) cells indicates that Smo(n/n) cells fail to contribute to osteoblasts in either the bone collar or the primary spongiosa but generate ectopic chondrocytes. In order to assess whether Ihh is sufficient to induce bone formation in vivo, we have analyzed the bone collar in the long bones of embryos in which Ihh was artificially expressed in all chondrocytes by the UAS-GAL4 bigenic system. Although ectopic Ihh does not induce overt ossification along the entire cartilage anlage, it promotes progression of the bone collar toward the epiphysis, suggesting a synergistic effect between ectopic Ihh and endogenous factors such as the bone morphogenetic proteins (BMPs). In keeping with this model, Hh signaling is further found to be required in BMP-induced osteogenesis in cultures of a limb-bud cell line. Taken together, these results demonstrate that Ihh signaling is directly required for the osteoblast lineage in the developing long bones and that Ihh functions in conjunction with other factors such as BMPs to induce osteoblast differentiation. We suggest that Ihh acts in vivo on a potential progenitor cell to promote osteoblast and prevent chondrocyte differentiation.

Developmental ossification sequences of the appendicular and axial ...

African Journals Online (AJOL)

A pre-hatch developmental study on ossification sequences of axial and appendicular skeletal system in Kuttanad duck embryos was undertaken using 78 viable embryos. From day 3 to day 7 of incubation no ossification densities were seen both by alizarin red staining and computerized radiography. The first indication of ...

Prophylactic post-operative radiotherapy prevents heterotopic ossification following traumatic acetabular fracture

International Nuclear Information System (INIS)

Meyer, Joseph T.; Hixson, William C.; Jennelle, Richard L. S.; Alonso, Jorge E.; Raben, David; Spencer, Sharon S.; Kim, Robert Y.

1996-01-01

Purpose/Objective: To determine the effect of post-operative radiation on the incidence of heterotopic ossification following traumatic acetabular fracture. Materials and Methods: A retrospective analysis was performed of the medical records and radiographs of all patients who received prophylactic radiotherapy to prevent heterotopic ossification. These results were compared to a similar group of patients receiving no prophylactic radiotherapy following traumatic acetabular fracture. Between 1987 and 1994, sixty-six patients received prophylactic radiotherapy to prevent heterotopic ossification. Results: Thirty-six patients (55%) received radiotherapy following operative repair of a traumatic acetabular fracture (median follow-up: 210 days). Three dose schedules were utilized: (28(36)) (77.8%) received 700 cGy/1 fx, (2(36)) (5.5%) 800 cGy/1 fx, and (6(36)) (16.7%) 1000 cGy/5 fxs. These patients were retrospectively compared with thirty-four patients who received similar operative management of traumatic acetabular fractures without post-operative radiotherapy (median follow-up: 378 days). Of the patients with heterotopic ossification, 96% developed it within 180 days. Complications and delayed wound healing rates were not significantly different in patients treated with or without post-operative radiotherapy, 6.4% and 6.3% respectively (p=0.49). The incidence of heterotopic ossification at last follow-up in patients treated with and without post-operative radiotherapy was (5(36)) (13.9%) and (19(34)) (55.9%), respectively (p=0.000332). For all patients, type of surgical approach was associated with development of heterotopic ossification: posterior, (7(38)) (18.4%), ilio-inguinal (1(3)) (33.3%), tri-radiate (13(19)) (68.4%), p=.000511. In patients receiving post-operative radiotherapy, variables associated with heterotopic ossification included dose (p=.00962), injury-to-radiation interval (p=.0038), and surgery-to-radiation interval (p=.0238). Fifty percent ((3

The role of EXT and growth signalling pathways in osteochondroma and its progression towards secondary peripheral chondrosarcoma

NARCIS (Netherlands)

Hameetman, Liesbeth

2007-01-01

Osteochondroma is a cartilage capped benign bone tumour, arising at the external surface of bones preformed by endochondral ossification. A small percentage of osteochondromas can progress towards its malignant counterpart, secondary peripheral chondrosarcoma. About 15% of osteochondromas occur in

The role of osteonecrosis in canine coronoid dysplasia: Arthroscopic and histopathological findings

NARCIS (Netherlands)

Mariee, I.C.; Gröne, A.; Theyse, L.F.H.

2014-01-01

Coronoid dysplasia (CD) or medial coronoid disease is part of canine elbowdysplasia and eventually results in osteoarthrosis. Although CDwas originally attributed to disturbed endochondral ossification,more recent data point to the subchondral bone. The objective of this study was to assess

Ossification of the bilateral Achilles tendon: a rare entity

International Nuclear Information System (INIS)

Arora, Abhishek J; Arora, Richa

2015-01-01

Ossification of the Achilles tendon is a rare clinical entity comprising of one or more segments of variable sized ossified masses in the fibrocartilaginous substance of the tendon. The etiology of ossification of the Achilles tendon is multifactorial with recurrent trauma and surgery comprising major predisposing factors, with others being metabolic, systemic, and infectious diseases. The possibility of a genetic predisposition towards this entity has also been raised, but has not yet been proven. We present a rare case of ossification of the bilateral Achilles tendons without any history of trauma or surgery in a 48-year-old female patient

Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

Energy Technology Data Exchange (ETDEWEB)

Jans, L., E-mail: lennartjans@hotmail.com [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Jaremko, J., E-mail: jjaremko@gmail.com [Department of Radiology, University of Alberta Hospital, 8440-112 Street, Edmonton T6G 2B7, Alberta (Canada); Ditchfield, M., E-mail: Michael.ditchfield@southernhealth.org.au [Department of Radiology, Monash University Clayton Campus, Wellington Road, Clayton 3800, VIC (Australia); De Coninck, T., E-mail: Tinekedeconinck@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Huysse, W., E-mail: Wouter.huysse@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium); Moon, A., E-mail: Anna.moon@rch.org.au [Department of Radiology, Royal Children' s Hospital, Flemington Road, Parkville 3052, VIC (Australia); Verstraete, K., E-mail: Koenraad.verstraete@ugent.be [Department of Radiology and Medical Imaging, Ghent University Hospital, De Pintelaan 185, 9000 Gent (Belgium)

2012-11-15

Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9-14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9-14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

Ossification variants of the femoral condyles are not associated with osteochondritis dissecans

International Nuclear Information System (INIS)

Jans, L.; Jaremko, J.; Ditchfield, M.; De Coninck, T.; Huysse, W.; Moon, A.; Verstraete, K.

2012-01-01

Purpose: To determine if ossification variants of the femoral condyles involving the subchondral bone plate are associated with osteochondritis dissecans (OCD). Materials and methods: The prevalence of ossification variants of the unaffected femoral condyle in 116 patients (aged 9–14 years) with unicondylar OCD on MRI (magnetic resonance imaging) of the knee was compared to a control group of 579 patients (aged 9–14 years) without OCD. The evolution of the ossification variants in both groups was studied by reviewing follow-up MR imaging side by side with the baseline study. Results: The prevalence of ossification variants in the unaffected condyle in patients with OCD (12.9%) and in the control group of patients without OCD (12.6%) was similar (p = 0.88). Evolution of ossification variants to OCD was not seen on follow-up MRI examinations. All variants had decreased in size or were no longer visible. Conclusion: Ossification variants of the femoral condyle that involve the subchondral bone plate are not associated with OCD. Clinical relevance statement: Ossification variants are not associated with OCD, indicating that routine MRI follow-up in affected children is not mandatory.

Radiation therapy of hyperplastic heterotopic ossifications in osteogenesis imperfecta

International Nuclear Information System (INIS)

Micke, O.; Wagner, W.; Poetter, R.; Prott, F.J.; Karbowski, A.

1994-01-01

Purpose: Osteogenesis imperfecta is a rare hereditary disease of connective tissue with a genetic defect in collagen synthesis. In osteogenesis imperfecta hyperplastic heterotopic ossification can be induced by hyperplastic callus formation caused by trauma or operation. Heterotopic ossifications can be found in numerous benign diseases. The successful use of low dose radiotherapy in the treatment of heterotopic ossifications in well-known from the literature. Patients and Methods: We treated two children (a 13-year old girl and a ten-year old boy) with heterotopic ossifications of the lower extremities in osteogenesis imperfecta type IV (Lobstein) with a low dose irradiation (10x1 Gy, respectively 6x1 Gy) under megavoltage conditions. Results: After radiotherapy the children were painfree and the hyperplastic callus was considerably reduced. The previously immobilized patients could partly be mobilized. Thereby it could be contributed to the rehabilitation of the patients. New hyperplastic callus formation was not observed in the irradiated areas so far. Conclusion: Analogous to the successful radiation of heterotopic ossifications in other benign diseases radiation therapy seems to be a successful treatment of hyperplastic callus formation in osteogenesis imperfecta. Despite the late risks of radiotherapy radiation treatment of benign diseases in children might be indicated. (orig.) [de

Conserved relative timing of cranial ossification patterns in early mammalian evolution.

Science.gov (United States)

Sánchez-Villagra, Marcelo R; Goswami, Anjali; Weisbecker, Vera; Mock, Orin; Kuratani, Shigeru

2008-01-01

We analyzed a comprehensive data set of ossification sequences including seven marsupial, 13 placental and seven sauropsid species. Data are provided for the first time for two major mammalian clades, Chiroptera and Soricidae, and for two rodent species; the published sequences of three species were improved with additional sampling. The relative timing of the onset of ossification in 17 cranial elements was recorded, resulting in 136 event pairs, which were treated as characters for each species. Half of these characters are constant across all taxa, 30% are variable but phylogenetically uninformative, and 19% potentially deliver diagnostic features for clades of two or more taxa. Using the conservative estimate of heterochronic changes provided by the program Parsimov, only a few heterochronies were found to diagnose mammals, marsupials, or placentals. A later onset of ossification of the pterygoid with respect to six other cranial bones characterizes therian mammals. This result may relate to the relatively small size of this bone in this clade. One change in relative onset of ossification is hypothesized as a potential human autapomorphy in the context of the sampling made: the earlier onset of the ossification of the periotic with respect to the lacrimal and to three basicranial bones. Using the standard error of scaled ranks across all species as a measure of each element's lability in developmental timing, we found that ossification of early, middle, and late events are similarly labile, with basicranial traits the most labile in timing of onset of ossification. Despite marsupials and placental mammals diverging at least 130 Ma, few heterochronic shifts in cranial ossification diagnose these clades.

Case Report: Multiple cervical vertebral fusion with ossification of ...

African Journals Online (AJOL)

The CT image of the specimen confirmed the ossification of the anterior longitudinal ligament with mild calcification of intervertebral discs. With the above features and bony ankylosis of articular facets, it was concluded that this fusion might be due to ankylosing spondylitis. Keywords: cervical vertebra; ossification; ligaments ...

The STR/ort mouse model of spontaneous osteoarthritis - an update.

Science.gov (United States)

Staines, K A; Poulet, B; Wentworth, D N; Pitsillides, A A

2017-06-01

Osteoarthritis is a degenerative joint disease and a world-wide healthcare burden. Characterized by cartilage degradation, subchondral bone thickening and osteophyte formation, osteoarthritis inflicts much pain and suffering, for which there are currently no disease-modifying treatments available. Mouse models of osteoarthritis are proving critical in advancing our understanding of the underpinning molecular mechanisms. The STR/ort mouse is a well-recognized model which develops a natural form of osteoarthritis very similar to the human disease. In this Review we discuss the use of the STR/ort mouse in understanding this multifactorial disease with an emphasis on recent advances in its genetics and its bone, endochondral and immune phenotypes. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pathological Calcification and Ossification in Relation to Leriche and Policard's Theory.

Science.gov (United States)

Jones, W; Roberts, R E

1933-05-01

(1) Pathology of calcification and ossification.-The Leriche-Policard theories. Hyperaemia of bone causes decalcification. Reduced blood supply causes sclerosis. Diminution of vascularity of fibrous tissue causes calcification. Excess of calcium, adequate blood supply and fibroblasts give rise to bone anywhere. Subperiosteal ossification. "Myositis ossificans."(2) Radiological significance of density of bone shadows.-Decalcification of disuse, of infections, of neoplasms. Traumatic and infective scquestra. Evidence that a fragment of bone is avascular.(3) Hyperaemic decalcification of bone.-Delayed and non-union of fractures. Kummel's disease. Spontaneous hyperaemic dislocation of the atlas. Hyperaemic decalcification and nephrolithiasis.(4) Anaemic sclerosis of bone.-Syphilitic bone disease. Malignant bone disease. Fragility of sclerosed bone-Paget's, Kienboch's, Kohler's and Panner's, Albers-Schönberg's diseases.(5) Pathological calcification.-Calcification of supraspinatus tendon. Calcification of tumours-angioma, haematoma, and thrombosed vessels, lipoma, cysts, etc. Calcification of semilunar cartilages and intervertebral discs.(6) Pathological ossification.-Ossification of tendons. Ossification of semilunar cartilages.

MR imaging of ossification of the posterior longitudinal ligament in the cervical spine

Energy Technology Data Exchange (ETDEWEB)

Yanase, Mitsuhiro; Yone, Kazunori; Taketomi, Eiji; Kawaida, Hidefumi; Sakou, Takashi (Kagoshima Univ. (Japan). Faculty of Medicine)

1992-09-01

Magnetic resonance (MR) images from consecutive 100 patients with ossification of the posterior longitudinal ligament (OPLL) were retrospectively reviewed to determine MR manifestations of OPLL foci (ossificated foci) and the surrounding tissue. MR images from 50 patients with cervical spondylosis served as controls for comparison. Inside ossificated foci were isointense or hyperintense on T1-weighted images in 43% of the OPLL cases and on T2-weighted images in 38%. According to X-ray proven ossification form, both T1- and T2-weighted images showed isointensity or hyperintensity in approximately half of the cases of continuous and mixed types of ossificated foci. Two characteristic morphologies of cervical disc were seen more frequently in OPLL than cervical spondylosis, which has clinical implication for continuously proliferated fibrocartilage in the cervical disc. Hypertrophy of the posterior longitudinal ligament was seen in 7% of OPLL cases on MR images, reflecting the likelihood of precursor condition of ossification. (N.K.).

Report of a man with heterotopic ossification of the legs.

Science.gov (United States)

García-Arpa, Mónica; Flores-Terry, Miguel A; Franco-Muñoz, Monserrat; Villasanti-Rivas, Natalia; González-Ruiz, Lucía; Banegas-Illescas, M Eugenia

2018-05-21

Heterotopic ossification is an uncommon disorder that consists of deposition of ectopic bone outside the extraskeletal tissues. In the skin, it can be primary, in association with genetic syndromes, or be secondary to different disorders. The latter include subcutaneous ossification of the legs in chronic venousinsufficiency, an infrequent and unrecognized complication. We report the case of a patient with subcutaneous ossification of both legs secondary to venous insufficiency and review the literature. Copyright © 2018 Sociedad Española de Reumatologña y Colegio Mexicano de Reumatologña. Publicado por Elsevier España, S.L.U. All rights reserved.

Liposarcoma of the thigh with mixed calcification and ossification

Directory of Open Access Journals (Sweden)

Jeremy R. Child, MD

2016-09-01

Full Text Available Liposarcoma is one of the most common soft-tissue sarcomas. Calcification and ossification can occur in liposarcoma; however, the presence of both ossification and calcification is a very rare entity. We present a case of a partially calcified and ossified dedifferentiated liposarcoma of the thigh in a 76-year-old woman, which contained heterologous elements of chondrosarcoma and rhabdomyosarcoma.

Evolution and functional significance of derived sternal ossification patterns in ornithothoracine birds

Science.gov (United States)

O’connor, J. K.; Zheng, X.-T.; Sullivan, C.; Chuong, C.-M.; Wang, X.-L.; Li, A.; Wang, Y.; Zhang, X.-M.; Zhou, Z.-H.

2017-01-01

The midline pattern of sternal ossification characteristic of the Cretaceous enantiornithine birds is unique among the Ornithodira, the group containing birds, nonavian dinosaurs and pterosaurs. This has been suggested to indicate that Enantiornithes is not the sister group of Ornithuromorpha, the clade that includes living birds and their close relatives, which would imply rampant convergence in many nonsternal features between enantiornithines and ornithuromorphs. However, detailed comparisons reveal greater similarity between neornithine (i.e. crown group bird) and enantiornithine modes of sternal ossification than previously recognized. Furthermore, a new subadult enantiornithine specimen demonstrates that sternal ossification followed a more typically ornithodiran pattern in basal members of the clade. This new specimen, referable to the Pengornithidae, indicates that the unique ossification pattern observed in other juvenile enantiornithines is derived within Enantiornithes. A similar but clearly distinct pattern appears to have evolved in parallel in the ornithuromorph lineage. The atypical mode of sternal ossification in some derived enantiornithines should be regarded as an autapomorphic condition rather than an indication that enantiornithines are not close relatives of ornithuromorphs. Based on what is known about molecular mechanisms for morphogenesis and the possible selective advantages, the parallel shifts to midline ossification that took place in derived enantiornithines and living neognathous birds appear to have been related to the development of a large ventral keel, which is only present in ornithuromorphs and enantiornithines. Midline ossification can serve to medially reinforce the sternum at a relatively early ontogenetic stage, which would have been especially beneficial during the protracted development of the superprecocial Cretaceous enantiornithines. PMID:26079847

MR imaging of capitellar ossification: a study in children of different ages

International Nuclear Information System (INIS)

Fader, Lauren M.; Laor, Tal; Eismann, Emily A.; Cornwall, Roger; Little, Kevin J.

2014-01-01

The capitellar ossification center is used routinely to evaluate elbow alignment on radiography. However, whether capitellar ossification is central and concentric to support this practice is unknown. To define the pattern of capitellar ossification at different ages of childhood. This HIPAA-compliant study was IRB approved. MR imaging examinations from 81 children (ages 1-13 years, at least 3 boys and 3 girls in each age group) were included. We determined the center points of the ossified capitellum and the cartilaginous capitellum on the sagittal and coronal sequences that best showed differentiation between cartilage and bone. Percentage offset of the center of the ossified capitellum from the center of the cartilaginous capitellum was calculated in anterior-posterior, proximal-distal and medial-lateral dimensions, and compared across age groups and between genders. Linear regressions were used to ascertain the effect of age on percentage offset for all patients and for each gender. Capitellar ossification begins eccentrically with sagittal anterior proximal offset and coronal medial offset. With age, ossification proceeds posteriorly, distally and laterally. Percentage offset gradually diminishes with age. The ossified capitellum centralizes in the sagittal plane by 12-13 years. In the coronal plane, the capitellum ossifies medially beyond the proximal radioulnar joint and remains eccentric at 12-13 years. Centralization in boys lags in the anterior-posterior dimension. Capitellar ossification is an eccentric process, with lag in anterior-posterior centralization in boys. Medial offset persists at 12-13 years. Recognition of this eccentric ossification may allow for more accurate assessment of elbow alignment on radiographs, especially in younger children. (orig.)

MR imaging of capitellar ossification: a study in children of different ages

Energy Technology Data Exchange (ETDEWEB)

Fader, Lauren M. [University of Cincinnati College of Medicine, Cincinnati, OH (United States); Laor, Tal [Cincinnati Children' s Hospital Medical Center, Department of Radiology, Cincinnati, OH (United States); Eismann, Emily A.; Cornwall, Roger; Little, Kevin J. [Cincinnati Children' s Hospital Medical Center, Division of Orthopaedic Surgery, Cincinnati, OH (United States)

2014-08-15

The capitellar ossification center is used routinely to evaluate elbow alignment on radiography. However, whether capitellar ossification is central and concentric to support this practice is unknown. To define the pattern of capitellar ossification at different ages of childhood. This HIPAA-compliant study was IRB approved. MR imaging examinations from 81 children (ages 1-13 years, at least 3 boys and 3 girls in each age group) were included. We determined the center points of the ossified capitellum and the cartilaginous capitellum on the sagittal and coronal sequences that best showed differentiation between cartilage and bone. Percentage offset of the center of the ossified capitellum from the center of the cartilaginous capitellum was calculated in anterior-posterior, proximal-distal and medial-lateral dimensions, and compared across age groups and between genders. Linear regressions were used to ascertain the effect of age on percentage offset for all patients and for each gender. Capitellar ossification begins eccentrically with sagittal anterior proximal offset and coronal medial offset. With age, ossification proceeds posteriorly, distally and laterally. Percentage offset gradually diminishes with age. The ossified capitellum centralizes in the sagittal plane by 12-13 years. In the coronal plane, the capitellum ossifies medially beyond the proximal radioulnar joint and remains eccentric at 12-13 years. Centralization in boys lags in the anterior-posterior dimension. Capitellar ossification is an eccentric process, with lag in anterior-posterior centralization in boys. Medial offset persists at 12-13 years. Recognition of this eccentric ossification may allow for more accurate assessment of elbow alignment on radiographs, especially in younger children. (orig.)

Diffuse pulmonary ossification. A case report

International Nuclear Information System (INIS)

Torres D, Carlos A; Ojeda L, Paulina

1997-01-01

The diffuse pulmonary ossification (DPO) is a rare disease characterized by metaplastic formation of bony tissue in the lung parenchyma. Generally it is associated with other disorders as mitral stenosis and interstitial fibrosis. Sometimes the DPO is idiopathic. We report the case of a 49-year-old man who presented with cough and hemoptysis. The radiological findings suggested an interstitial lung disease. The fiber optic bronchoscopy was normal. The pulmonary function tests showed a mild airway obstruction. The bacteriological and serological studies for tuberculosis, mycosis, and collagen-vascular disease were negatives. An open lung biopsy was performed and the pathologic findings were interpreted as diffuse pulmonary ossification (DPO). Any other disease was found; so, in this case the DPO was classified as idiopathic

Single-dose radiation therapy for prevention of heterotopic ossification after total hip arthroplasty

International Nuclear Information System (INIS)

Healy, W.L.; Lo, T.C.; Covall, D.J.; Pfeifer, B.A.; Wasilewski, S.A.

1990-01-01

Single-dose radiation therapy was prospectively evaluated for its efficacy in prevention of heterotopic ossification in patients at high risk after total hip arthroplasty. Thirty-one patients (34 hips) were treated between 1981 and 1988. Risk factors for inclusion in the protocol included prior evidence of heterotopic ossification, ankylosing spondylitis, and diffuse idiopathic skeletal hyperostosis. Patients with hypertrophic osteoarthritis or traumatic arthritis with osteophytes were not included. Operations on 34 hips included 19 primary total and 11 revision total hip arthroplasties and 4 excisions of heterotopic ossification. All patients received radiotherapy to the hip after operation with a single dose of 700 centigray. Radiotherapy is recommended on the first postoperative day. After this single-dose radiation treatment, no patient had clinically significant heterotopic ossification. Recurrent disease developed in two hips (6%), as seen on radiography (grades 2 and 3). This series documents a 100% clinical success rate and a 94% radiographic success rate in preventing heterotopic ossification in patients at high risk after total hip arthroplasty. Single-dose radiotherapy is as effective as other radiation protocols in preventing heterotopic ossification after total hip arthroplasty. It is less expensive and easier to administer than multidose radiotherapy

The urokinase plasminogen activator receptor-associated protein/endo180 is coexpressed with its interaction partners urokinase plasminogen activator receptor and matrix metalloprotease-13 during osteogenesis

DEFF Research Database (Denmark)

Engelholm, L H; Nielsen, B S; Netzel-Arnett, Sarah

2001-01-01

), and collagen V on the cell surface. We have determined the sites of expression of this novel receptor during murine postimplantation development. uPARAP/Endo180 was expressed in all tissues undergoing primary ossification, including the developing bones of the viscerocranium and calvarium that ossify...... intramembranously, and developing long bones undergoing endochondral ossification. uPARAP/Endo180 mRNA was expressed by both immature osteoblasts and by mature osteocalcin-producing osteoblasts-osteocytes, and was coexpressed with MMP-13. Interestingly, osteoblasts also expressed uPAR. Besides bone-forming tissues...

Medial patellar ossification after patellar instability: a radiographic finding indicative of prior patella subluxation/dislocation

Energy Technology Data Exchange (ETDEWEB)

Jerabek, Seth A. [Harvard Combined Orthopaedic Surgery Residency Program, Boston, MA (United States); Asnis, Peter D.; Poon, Steven K.; Gill, Thomas J. [Massachusetts General Hospital, Department of Orthopaedic Surgery, Boston, MA (United States); Bredella, Miriam A.; Ouellette, Hugue A. [Massachusetts General Hospital, Department of Radiology, Boston, MA (United States)

2009-08-15

To describe the correlation between medial patellar ossification and prior patella subluxation and/or dislocation. A retrospective billing database search identified 544 patients who had been diagnosed with patellar instability over a 13-year period. One hundred twenty-eight patients met the inclusion criteria. After review by a staff orthopedic surgeon and two musculoskeletal radiologists, 28 patients were found to have medial patellar ossification. The size and location of medial patellar ossification was recorded. Of the 28 patients (20 males, eight females, age 13-66 years, mean 28 years) who were found to have medial patellar ossification, 22 had radiographs, 16 had magnetic resonance imaging, and ten had both. The medial patellar ossification ranged in size from 2 to 18 mm with an average of 6.8 mm. Twelve were located in the medial patellofemoral ligament (MPFL), 14 in the medial joint capsule, and two in both the MPFL and joint capsule. Twenty-seven of 28 patients had a single ossification, and one patient had two ossifications. The timing from injury to first imaging of the lesion ranged from 10 days to a chronic history ({>=}35 years) of patellar instability. Medial patellar ossification correlates with a history of prior patella subluxation and/or dislocation. The medial ossification can be seen within the MPFL or the medial joint capsule, suggesting remote injury to these structures. The presence of this lesion will prompt physicians to evaluate for patellar instability. (orig.)

Medial patellar ossification after patellar instability: a radiographic finding indicative of prior patella subluxation/dislocation

International Nuclear Information System (INIS)

Jerabek, Seth A.; Asnis, Peter D.; Poon, Steven K.; Gill, Thomas J.; Bredella, Miriam A.; Ouellette, Hugue A.

2009-01-01

To describe the correlation between medial patellar ossification and prior patella subluxation and/or dislocation. A retrospective billing database search identified 544 patients who had been diagnosed with patellar instability over a 13-year period. One hundred twenty-eight patients met the inclusion criteria. After review by a staff orthopedic surgeon and two musculoskeletal radiologists, 28 patients were found to have medial patellar ossification. The size and location of medial patellar ossification was recorded. Of the 28 patients (20 males, eight females, age 13-66 years, mean 28 years) who were found to have medial patellar ossification, 22 had radiographs, 16 had magnetic resonance imaging, and ten had both. The medial patellar ossification ranged in size from 2 to 18 mm with an average of 6.8 mm. Twelve were located in the medial patellofemoral ligament (MPFL), 14 in the medial joint capsule, and two in both the MPFL and joint capsule. Twenty-seven of 28 patients had a single ossification, and one patient had two ossifications. The timing from injury to first imaging of the lesion ranged from 10 days to a chronic history (≥35 years) of patellar instability. Medial patellar ossification correlates with a history of prior patella subluxation and/or dislocation. The medial ossification can be seen within the MPFL or the medial joint capsule, suggesting remote injury to these structures. The presence of this lesion will prompt physicians to evaluate for patellar instability. (orig.)

Variation in timing of ossification affects inferred heterochrony of cranial bones in Lissamphibia.

Science.gov (United States)

Sheil, Christopher A; Jorgensen, Michael; Tulenko, Frank; Harrington, Sean

2014-09-01

The evolutionary origin of Lissamphibia likely involved heterochrony, as demonstrated by the biphasic lifestyles of most extant orders, differences between Anura (with tadpole-to-froglet metamorphosis) and Urodela (which lack strongly defined metamorphosis), and the appearance of direct development among separate lineages of frogs. Patterns in the timing of appearance of skeletal elements (i.e., ossification sequence data) represent a possible source of information for understanding the origin of Lissamphibia, and with the advent of analytical methods to directly optimize these data onto known phylogenies, there has been a renewed interest in assessing the role of changes in these developmental events. However, little attention has been given to the potential impact of variation in ossification sequence data--this is particularly surprising given that different criteria for collecting these data have been employed. Herein, new and previously published ossification data are compiled and all pairs of data for same-species comparisons are selected. Analyses are run to assess the impact of using data that were collected by different methodologies: (1) wild- versus lab-raised animals; (2) different criteria for recognizing timing of ossification; and (3) randomly selecting ossification sequences for species from which multiple studies have been published, but for which the data were collected by different criteria. Parsimov-based genetic inference is utilized to map ossification sequence data onto an existing phylogeny to reconstruct ancestral sequences of ossification and infer instances of heterochrony. All analyses succeeded in optimizing sequence data on internal nodes and instances of heterochrony were identified. However, among all analyses little congruence was found in reconstructed ancestral sequences or among inferred instances of heterochrony. These results indicate a high degree of variation in timing of ossification, and suggest a cautionary note about use

Histological evolution of the regenerate during bone transport: an experimental study in sheep.

Science.gov (United States)

López-Pliego, Esperanza Macarena; Giráldez-Sánchez, Miguel Ángel; Mora-Macías, Juan; Reina-Romo, Esther; Domínguez, Jaime

2016-09-01

Bone transport (BT) for segmentary bone defects is a well-known technique as it enables correction with new bone formation, which is similar to the previous bone. Despite the high number of experimental studies of distraction osteogenesis in bone lengthening, the types of ossification and histological changes that occur in the regenerate of the bone transport process remain controversial. The aim of this study is to provide the complete evolution of tissues and the types of ossification in the regenerate during the different phases of bone formation after BT until the end of the remodelling period. A histological study was performed using ten adult sheep that were submitted to BT. The types of ossification as well as the evolution of different tissues in the regenerate were determined using histomorphometry and inmunohistochemical studies. The evolution of trabeculae thickness, osteoblast and osteoclast densities, relationship between collagen types and changes in vascularization were also studied. Ossification was primarily intramembranous, with some focus of endochondral ossification in isolated animals. The cell counts showed a progression of cellular activity from the periphery to the centre, presenting the same progression as the growth of bone trabeculae, whose trabeculae thickness was quadrupled at the end of remodelling. Inmunohistochemical studies confirmed the prevalence of type I collagen and the ratio of the Type I/Type II collagen ratio was found to be 2.48. The percentages of the vascularized areas were proximally higher than distally in all animals, but distal zone obtained higher rates than the central region. Bone transport regenerate exhibits a centripetal ossification model and a mixed pattern with predominance of intramembranous over endochondral ossification. The data obtained resemble partially to those found in models of bone lengthening applied to large animals. This study provides a detailed structural characterization of the newly formed

Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty?

NARCIS (Netherlands)

Brunnekreef, J.J.; Hoogervorst, P.; Ploegmakers, M.J.M.; Rijnen, W.H.C.; Schreurs, B.W.

2013-01-01

PURPOSE: Heterotopic ossification is a common complication after total hip arthroplasty. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to prevent heterotopic ossifications effectively, however gastrointestinal complaints are reported frequently. In this study, we investigated whether

A Unique Surgical Technique for Tracheostomy in Heterotopic Ossification: A Case Report.

Science.gov (United States)

Cheng, Esther; Thorpe, Eric

2016-11-01

To describe a technique for tracheostomy in heterotopic ossification that has not yet been described in the literature. We report a case of difficult tracheostomy while using conventional techniques in a 68-year-old patient who underwent mitral valve replacement requiring warfarin therapy three months prior. Imaging revealed heterotopic ossification overlying the trachea. A literature review was performed to identify similar cases or techniques. Extensive surgical planning was pursued after the initial attempted tracheostomy failed, and the airway was eventually accessed using a lighted intubation stylet for guidance and a drill. Heterotopic ossification has been described after orthopedic and abdominal surgeries. We identified one case report in the literature of tracheostomy performed in the setting of heterotopic ossification by an unspecified mechanism. There are few reported cases of tracheobronchial calcification in cardiac patients receiving warfarin therapy; however, these patients had characteristic imaging findings that were not consistent with those of our patient. We illustrate a safe and effective technique for tracheostomy in heterotopic ossification that has not been reported. Coordination with the anesthesia service was paramount for a successful operation. © The Author(s) 2016.

Variants of ossification in the stylohyoid chain; Ossifikationsvarianten der stylohyoidalen Kette

Energy Technology Data Exchange (ETDEWEB)

Krennmair, G. [Vienna Univ. (Austria). Klinik fuer Zahn-, Mund- und Kieferheilkunde; Privatklinik Sanatorium Wels (Austria); Lenglinger, F.; Lugmayr, H. [Allgemeines Krankenhaus Wels (Austria). Inst. Radiologie I

2001-03-01

Purpose: Evaluation of age-related differences in the incidence, length and topographic location of ossifications in the stylohyoid chain. Method: Panoramic radiographs of 380 patients (718 reviewed stylohyoid chains), subdivided into 4 age groups (up to 20 years, 21 to 40 years, 41 to 60 years, older than 60 years), were reviewed and examined for the incidence, length and topographic location of stylohyoidal ossification. Results: 221 (30.8%) of 718 reviewed stylohyoidal chains showed radiological variants (elongation of the stylohyoidal process and/or ossification of the stylohyoid ligament). With increasing age, there was an increase in the incidence and length of stylohyoidal ossifications (p<0.01). A significant linear correlation between the length of the stylohyoidal ossifications and age was only found in the young age group (up to 20 years; p<0.01). In the young age group (up to 20 years), there was also a preferred presence of isolated locations in the superior stylohyoidal segment. With increasing age, there was a pronounced presence of ossifications in the middle and inferior stylohyoid segments and combinations of ossified variabilities. Conclusion: Stylohyoidal ossifications show age-related differences in incidence, length and topography and can also be put down to different pathological events. Stylohyoidal ossifications gain a different importance in adult patients from that in young people. (orig.) [German] Ziel: Evaluierung des altersabhaengigen Unterschieds der Haeufigkeit, der Laenge und der Topographie von Ossifikationen innerhalb der stylohyoidalen Kette. Methoden: Panoramaschichtaufnahmen von 380 Patienten (718 beurteilbare Stylohoyoid-Komplexe), unterteilt in 4 Altersperioden (-20 Jahre, 21-40 Jahre, 41-60 Jahre, aelter als 60 Jahre), werden herangezogen und dabei auf die Inzidenz-, die Laengen- und die topographischen Lokalisationsunterschiede von stylohyoidalen Ossifikationen untersucht. Ergebnisse: 221 (30,8%) der 718 beurteilbaren

Ultrasonography in Early Diagnosis of Heterotopic Ossification

Directory of Open Access Journals (Sweden)

Shan-Hui Lin

2014-12-01

Full Text Available We report here the case of a 32-year-old man with a history of traumatic brain injury who presented with swelling of his right thigh. Soft tissue ultrasonography performed 3 days after the onset of symptoms showed a heterogeneous hyperechoic lesion with the formation of cysts and hypervascularity in the right iliopsoas abutting the surface of the femoral bone. This became a diffuse echogenic plaque with a posterior acoustic shadowing 12 days later. A diagnosis of heterotopic ossification was made on the basis of the presence of typical ultrasonographic findings and was confirmed by pathology. We emphasize that an early diagnosis of heterotopic ossification can be made with ultrasonography and can lead to early treatment.

Stage-I osteochondritis dissecans versus normal variants of ossification in the knee in children

International Nuclear Information System (INIS)

Gebarski, Kathleen; Hernandez, Ramiro J.

2005-01-01

Juvenile osteochondritis dissecans (OCD) has a better prognosis than the adult type. We postulated that the excellent prognosis of juvenile OCD could be explained, at least in part, by the erroneous diagnosis of some developmental variants of ossification as stage-I OCD. Knee MRIs of 38 children, ages 7.5-17.7 years (mean and median age 13 years), were retrospectively reviewed to look for features that might separate normal variants of ossification from stage-I OCD. These included age, gender, site, configuration of the lesion, residual cartilaginous model and presence of edema. Twenty-three patients (32 condyles) had ossification defects with intact articular cartilage suggestive of stage-I lesions. No stage-II lesions were seen in the posterior femoral condyles. Accessory ossification centers were seen in 11/16 posterior condyles and 3/16 central condyles. Spiculation of existing ossification was seen in 12/16 posterior condylar lesions and 1/16 central condyles. There was a predominance of accessory ossifications and spiculations in the patients with 10% or greater residual cartilaginous model. No edema signal greater than diaphyseal red-marrow signal was seen in the posterior condyles. Clinical follow-up ranged from 0.5 to 38 months, with clinical improvement in 22 out of 23 patients. Inclusion of normal variants in the stage-I OCD category might explain, in part, the marked difference in published outcome between the juvenile and adult forms of OCD. Ossification defects in the posterior femoral condyles with intact overlying articular cartilage, accessory ossification centers, spiculation, residual cartilaginous model, and lack of bone-marrow edema are features of developmental variants rather than OCD. (orig.)

The normal development of proximal humeral epiphyseal ossification center in the first 2 years of life

International Nuclear Information System (INIS)

Kim, Seung Cheol

1998-01-01

The purpose of this study is to ascertain the normal maturation of proximal epiphyseal ossification centers by monthly age during the first years of life. The distribution of age was 0 to 24 months. Six hundred and seventy-five infants were male and 436 were female; their ages were measured in months, and there was no evidence of developmental problems. Proximal humeral epiphyseal ossification centers were evaluated from chest radiographs ; if not visualized, they were graded as 0, and otherwise, as follows : grade 1 : visualized with poor margin or a diameter of less than 1/4 of metaphyseal width; grade 2: visualized with good margin or a diameter of more than 1/4 of metaphyseal width; in grade 3 and 4, two ossification centers were visualized. Grade 3 indicated that one ossification center had the morphology of grade 2. Grade 5 indicated that two ossification centers were fused. We then assessed the relationship between the development of an ossification center and monthly age. A proximal humeral epiphyseal ossification center shows regular maturational features according to monthly age. 6 refs., 2 tabs., 5 figs

Heterotopic Ossification After the Arthroscopic Treatment of Lateral Epicondylitis.

Science.gov (United States)

Desai, Mihir J; Ramalingam, Hari; Ruch, David S

2017-05-01

Heterotopic ossification (HO) is a well-known complication following the surgical treatment of fractures and dislocations about the elbow but it is not commonly discussed as a complication following arthroscopy. We present a case of a young athlete who developed HO after the arthroscopic treatment of lateral epicondylitis. This is a case report chart review of a 24 year old male with lateral epicondylitis. After failing conservative measures, arthroscopic debridement of the extensor carpi radialis brevis (ECRB) origin ensued. The treatment and patient's final disposition were reported. The patient developed heterotopic ossification of the elbow follow arthroscopic debridement of the ECRB origin. Further surgery was required to excise the heterotopic ossification. Good recovery of motion was achieved. To our knowledge, we present the first case of HO development after elbow arthroscopy for lateral epicondylitis. As the use of elbow arthroscopy continues to grow, there is a need for identification of the risk factors and primary prophylaxis for HO.

Neurogenic heterotopic ossification: epidemiology and morphology on conventional radiographs in an early neurological rehabilitation population

International Nuclear Information System (INIS)

Seipel, R.; Langner, S.; Lippa, M.; Kuehn, J.P.; Hosten, N.; Platz, T.

2012-01-01

To retrospectively evaluate neurogenic heterotopic ossification in an early neurological rehabilitation population (phases B and C) with respect to epidemiology and morphology on conventional radiographs. Over a 4-year period, 1,463 patients treated at a clinic for early neurological rehabilitation were evaluated for clinical symptoms of neurogenic heterotopic ossification. In case of clinical suspicion, plain radiographs of the expected sites were obtained. If heterotopic ossification was detected, the initial and subsequent radiographs were retrospectively analyzed for sites, size, and morphology. Immature lesions were categorized as small (<10 mm) or large (10-100 mm). The prevalence rate of neurogenic heterotopic ossification was 2.05%. The condition was most common in young male adults. The hip was the most common site accounting for more than half of the cases. Two or more ossifications were seen in 56.7% of the affected patients with approximately two-thirds showing bilateral symmetric involvement of corresponding joint regions. The size of ossifications strongly varied interindividually. Small immature lesions demonstrated less progression in size than large lesions during maturation (P < 0.05). Standard radiographs, as a fast and inexpensive technique, allow the expected size progression of heterotopic ossifications during maturation to be estimated, which is relevant in terms of therapeutic decisions, patient mobilization, and neurological rehabilitation. (orig.)

Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype

Science.gov (United States)

Murakami, Shunichi; Balmes, Gener; McKinney, Sandra; Zhang, Zhaoping; Givol, David; de Crombrugghe, Benoit

2004-01-01

We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1. PMID:14871928

Radiological study of the pelvic limb in the growing Iberian pig [ossification

International Nuclear Information System (INIS)

Mayoral, A.I.; Regodon, S.; Franco, A.; Lignereux, Y.; Robina, A.

1997-01-01

The chronology of ossification of the pelvic limb of the growing Iberian pig is analyzed by the radiological method, from birth to 482 days(16 months). Forty eight individuals have been used, 24 males and 24 females born from eight gilts; all were castrated and distributed within 6 age groups : birth (1 day), weaning (58 days), preparation ( >, 234 days), beginning ( >, 352 days), half ( >, 424 days) and end ( >, 482 days) of fattening. The appearance and the evolution of the ossification centers are observed, as well as some phenomena occurring during the fusion of the ossification centers [fr

The effect of dexamethasone and triiodothyronine on terminal differentiation of primary bovine chondrocytes and chondrogenically differentiated mesenchymal stem cells.

Science.gov (United States)

Randau, Thomas M; Schildberg, Frank A; Alini, Mauro; Wimmer, Matthias D; Haddouti, El-Mustapha; Gravius, Sascha; Ito, Keita; Stoddart, Martin J

2013-01-01

The newly evolved field of regenerative medicine is offering solutions in the treatment of bone or cartilage loss and deficiency. Mesenchymal stem cells, as well as articular chondrocytes, are potential cells for the generation of bone or cartilage. The natural mechanism of bone formation is that of endochondral ossification, regulated, among other factors, through the hormones dexamethasone and triiodothyronine. We investigated the effects of these hormones on articular chondrocytes and chondrogenically differentiated mesenchymal stem cells, hypothesizing that these hormones would induce terminal differentiation, with chondrocytes and differentiated stem cells being similar in their response. Using a 3D-alginate cell culture model, bovine chondrocytes and chondrogenically differentiated stem cells were cultured in presence of triiodothyronine or dexamethasone, and cell proliferation and extracellular matrix production were investigated. Collagen mRNA expression was measured by real-time PCR. Col X mRNA and alkaline phosphatase were monitored as markers of terminal differentiation, a prerequisite of endochondral ossification. The alginate culture system worked well, both for the culture of chondrocytes and for the chondrogenic differentiation of mesenchymal stem cells. Dexamethasone led to an increase in glycosaminoglycan production. Triiodothyronine increased the total collagen production only in chondrocytes, where it also induced signs of terminal differentiation, increasing both collagen X mRNA and alkaline phosphatase activity. Dexamethasone induced terminal differentiation in the differentiated stem cells. The immature articular chondrocytes used in this study seem to be able to undergo terminal differentiation, pointing to their possible role in the onset of degenerative osteoarthritis, as well as their potential for a cell source in bone tissue engineering. When chondrocyte-like cells, after their differentiation, can indeed be moved on towards terminal

Characteristic calcaneal ossification: an additional early radiographic finding in infants with fibrodysplasia ossificans progressiva

Energy Technology Data Exchange (ETDEWEB)

Hasegawa, Sachi [Nagoya University Graduate School of Medicine, Department of Orthopaedic Surgery, Nagoya, Aichi (Japan); Victoria, Teresa [Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Kayserili, Huelya [Koc University School of Medicine (KUSOM), Medical Genetics Department, Istanbul (Turkey); Zackai, Elaine [Children' s Hospital of Philadelphia, Department of Medical Genetics, Philadelphia, PA (United States); Nishimura, Gen; Haga, Nobuhiko; Nakashima, Yasuharu; Miyazaki, Osamu [The Research Committee on Fibrodysplasia Ossificans Progressiva, Tokyo (Japan); Kitoh, Hiroshi [Nagoya University Graduate School of Medicine, Department of Orthopaedic Surgery, Nagoya, Aichi (Japan); The Research Committee on Fibrodysplasia Ossificans Progressiva, Tokyo (Japan)

2016-10-15

We have clinically encountered children with fibrodysplasia ossificans progressiva who had abnormal calcaneal ossification. To evaluate whether calcaneal ossification variants are significant radiographic findings in children with fibrodysplasia ossificans progressiva. Lateral feet radiographs in nine children who fulfilled the diagnostic criteria of fibrodysplasia ossificans progressiva were reviewed. The studies were obtained during infancy or early childhood. Fourteen lateral foot radiographs of fibrodysplasia ossificans progressiva were available for this study (ages at examination: 1-104 months). Four children ages 2 months to 11 months showed double calcaneal ossification centers; 7 children had plantar calcaneal spurs that decreased in size with age. Overall, eight of nine children with fibrodysplasia ossificans progressiva demonstrated double calcaneal ossifications and/or plantar calcaneal spurs in infancy or childhood. Double calcaneal ossification centers in early infancy and plantar calcaneal spurs in childhood are frequently seen in children with fibrodysplasia ossificans progressiva and may be a useful radiologic indicator for early diagnosis. (orig.)

Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia

Science.gov (United States)

Horiki, Mitsuru; Imamura, Takeshi; Okamoto, Mina; Hayashi, Makoto; Murai, Junko; Myoui, Akira; Ochi, Takahiro; Miyazono, Kohei; Yoshikawa, Hideki; Tsumaki, Noriyuki

2004-01-01

Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs). However, their in vivo functions are largely unknown. Here, we generated transgenic mice overexpressing Smad6 in chondrocytes. Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes. Endochondral ossification during development in these mice was associated with almost normal chondrocyte proliferation, significantly delayed chondrocyte hypertrophy, and thin trabecular bone. The reduced population of hypertrophic chondrocytes after birth seemed to be related to impaired bone growth and formation. Organ culture of cartilage rudiments showed that chondrocyte hypertrophy induced by BMP2 was inhibited in cartilage prepared from Smad6 transgenic mice. We then generated transgenic mice overexpressing Smurf1 in chondrocytes. Abnormalities were undetectable in Smurf1 transgenic mice. Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice. These results provided evidence that Smurf1 supports Smad6 function in vivo. PMID:15123739

Histone Deacetylase 3 Suppresses Erk Phosphorylation and Matrix Metalloproteinase (Mmp)-13 Activity in Chondrocytes

Science.gov (United States)

Carpio, Lomeli R.; Bradley, Elizabeth W.; Westendorf, Jennifer J.

2017-01-01

Histone deacetylase inhibitors are emerging therapies for many diseases including cancers and neurological disorders; however, these drugs are teratogens to the developing skeleton. Hdac3 is essential for proper endochondral ossification as its deletion in chondrocytes increases cytokine signaling and the expression of matrix remodeling enzymes. Here we explored the mechanism by which Hdac3 controls Mmp13 expression in chondrocytes. In Hdac3-depleted chondrocytes, Erk1/2 as well as its downstream substrate, Runx2, were hyperphosphorylated as a result of decreased expression and activity of the Erk1/2 specific phosphatase, Dusp6. Erk1/2 kinase inhibitors and Dusp6 adenoviruses reduced Mmp13 expression and partially rescued matrix production in Hdac3-deficient chondrocytes. Postnatal chondrocyte-specific deletion of Hdac3 with an inducible Col2a1-Cre caused premature production of pErk1/2 and Mmp13 in the growth plate. Thus, Hdac3 controls the temporal and spatial expression of tissue-remodeling genes in chondrocytes to ensure proper endochondral ossification during development. PMID:27662443

Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes

Science.gov (United States)

Hata, Kenji; Takashima, Rikako; Amano, Katsuhiko; Ono, Koichiro; Nakanishi, Masako; Yoshida, Michiko; Wakabayashi, Makoto; Matsuda, Akio; Maeda, Yoshinobu; Suzuki, Yutaka; Sugano, Sumio; Whitson, Robert H.; Nishimura, Riko; Yoneda, Toshiyuki

2013-11-01

Histone modification, a critical step for epigenetic regulation, is an important modulator of biological events. Sox9 is a transcription factor critical for endochondral ossification; however, proof of its epigenetic regulation remains elusive. Here we identify AT-rich interactive domain 5b (Arid5b) as a transcriptional co-regulator of Sox9. Arid5b physically associates with Sox9 and synergistically induces chondrogenesis. Growth of Arid5b-/- mice is retarded with delayed endochondral ossification. Sox9-dependent chondrogenesis is attenuated in Arid5b-deficient cells. Arid5b recruits Phf2, a histone lysine demethylase, to the promoter region of Sox9 target genes and stimulates H3K9me2 demethylation of these genes. In the promoters of chondrogenic marker genes, H3K9me2 levels are increased in Arid5b-/- chondrocytes. Finally, we show that Phf2 knockdown inhibits Sox9-induced chondrocyte differentiation. Our findings establish an epigenomic mechanism of skeletal development, whereby Arid5b promotes chondrogenesis by facilitating Phf2-mediated histone demethylation of Sox9-regulated chondrogenic gene promoters.

Heterotopic Ossification on the Right Atrial Wall of an 11 year old ...

African Journals Online (AJOL)

Heterotopic ossification (HO) is the formation of mature histologically indistinguishable lamella bone in soft tissues which normally exhibits no properties of ossification. HO does not grow out of bone, is not connected to periosteum and is not formed intra-articularly (Maheswarappa et al., 2004). We report here, the ...

Severe Heterotopic Ossification following Total Knee Replacement

Directory of Open Access Journals (Sweden)

Alexander L. Dodds

2014-01-01

Full Text Available Although the incidence of minor heterotopic ossification is probably higher than what is usually expected, severe heterotopic ossification (HO is an extremely rare event following total knee replacement surgery. We present the case of a 66-year-old woman who initially had achieved an excellent range of motion following bilateral uncemented rotating platform total knee replacement, before presenting with pain and loss of range of motion at 2 months after surgery. Severe HO was diagnosed on X-rays. Treatment consisted of nonoperative measures only, including physiotherapy with hydrotherapy and anti-inflammatories. She eventually regained her range of motion when seen at 8 months after operation. This case illustrates that nonoperative treatment without the use of radiotherapy or surgery can be used to safely resolve stiffness caused by HO after total knee replacement.

Poly-epiphyseal overgrowth: description of a previously unreported skeletal dysplasia

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Pazzaglia, Ugo E.; Bonaspetti, Giovanni [University of Brescia, Orthopaedic Clinic, Brescia (Italy); Beluffi, Giampiero [Fondazione IRCCS Policlinico San Matteo, Department of Paediatric Radiology, Pavia (Italy); Marchi, Antonietta; Bozzola, Mauro; Savasta, Salvatore [Fondazione IRCCS Policlinico San Matteo, Paediatric Clinic, University of Pavia, Pavia (Italy)

2007-10-15

A skeletal dysplasia with previously unreported features is presented. Its evolution was characterized by growth abnormalities of bones without involvement of other organs. Advanced bone age, increased stature and irregular epiphyseal ossification with stippling of the main long bones were documented. Physeal overgrowth was massive in the left proximal humerus and femur. Furthermore, the hip joint appeared fused with an abundant mass of pathological calcific tissue extending from the femur to the ilium. Pathological epiphyses were characterized by anarchic cartilaginous proliferation with multiple ossification centres, while lamellar bone apposition and remodelling were normal. The observed bone changes were different from those in any previously reported syndrome, metabolic defect or bone dysplasia. However, they clearly indicated a defect of endochondral ossification with some resemblance to phenotypes observed in dysplasia epiphysealis hemimelica. (orig.)

Poly-epiphyseal overgrowth: description of a previously unreported skeletal dysplasia

International Nuclear Information System (INIS)

Pazzaglia, Ugo E.; Bonaspetti, Giovanni; Beluffi, Giampiero; Marchi, Antonietta; Bozzola, Mauro; Savasta, Salvatore

2007-01-01

A skeletal dysplasia with previously unreported features is presented. Its evolution was characterized by growth abnormalities of bones without involvement of other organs. Advanced bone age, increased stature and irregular epiphyseal ossification with stippling of the main long bones were documented. Physeal overgrowth was massive in the left proximal humerus and femur. Furthermore, the hip joint appeared fused with an abundant mass of pathological calcific tissue extending from the femur to the ilium. Pathological epiphyses were characterized by anarchic cartilaginous proliferation with multiple ossification centres, while lamellar bone apposition and remodelling were normal. The observed bone changes were different from those in any previously reported syndrome, metabolic defect or bone dysplasia. However, they clearly indicated a defect of endochondral ossification with some resemblance to phenotypes observed in dysplasia epiphysealis hemimelica. (orig.)

Ossification score is a better indicator of maturity related changes in eating quality than animal age.

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Bonny, S P F; Pethick, D W; Legrand, I; Wierzbicki, J; Allen, P; Farmer, L J; Polkinghorne, R J; Hocquette, J-F; Gardner, G E

2016-04-01

Ossification score and animal age are both used as proxies for maturity-related collagen crosslinking and consequently decreases in beef tenderness. Ossification score is strongly influenced by the hormonal status of the animal and may therefore better reflect physiological maturity and consequently eating quality. As part of a broader cross-European study, local consumers scored 18 different muscle types cooked in three ways from 482 carcasses with ages ranging from 590 to 6135 days and ossification scores ranging from 110 to 590. The data were studied across three different maturity ranges; the complete range of maturities, a lesser range and a more mature range. The lesser maturity group consisted of carcasses having either an ossification score of 200 or less or an age of 987 days or less with the remainder in the greater maturity group. The three different maturity ranges were analysed separately with a linear mixed effects model. Across all the data, and for the greater maturity group, animal age had a greater magnitude of effect on eating quality than ossification score. This is likely due to a loss of sensitivity in mature carcasses where ossification approached and even reached the maximum value. In contrast, age had no relationship with eating quality for the lesser maturity group, leaving ossification score as the more appropriate measure. Therefore ossification score is more appropriate for most commercial beef carcasses, however it is inadequate for carcasses with greater maturity such as cull cows. Both measures may therefore be required in models to predict eating quality over populations with a wide range in maturity.

Runx2 is required for early stages of endochondral bone formation but delays final stages of bone repair in Axin2-deficient mice

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McGee-Lawrence, Meghan E.; Carpio, Lomeli R.; Bradley, Elizabeth W.; Dudakovic, Amel; Lian, Jane B.; van Wijnen, Andre J.; Kakar, Sanjeev; Hsu, Wei; Westendorf, Jennifer J.

2014-01-01

Runx2 and Axin2 regulate skeletal development. We recently determined that Axin2 and Runx2 molecularly interact in differentiating osteoblasts to regulate intramembranous bone formation, but the relationship between these factors in endochondral bone formation was unresolved. To address this, we examined the effects of Axin2 deficiency on the cleidocranial dysplasia (CCD) phenotype of Runx2+/− mice, focusing on skeletal defects attributed to improper endochondral bone formation. Axin2 deficiency unexpectedly exacerbated calvarial components of the CCD phenotype in the Runx2+/− mice; the endocranial layer of the frontal suture, which develops by endochondral bone formation, failed to mineralize in the Axin2−/−:Runx2+/− mice, resulting in a cartilaginous, fibrotic and larger fontanel than observed in Runx2+/− mice. Transcripts associated with cartilage development (e.g., Acan, miR140) were expressed at higher levels, whereas blood vessel morphogenesis transcripts (e.g., Slit2) were suppressed in Axin2−/−:Runx2+/− calvaria. Cartilage maturation was impaired, as primary chondrocytes from double mutant mice demonstrated delayed differentiation and produced less calcified matrix in vitro. The genetic dominance of Runx2 was also reflected during endochondral fracture repair, as both Runx2+/− and double mutant Axin2−/−:Runx2+/− mice had enlarged fracture calluses at early stages of healing. However, by the end stages of fracture healing, double mutant animals diverged from the Runx2+/− mice, showing smaller calluses and increased torsional strength indicative of more rapid end stage bone formation as seen in the Axin2−/− mice. Taken together, our data demonstrate a dominant role for Runx2 in chondrocyte maturation, but implicate Axin2 as an important modulator of the terminal stages of endochondral bone formation. PMID:24973690

Retinoic acid modulates chondrogenesis in the developing mouse cranial base.

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Kwon, Hyuk-Jae; Shin, Jeong-Oh; Lee, Jong-Min; Cho, Kyoung-Won; Lee, Min-Jung; Cho, Sung-Won; Jung, Han-Sung

2011-12-15

The retinoic acid (RA) signaling pathway is known to play important roles during craniofacial development and skeletogenesis. However, the specific mechanism involving RA in cranial base development has not yet been clearly described. This study investigated how RA modulates endochondral bone development of the cranial base by monitoring the RA receptor RARγ, BMP4, and markers of proliferation, programmed cell death, chondrogenesis, and osteogenesis. We first examined the dynamic morphological and molecular changes in the sphenooccipital synchondrosis-forming region in the mouse embryo cranial bases at E12-E16. In vitro organ cultures employing beads soaked in RA and retinoid-signaling inhibitor citral were compared. In the RA study, the sphenooccipital synchondrosis showed reduced cartilage matrix and lower BMP4 expression while hypertrophic chondrocytes were replaced with proliferating chondrocytes. Retardation of chondrocyte hypertrophy was exhibited in citral-treated specimens, while BMP4 expression was slightly increased and programmed cell death was induced within the sphenooccipital synchondrosis. Our results demonstrate that RA modulates chondrocytes to proliferate, differentiate, or undergo programmed cell death during endochondral bone formation in the developing cranial base. Copyright © 2011 Wiley Periodicals, Inc., A Wiley Company.

Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model.

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Eun-Jung Kim

Full Text Available Endochondral bone formation begins with the development of a cartilage intermediate that is subsequently replaced by calcified bone. The mechanisms occurring during early chondrogenesis that control both mesenchymal cell differentiation into chondrocytes and cell proliferation are not clearly understood in vertebrates. Indian hedgehog (Ihh, one of the hedgehog signaling molecules, is known to control both the hypertrophy of chondrocytes and bone replacement; these processes are particularly important in postnatal endochondral bone formation rather than in early chondrogenesis. In this study, we utilized the maternal transfer of 5E1 to E12.5 in mouse embryos, a process that leads to an attenuation of Ihh activity. As a result, mouse limb bud chondrogenesis was inhibited, and an exogenous recombinant IHH protein enhanced the proliferation and differentiation of mesenchymal cells. Analysis of the genetic relationships in the limb buds suggested a more extensive role for Ihh and Runx genes in early chondrogenesis. The transfer of 5E1 decreased the expression of Runx2 and Runx3, whereas an exogenous recombinant IHH protein increased Runx2 and Runx3 expression. Moreover, a transcription factor Gli1 in hedgehog pathway enhances the direct induction of both Runx2 and Runx3 transcription. These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3.

Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis: a mouse model.

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Kim, Eun-Jung; Cho, Sung-Won; Shin, Jeong-Oh; Lee, Min-Jung; Kim, Kye-Seong; Jung, Han-Sung

2013-01-01

Endochondral bone formation begins with the development of a cartilage intermediate that is subsequently replaced by calcified bone. The mechanisms occurring during early chondrogenesis that control both mesenchymal cell differentiation into chondrocytes and cell proliferation are not clearly understood in vertebrates. Indian hedgehog (Ihh), one of the hedgehog signaling molecules, is known to control both the hypertrophy of chondrocytes and bone replacement; these processes are particularly important in postnatal endochondral bone formation rather than in early chondrogenesis. In this study, we utilized the maternal transfer of 5E1 to E12.5 in mouse embryos, a process that leads to an attenuation of Ihh activity. As a result, mouse limb bud chondrogenesis was inhibited, and an exogenous recombinant IHH protein enhanced the proliferation and differentiation of mesenchymal cells. Analysis of the genetic relationships in the limb buds suggested a more extensive role for Ihh and Runx genes in early chondrogenesis. The transfer of 5E1 decreased the expression of Runx2 and Runx3, whereas an exogenous recombinant IHH protein increased Runx2 and Runx3 expression. Moreover, a transcription factor Gli1 in hedgehog pathway enhances the direct induction of both Runx2 and Runx3 transcription. These findings suggested that Ihh signaling plays an important role in chondrocyte proliferation and differentiation via interactions with Runx2 and Runx3.

An Unusual Complication of an Infiltrated Intravenous Catheter: Heterotopic Ossification in a Newborn

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Lavi Nissim

2008-08-01

Full Text Available

Heterotopic ossification refers to formation of lamellar  bone in soft tissues. The etiology is diverse and includes genetic, post-traumatic, and metabolic causes. Elicitation of  bone morphogenic proteins are thought to play a key role in the pathogenic process. Initially, heterotopic ossification presents a clinical and radiographic challenge in that it can be mistaken for other more worrisome entities which present with calcified soft tissue masses. However, a spontaneous clinical resolution, temporal relationship to an inciting agent, and radiographic evolution to a peripherally-calcified lesion are all clues to the diagnosis. Here we present the clinical and radiographic features of heterotopic ossification as a result of an infiltrated peripheral IV. 

Diffuse arachnoid ossification and multiple arachnoid cysts presenting with progressive thoracic myelopathy

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Sakai, Toshinori; Sairyo, Koichi; Kashima, Masahiro; Kosaka, Hirofumi; Katoh, Shinsuke; Yasui, Natsuo [The University of Tokushima Graduate School, Department of Orthopedics, Institute of Health Biosciences, Tokushima (Japan)

2010-03-15

An ossified arachnoid membrane combined with cystic formation is rarely reported as a cause of spinal cord compression. We report the case of a 60-year-old man who presented with diffuse ossification of the arachnoid membrane (arachnoid ossification) and multiple cystic changes (arachnoid cyst) at the thoracic and lumbar spine. The lesions were surgically removed and progressive deterioration was prevented, although no marked improvement of neurological symptoms was attained. (orig.)

Rickets or abuse? A histologic comparison of rickets and child abuse-related fractures.

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Kepron, Charis; Pollanen, Michael S

2015-03-01

The bone changes of vitamin D deficiency rickets have been invoked as an alternate explanation for child-abuse related fractures identified through medical imaging. The lack of modern histopathologic comparisons between these two entities limits the abilities of the forensic pathologist to address this differential diagnosis, both in their autopsy reports and on the witness stand. We report a comparison of the histologic appearance of the bones in a two year old child with vitamin D deficiency rickets with fractures occurring in three young children with child abuse. In the case of rickets, there was marked architectural disorganization of endochondral ossification at the costochondral junctions and growth plates of long bones. The child abuse-related fractures showed osteochondral callus at different stages of healing, either centered on a discrete fracture line or at metaphyses (e.g. classical metaphyseal lesions). In many instances, the healing fractures disrupted the line of endochondral ossification. In none of the child abuse-related fractures was there any similarity to the histologic appearance of rickets. The maturation disturbance in the growth plate that occurs in rickets is a distinctive entity that cannot be confused histologically with healing fractures, including the classical metaphyseal lesion.

[Clinical and ossification outcome of custom-made hydroxyapatite prothese for large skull defect].

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Hardy, H; Tollard, E; Derrey, S; Delcampe, P; Péron, J-M; Fréger, P; Proust, F

2012-02-01

Cranioplasty is an everyday concern in neurosurgery, especially in decompressive craniectomy cases. Our surgical team uses custom-made hydroxyapatite implants for large and/or complex defects. Eight patients had a custom-made prosthesis. Each of them has been reviewed by an independent observer. Each patient described his feeling of satisfaction, using a questionnaire, graduated from "A" (really satisfied) to "D" (unsatisfied). Each of them also underwent a CT-scan (helicoidal acquisition, 0.6mm thick for multiplanar reconstruction) to evaluate qualitatively the ossification graduated from "0" (no ossification) to "5" (continuous ossification). Maximal under-prosthetic bone thickness, intra-prosthetic calcic density were also reported. Supervision delay was 43.7 months [6-99 months], average defect surface was 85.5 cm(2) [27.6-137.6 cm(2)], the craniectomy etiologies were intracranial hypertension (seven patients) and calvarial invasion (one patient). Implant tolerance was reparted in "A" score (50%) and "B" score (50%). Concerning ossification, six patients (75%) had a score of "2" or less and two patients had a score of "3" or "4". Hydroxyapatite custom-made implants for cranioplasty appear to be ideal for good aesthetic and tolerance results, but their ossification is hardly analyzed due to the prosthesis density higher than the bone's density. This is why we recommend them for children and in cases of complex defects such as pterion location. Copyright © 2011. Published by Elsevier Masson SAS.

Surgical treatment of hip ankylosis due to heterotopic ossification secondary to spinal cord injury.

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Romero-Muñoz, L M; Barriga-Martín, A; DeJuan-García, J

2018-02-21

To expose our experience in the diagnostic and surgical treatment of neurogenic heterotopic ossification of the hip. We designed an observational retrospective descriptive study including 20 patients (30 hips) with neurogenic heterotopic ossification of the hip secondary to spinal cord injury attended in our institution in the last 10 years, with a minimum of one year follow-up. Medical files and imaging studies were reviewed. The study variables analyzed were: type and localization of neurogenic heterotopic ossification, pre-post excision range of motion, level and aetiology of spinal cord injury, ASIA score, smoking history, surgical approach and complications associated with surgery. A total of 20 patients were treated with resection of heterotopic ossification in 30 hips. 16 patients presented ASIA A spinal cord injury and 4 ASIA B spinal cord injury. Preoperatively all the patients had severe ankylosis in the hip that made sitting in a wheel chair and activities such as repositioning and hygiene difficult. The average postoperative motion at the follow-up evaluation was 90° in flexion, 20° of internal rotation and 40° of external rotation. Immediately after surgery all the patients followed a specific intensive physiotherapy regime for the hip and celecoxib 200 mg was administrated daily orally for a month to prevent recurrence of heterotopic bone formation. None of the patients reviewed suffered a recurrence of heterotopic bone formation. Surgical excision of hip ossification in order to achieve functional ROM of the hip is the best treatment for patients with neurogenic heterotopic ossification of the hip. Copyright © 2018 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

Anomalies of ossification in the posterolateral femoral condyle: assessment by MRI

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Nawata, K.; Teshima, Ryota; Morio, Yasuo; Hagino, Hiroshi [Department of Orthopaedic Surgery, Faculty of Medicine, Tottori University, Yonaga (Japan)

1999-10-01

Background. Anomalies of ossification in the lower femoral epiphysis are often radiographically indistinguishable from juvenile osteochondritis dissecans. Objective. To clarify the MRI characteristics of the anomalies of ossification in the posterolateral femoral condyle that distinguish it from juvenile osteochondritis dissecans. Materials and methods. We retrospectively examined the medical records, plain radiographs (n = 4), MRI (n = 4) and follow-up MRI (n = 2) of four boys (age 8-11 years) with anomalies of ossification in the posterolateral femoral condyle. Results. Plain radiography showed symmetrical marginal irregularity of the posterolateral femoral condyles of both knees. These lesions were asymptomatic, and the areas of irregular radiographic appearances reduced in size or disappeared without treatment within a mean observation period of 3.5 months. MRI showed a clearly demarcated low-intensity islet with the same signal intensity as subchondral bone (which was considered to be an accessory ossification nucleus) in a high-signal area in which the signal intensity was equal to that of normal articular cartilage. The areas observed as radiolucent zones on plain radiography were visualised at the same signal intensity as articular cartilage, and were continuous with articular cartilage on MRI; thus they were regarded as uncalcified cartilage. These MR findings are different from MR images of osteochondritis dissecans. Conclusions. MRI is considered to be the most effective non-invasive diagnostic method for these two conditions. (orig.) With 3 figs., 1 tab., 10 refs.

Is radiation superior to indomethacin to prevent heterotopic ossification in acetabular fractures?: a systematic review.

NARCIS (Netherlands)

Blokhuis, T.J.; Frolke, J.P.M.

2009-01-01

Heterotopic ossification is a well-known complication after fixation of an acetabular fracture. Indomethacin and radiation therapy are used as prophylaxis to prevent heterotopic ossification. It is unclear, however, whether either is superior, although this may relate to lack of power in individual

The trochlear pre-ossification center: a normal developmental stage and potential pitfall on MR images

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Jaimes, Camilo [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Jimenez, Mauricio [Hospital of the University of Pennsylvania, Department of Radiology, Philadelphia, PA (United States); Marin, Diana [Miami Children' s Hospital, Department of Radiology, Miami, FL (United States); Ho-Fung, Victor; Jaramillo, Diego [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States)

2012-11-15

The hypertrophic changes that occur in the cartilage of an epiphysis prior to the onset of ossification are known as the pre-ossification center. Awareness of the appearance of the pre-ossification center on MR images is important to avoid confusing normal developmental changes with pathology. The purpose of this study was to determine the characteristics of the trochlear pre-ossification center on MR imaging and examine age and gender differences. We retrospectively analyzed MR images from 61 children. The trochleas were categorized into three types on the basis of signal intensity (SI). Trochlear types were compared to age and gender. There was no significant difference between the ages of boys and girls. Type 1 trochleas showed homogeneous SI on all pulse sequences. Type 2 trochleas demonstrated a focus of high SI in the epiphyseal cartilage on fat-suppressed water-sensitive sequences, with high or intermediate SI on gradient-echo images (pre-ossification center). Type 3 trochleas showed low SI on fat-suppressed water-sensitive sequences and gradient-echo images. Thirty-seven trochleas were described as type 1, sixteen as type 2 and eight as type 3. ANOVAs confirmed a statistically significant difference in the age of children with type 3 trochleas and those with types 1 and 2 (P < 0.001). Spearman rank correlations determined a positive relationship between trochlear type and age of the children (r = 0.53). Development-related changes in the trochlea follow a predictable pattern. The signal characteristics of the pre-ossification center likely reflect normal chondrocyte hypertrophy and an increase in free water in the matrix. (orig.)

Achondroplasia manifesting as enchondromatosis and ossification of the spinal ligaments: a case report

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Al Kaissi Ali

2008-08-01

Full Text Available Abstract Introduction A girl presented with achondroplasia manifested as mild knee pain associated with stiffness of her back. A skeletal survey showed enchondroma-like metaphyseal dysplasia and ossification of the spinal ligaments. Magnetic resonance imaging of the spine further clarified the pathological composites. Case presentation A 7-year-old girl presented with the classical phenotypic features of achondroplasia. Radiographic documentation showed the co-existence of metaphyseal enchondromatosis and development of spinal bony ankylosis. Magnetic resonance imaging showed extensive ossification of the anterior and posterior spinal ligaments. Additional features revealed by magnetic resonance imaging included calcification of the peripheral vertebral bodies associated with anterior end-plate irregularities. Conclusion Enchondromas are metabolically active and may continue to grow and evolve throughout the patient's lifetime; thus, progressive calcification over a period of years is not unusual. Ossification of the spinal ligaments has a specific site of predilection and often occurs in combination with senile ankylosing vertebral hyperostosis. Nevertheless, ossification of the spinal ligaments has been encountered in children with syndromic malformation complex. It is a multifactorial disease in which complex genetic and environmental factors interact, potentially leading to chronic pressure on the spinal cord and nerve roots with subsequent development of myeloradiculopathy. Our patient presented with a combination of achondroplasia, enchondroma-like metaphyseal dysplasia and calcification of the spinal ligaments. We suggest that the development of heterotopic bone formation along the spinal ligaments had occurred through an abnormal ossified enchondral mechanism. We postulate that ossification of the spinal ligaments and metaphyseal enchondromatous changes are related to each other and represent impaired terminal differentiation of

Isolation and differentiation of chondrocytic cells derived from human embryonic stem cells using dlk1/FA1 as a novel surface marker

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Harkness, Linda; Taipaleenmaki, Hanna; Mahmood, Amer

2009-01-01

of dlk1/FA1 as a novel surface marker for chondroprogenitor cells during hESC differentiation. We found that, Dlk1/FA1 is expressed specifically in cells undergoing transition from proliferating to prehypertrophic chondrocytes during endochondral ossification of the mouse limb. In hESC cells, dlk1/FA1...... was not expressed by undifferentiated hESC, but expressed during in vitro embryoid bodies (hEBs) formation upon down-regulation of undifferentiated markers e.g. Oct 3/4. Similarly, dlk1/FA1 was expressed in chondrocytic cells during in vivo teratoma formation. Interestingly, treatment of hEBs with Activin B......, a member of TGF-ss family, markedly increased Dlk1 expression in association with up-regulation of the mesoderm-specific markers (e.g. FOXF1, KDR and VE-cadherin) and SOX9. dlk1/FA1(+) cells isolated by fluorescence activated cell sorting (FACS) were capable of differentiating into chondrocytic cells when...

Heterotopic ossification (myositis ossificans) in acquired immune deficiency syndrome. Detection by gallium scintigraphy

International Nuclear Information System (INIS)

Drane, W.E.; Tipler, B.M.

1987-01-01

A case of heterotopic ossification (myositis ossificans) secondary to the central nervous system complications of acquired immune deficiency syndrome (AIDS) is reported. Because of the overwhelming suspicion of infection in this patient, this diagnosis was not considered until a gallium scan revealed the typical findings of heterotopic ossification. Because of the increasing utilization of gallium imaging in the AIDS population, every imaging specialist should be aware of this potential disorder

Synostosis Between Pubic Bones due to Neurogenic, Heterotopic Ossification

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Subramanian Vaidyanathan

2006-01-01

Full Text Available Neurogenic, heterotopic ossification is characterised by the formation of new, extraosseous (ectopic bone in soft tissue in patients with neurological disorders. A 33-year-old female, who was born with spina bifida, paraplegia, and diastasis of symphysis pubis, had indwelling urethral catheter drainage and was using oxybutynin bladder instillations. She was prescribed diuretic for swelling of feet, which aggravated bypassing of catheter. Hence, suprapubic cystostomy was performed. Despite anticholinergic therapy, there was chronic urine leak around the suprapubic catheter and per urethra. Therefore, the urethra was mobilised and closed. After closure of the urethra, there was no urine leak from the urethra, but urine leak persisted around the suprapubic catheter. Cystogram confirmed the presence of a Foley balloon inside the bladder; there was no urinary fistula. The Foley balloon ruptured frequently, leading to extrusion of the Foley catheter. X-ray of abdomen showed heterotopic bone formation bridging the gap across diastasis of symphysis pubis. CT of pelvis revealed heterotopic bone lying in close proximity to the balloon of the Foley catheter; the sharp edge of heterotopic bone probably acted like a saw and led to frequent rupture of the balloon of the Foley catheter. Unique features of this case are: (1 temporal relationship of heterotopic bone formation to suprapubic cystostomy and chronic urine leak; (2 occurrence of heterotopic ossification in pubic region; (3 complications of heterotopic bone formation viz. frequent rupture of the balloon of the Foley catheter by the irregular margin of heterotopic bone and difficulty in insertion of suprapubic catheter because the heterotopic bone encroached on the suprapubic track; (4 synostosis between pubic bones as a result of heterotopic ossification..Common aetiological factors for neurogenic, heterotopic ossification, such as forceful manipulation, trauma, or spasticity, were absent in this

Circulatory CNP Rescues Craniofacial Hypoplasia in Achondroplasia.

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Yamanaka, S; Nakao, Kazumasa; Koyama, N; Isobe, Y; Ueda, Y; Kanai, Y; Kondo, E; Fujii, T; Miura, M; Yasoda, A; Nakao, Kazuwa; Bessho, K

2017-12-01

Achondroplasia is the most common genetic form of human dwarfism, characterized by midfacial hypoplasia resulting in occlusal abnormality and foramen magnum stenosis, leading to serious neurologic complications and hydrocephalus. Currently, surgery is the only way to manage jaw deformity, neurologic complications, and hydrocephalus in patients with achondroplasia. We previously showed that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth of long bones and vertebrae and is also a potent stimulator in the craniofacial region, which is crucial for midfacial skeletogenesis. In this study, we analyzed craniofacial morphology in a mouse model of achondroplasia, in which fibroblast growth factor receptor 3 (FGFR3) is specifically activated in cartilage ( Fgfr3 ach mice), and investigated the mechanisms of jaw deformities caused by this mutation. Furthermore, we analyzed the effect of CNP on the maxillofacial area in these animals. Fgfr3 ach mice exhibited midfacial hypoplasia, especially in the sagittal direction, caused by impaired endochondral ossification in craniofacial cartilage and by premature closure of the spheno-occipital synchondrosis, an important growth center in craniomaxillofacial skeletogenesis. We crossed Fgfr3 ach mice with transgenic mice in which CNP is expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP ( Fgfr3 ach /SAP-Nppc-Tg mice). In the progeny, midfacial hypoplasia in the sagittal direction observed in Fgfr3 ach mice was improved significantly by restoring the thickness of synchondrosis and promoting proliferation of chondrocytes in the craniofacial cartilage. In addition, the foramen magnum stenosis observed in Fgfr3 ach mice was significantly ameliorated in Fgfr3 ach /SAP-Nppc-Tg mice due to enhanced endochondral bone growth of the anterior intraoccipital synchondrosis. These results clearly demonstrate the therapeutic

Could Ossification of the Achilles Tendon Have a Hereditary Component?

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Chawki Cortbaoui

2013-01-01

Full Text Available Ossification of the Achilles tendon (OTA is an unusual clinical condition. It is characterized by the presence of an ossified mass within the fibrocartilaginous substance of the Achilles tendon. The etiology of the ossification of the Achilles tendon is unknown. Review of the literature suggests that its etiology is multifactorial. The major contributing factors are trauma and surgery with other minor causes such as systemic diseases, metabolic conditions, and infections. To our knowledge, no previous reports suggest any genetic/hereditary predisposition in OAT. We report 3 siblings who have OAT with no history of any of the aforementioned predisposing factors. Could OAT have a hereditary component as one of its etiologies?

Radionuclide assessment of heterotopic ossification in spinal cord injury patients

International Nuclear Information System (INIS)

Prakash, V.

1983-01-01

Whole body /sup 99m/T-pyrophosphate bone scans were obtained and correlated with skeletal radiographs for detection of heterotopic ossification in 135 spinal injury patients. There were 40 patients with recent injury (less than 6 months) and 95 with injury of over 6 months duration. Heterotopic new bone was detected on the bone scan in 33.7% of 95 patients with spinal cord injuries of more than 6 months duration and 30% of 40 patients with injuries of less than 6 months. The radionuclide scan was found to be useful in detection of heterotopic ossification at its early stage and in its differentiation from other complications in spinal cord injury patients

Heterotopic Ossification Formation Following a Simple Concussion: A Case Report.

Science.gov (United States)

O'Callaghan, Patrick K; Carter, Elliott; Walton, Zeke; Chapin, Russell; Bruner, Evelyn

2018-05-09

A 19-year-old woman presented with a 3-month history of an enlarging lesion on the proximal aspect of the femur. After imaging studies and a biopsy had been performed, the mass was determined to represent heterotopic ossification (HO). The only known risk factor was a history of concussion. The mass was resected and, as of the 12-month follow-up, had not recurred. HO is a potentially serious complication of ossification in soft tissues that can develop secondary to several disease states; it commonly occurs following traumatic brain injury. To our knowledge, this is the only case report that describes HO associated with a concussion and no other risk factors.

Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis.

Science.gov (United States)

Subhas, N; Sundaram, M; Bauer, T W; Seitz, W H; Recht, M P

2008-02-01

We report a case of a 47-year-old man who presented with progressive loss of motion and pain in the right shoulder. Radiographs of the shoulder demonstrated dense ossification in the glenoid and humeral head with extension into the periarticular soft tissues. CT and MRI scans confirmed the radiographic findings and also revealed ossification of the glenoid labrum. A radiographic diagnosis of melorheostosis, an uncommon benign sclerosing bone dysplasia, was made. Because of the patient's severe symptomatology, he underwent total shoulder arthroplasty. Histological analysis of the resected masses was consistent with melorheostosis with a few areas covered by a cartilage cap. This case illustrates several uncommon but important features of melorheostosis, including mechanical obstruction of joint motion requiring joint replacement, ossification of the glenoid labrum, and cartilage-covering portions of the intra-articular masses, not to be confused with cartilage-producing tumors.

Fungal osteomyelitis with vertebral re-ossification.

Science.gov (United States)

O Guinn, Devon J; Serletis, Demitre; Kazemi, Noojan

2016-01-01

We present a rare case of thoracic vertebral osteomyelitis secondary to pulmonary Blastomyces dermatitides. A 27-year-old male presented with three months of chest pains and non-productive cough. Examination revealed diminished breath sounds on the right. CT/MR imaging confirmed a right-sided pre-/paravertebral soft tissue mass and destructive lytic lesions from T2 to T6. CT-guided needle biopsy confirmed granulomatous pulmonary Blastomycosis. Conservative management with antifungal therapy was initiated. Neurosurgical review confirmed no clinical or profound radiographic instability, and the patient was stabilized with TLSO bracing. Serial imaging 3 months later revealed near-resolution of the thoracic soft tissue mass, with vertebral re-ossification from T2 to T6. Fungal osteomyelitis presents a rare entity in the spectrum of spinal infections. In such cases, lytic spinal lesions are classically seen in association with a large paraspinous mass. Fungal infections of the spinal column may be treated conservatively, with surgical intervention reserved for progressive cases manifesting with neurological compromise and/or spinal column instability. Here, we found unexpected evidence for vertebral re-ossification across the affected thoracic levels (T2-6) in response to IV antibiotic therapy and conservative bracing, nearly 3 months later. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pellegrini-Stieda disease: a heterogeneous disorder not synonymous with ossification/calcification of the tibial collateral ligament - anatomic and imaging investigation

International Nuclear Information System (INIS)

Mendes, Luiz F.A.; Cho, Jae H.; Garcia, Glenn M.; Resnick, Donald L.; Chung, Christine B.; Pretterklieber, Michael L.

2006-01-01

Ossification/calcification around the medial femoral condyle has been known as Pellegrini-Stieda (PS) disease for almost 100 years. Little attention has been given to magnetic resonance (MR) imaging characteristics. Our purpose is to demonstrate the anatomy in the medial femoral compartment and imaging findings of PS disease, determining the sites and patterns of ossification. In a cadaveric study seven specimens were dissected to show the anatomic relations of the tibial collateral ligament (TCL) and the tendon of the ischiocondylar part of the adductor magnus muscle, in the medial femoral epicondyle. In order to determine the nature of ossification/calcification in PS disease, MR imaging and radiographic findings in nine patients were analyzed by two observers with attention to the specific site, shape, and orientation of the ossification and its relationship to the tibial collateral ligament (TCL) and adductor magnus tendon. Available clinical history was recorded. A classification system addressing different sites and patterns of ossification was developed. The anatomic study showed that the TCL and the adductor magnus tendon insert at different sites in the medial femoral condyle and there is no continuation; however, some fibers of the posterior bundle of the TCL overlap the anterior aspect of the adductor magnus tendon. The imaging study showed that shape, orientation, and location of the abnormal calcification and ossification were similar on radiographic and MR imaging analysis. Ossification had an inferior orientation in six cases, a superior orientation in two cases, and both in one case. Four patterns of ossification were noted: (I) a beak-like appearance with an inferior orientation and femoral attachment was present in five cases; (II) a drop-like appearance with an inferior orientation, parallel to the femur, was evident in one case; (III) an elongated appearance with a superior orientation, parallel to the femur, was seen in two cases; and (IV) a

Pellegrini-Stieda disease: a heterogeneous disorder not synonymous with ossification/calcification of the tibial collateral ligament - anatomic and imaging investigation

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Mendes, Luiz F.A.; Cho, Jae H.; Garcia, Glenn M.; Resnick, Donald L.; Chung, Christine B. [Veterans Administration Medical Center, Department of Radiology, San Diego, CA (United States); Pretterklieber, Michael L. [Department of Applied Anatomy, Center of Anatomy and Cell Biology, Vienna (Austria)

2006-12-15

Ossification/calcification around the medial femoral condyle has been known as Pellegrini-Stieda (PS) disease for almost 100 years. Little attention has been given to magnetic resonance (MR) imaging characteristics. Our purpose is to demonstrate the anatomy in the medial femoral compartment and imaging findings of PS disease, determining the sites and patterns of ossification. In a cadaveric study seven specimens were dissected to show the anatomic relations of the tibial collateral ligament (TCL) and the tendon of the ischiocondylar part of the adductor magnus muscle, in the medial femoral epicondyle. In order to determine the nature of ossification/calcification in PS disease, MR imaging and radiographic findings in nine patients were analyzed by two observers with attention to the specific site, shape, and orientation of the ossification and its relationship to the tibial collateral ligament (TCL) and adductor magnus tendon. Available clinical history was recorded. A classification system addressing different sites and patterns of ossification was developed. The anatomic study showed that the TCL and the adductor magnus tendon insert at different sites in the medial femoral condyle and there is no continuation; however, some fibers of the posterior bundle of the TCL overlap the anterior aspect of the adductor magnus tendon. The imaging study showed that shape, orientation, and location of the abnormal calcification and ossification were similar on radiographic and MR imaging analysis. Ossification had an inferior orientation in six cases, a superior orientation in two cases, and both in one case. Four patterns of ossification were noted: (I) a beak-like appearance with an inferior orientation and femoral attachment was present in five cases; (II) a drop-like appearance with an inferior orientation, parallel to the femur, was evident in one case; (III) an elongated appearance with a superior orientation, parallel to the femur, was seen in two cases; and (IV) a

Proteomic Analysis of Trauma-Induced Heterotopic Ossification Formation

Science.gov (United States)

2016-10-01

60% of these patients go on to form abnormal bone within the soft tissue of their injured limbs. This condition, known as Heterotopic Ossification... psychological and physical damage sustained as a result of multiple orthopaedic surgical procedures. As a result, the effort, time, and cost of wounded

Can the growth factors PTHrP, Ihh and VEGF, together regulate the development of a long bone?

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Brouwers, J E M; van Donkelaar, C C; Sengers, B G; Huiskes, R

2006-01-01

Endochondral ossification is the process of differentiation of cartilaginous into osseous tissue. Parathyroid hormone related protein (PTHrP), Indian hedgehog (Ihh) and vascular endothelial growth factor (VEGF), which are synthesized in different zones of the growth plate, were found to have crucial roles in regulating endochondral ossification. The aim of this study was to evaluate whether the three growth factors PTHrP, Ihh and VEGF, together, could regulate longitudinal growth in a normal human, fetal femur. For this purpose, a one-dimensional finite element (FE) model, incorporating growth factor signaling, was developed of the human, distal, femoral growth plate. It included growth factor synthesis in the relevant zones, their transport and degradation and their effects. Simulations ran from initial hypertrophy in the center of the bone until secondary ossification starts at approximately 3.5 months postnatal. For clarity, we emphasize that no mechanical stresses were considered. The FE model showed a stable growth plate in which the bone growth rate was constant and the number of cells per zone oscillated around an equilibrium. Simulations incorporating increased and decreased PTHrP and Ihh synthesis rates resulted, respectively, in more and less cells per zone and in increased and decreased bone growth rates. The FE model correctly reflected the development of a growth plate and the rate of bone growth in the femur. Simulations incorporating increased and decreased PTHrP and Ihh synthesis rates reflected growth plate pathologies and growth plates in PTHrP-/- and Ihh-/- mice. The three growth factors, PTHrP, Ihh and VEGF, could potentially together regulate tissue differentiation.

Radiological study of the calcanean ossification secondary nucleus development

International Nuclear Information System (INIS)

Carvalho Filho, Guaracy.

1994-01-01

This work describes the normal aspects of the calcanean ossification secondary nucleus radiological development, the appearing time, his form, localization, fragmentation and evolution of area, from a sample of normal individuals. (author). 14 refs., 16 figs., 8 tabs

Bilateral ossification of the auricles: an unusual entity and review of the literature

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Siabi Vassiliki

2009-10-01

Full Text Available Abstract Background True ossification of the auricle with cartilage replacement by bone, is a very rare clinical entity and can result in an entirely rigid auricle. Case presentation We present a rare case of bilateral ossification of the auricles in a 75-years old man with profound progressive rigidity of both auricles. His main complaint was a mild discomfort during resting making sleeping unpleasant without any other serious symptoms. His medical history was significant for predisposing factors for this condition such as, Addison's disease and diabetes mellitus. Excisional biopsy was performed confirming the ossified nature of the auricles. Further treatment deemed unnecessary in our case due to his mild clinical picture. Conclusion True auricular ossification is a quite rare clinical entity with unclear pathogenesis and one should have in mind that there is always the possibility of a serious co-existed disease like endocrinopathy.

Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis

International Nuclear Information System (INIS)

Subhas, N.; Sundaram, M.; Recht, M.P.; Bauer, T.W.; Seitz, W.H.

2008-01-01

We report a case of a 47-year-old man who presented with progressive loss of motion and pain in the right shoulder. Radiographs of the shoulder demonstrated dense ossification in the glenoid and humeral head with extension into the periarticular soft tissues. CT and MRI scans confirmed the radiographic findings and also revealed ossification of the glenoid labrum. A radiographic diagnosis of melorheostosis, an uncommon benign sclerosing bone dysplasia, was made. Because of the patient's severe symptomatology, he underwent total shoulder arthroplasty. Histological analysis of the resected masses was consistent with melorheostosis with a few areas covered by a cartilage cap. This case illustrates several uncommon but important features of melorheostosis, including mechanical obstruction of joint motion requiring joint replacement, ossification of the glenoid labrum, and cartilage-covering portions of the intra-articular masses, not to be confused with cartilage-producing tumors. (orig.)

Glenoid labrum ossification and mechanical restriction of joint motion: extraosseous manifestations of melorheostosis

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Subhas, N.; Sundaram, M.; Recht, M.P. [Cleveland Clinic, Department of Diagnostic Radiology, Cleveland, OH (United States); Bauer, T.W. [Cleveland Clinic, Department of Anatomic Pathology, Cleveland, OH (United States); Seitz, W.H. [Cleveland Clinic, Department of Orthopaedic Surgery, Cleveland, OH (United States)

2008-02-15

We report a case of a 47-year-old man who presented with progressive loss of motion and pain in the right shoulder. Radiographs of the shoulder demonstrated dense ossification in the glenoid and humeral head with extension into the periarticular soft tissues. CT and MRI scans confirmed the radiographic findings and also revealed ossification of the glenoid labrum. A radiographic diagnosis of melorheostosis, an uncommon benign sclerosing bone dysplasia, was made. Because of the patient's severe symptomatology, he underwent total shoulder arthroplasty. Histological analysis of the resected masses was consistent with melorheostosis with a few areas covered by a cartilage cap. This case illustrates several uncommon but important features of melorheostosis, including mechanical obstruction of joint motion requiring joint replacement, ossification of the glenoid labrum, and cartilage-covering portions of the intra-articular masses, not to be confused with cartilage-producing tumors. (orig.)

Radiographic monitoring of the ossification of long bones in kori (Ardeotis kori) and white-bellied (Eupodotis senegalensis) bustards

International Nuclear Information System (INIS)

Naldo, J.L.; Samour, J.H.; Bailey, T.A.

1998-01-01

A serial radiographic study was conducted on eight kori bustard (Ardeotis kori) and four white-bellied bustard (Eupodotis senegalensis) chicks to determine the pattern of long bone development and to establish radiographic standards for assessing skeletal maturity. The ossification pattern, appearance of secondary ossification centres, and epiphyseal fusion of the long bones in kori and white-bellied bustards were similar to those in houbara bustards (Chlamydotis undulata macqueenii),rufous-crested bustards (Eupodotis ruficrista), domestic fowl (Gallusgallus), house wrens (Troglodytes aedon aedon), racing pigeons (Columba livia), and barn owls (Tyto alba). Secondary ossification centres were present at the proximal and distal tibiotarsus, proximal tarsometatarsus and proximal metacarpal III. The ossification of long bones occurred earlier in female kori bustards compared with males

Radiological study of the thoracic limb in the growing Iberian pig (from birth to 16 months) [ossification

International Nuclear Information System (INIS)

Mayoral, A.J.; Vivo, J.M.; Guillen, M.T.; Regodon, S.

1995-01-01

The chronology of the ossification of the thoracic limb of the growing Iberian pig is analyzed by the radiological method, from birth to 482 days (16 months). 48 individuals have been used (24 males, 24 females), from different origins and distributed within 6 age groups : birth(1 day), weaning (58 days), preparation (234 days), beginning (352 days), half (424 days) and end (482 days) of fattening. The appearance and the evolution of the ossification centres were observed, as well as some phenomena occurring during the fusion of the ossification centres

Cellular ATP synthesis mediated by type III sodium-dependent phosphate transporter Pit-1 is critical to chondrogenesis.

Science.gov (United States)

Sugita, Atsushi; Kawai, Shinji; Hayashibara, Tetsuyuki; Amano, Atsuo; Ooshima, Takashi; Michigami, Toshimi; Yoshikawa, Hideki; Yoneda, Toshiyuki

2011-01-28

Disturbed endochondral ossification in X-linked hypophosphatemia indicates an involvement of P(i) in chondrogenesis. We studied the role of the sodium-dependent P(i) cotransporters (NPT), which are a widely recognized regulator of cellular P(i) homeostasis, and the downstream events in chondrogenesis using Hyp mice, the murine homolog of human X-linked hypophosphatemia. Hyp mice showed reduced apoptosis and mineralization in hypertrophic cartilage. Hyp chondrocytes in culture displayed decreased apoptosis and mineralization compared with WT chondrocytes, whereas glycosaminoglycan synthesis, an early event in chondrogenesis, was not altered. Expression of the type III NPT Pit-1 and P(i) uptake were diminished, and intracellular ATP levels were also reduced in parallel with decreased caspase-9 and caspase-3 activity in Hyp chondrocytes. The competitive NPT inhibitor phosphonoformic acid and ATP synthesis inhibitor 3-bromopyruvate disturbed endochondral ossification with reduced apoptosis in vivo and suppressed apoptosis and mineralization in conjunction with reduced P(i) uptake and ATP synthesis in WT chondrocytes. Overexpression of Pit-1 in Hyp chondrocytes reversed P(i) uptake and ATP synthesis and restored apoptosis and mineralization. Our results suggest that cellular ATP synthesis consequent to P(i) uptake via Pit-1 plays an important role in chondrocyte apoptosis and mineralization, and that chondrogenesis is ATP-dependent.

Evaluation of insulin medium or chondrogenic medium on proliferation and chondrogenesis of ATDC5 cells.

Science.gov (United States)

Yao, Yongchang; Zhai, Zhichen; Wang, Yingjun

2014-01-01

The ATDC5 cell line is regarded as an excellent cell model for chondrogenesis. In most studies with ATDC5 cells, insulin medium (IM) was used to induce chondrogenesis while chondrogenic medium (CM), which was usually applied in chondrogenesis of mesenchymal stem cells (MSCs), was rarely used for ATDC5 cells. This study was mainly designed to investigate the effect of IM, CM, and growth medium (GM) on chondrogenesis of ATDC5 cells. ATDC5 cells were, respectively, cultured in IM, CM, and GM for a certain time. Then the proliferation and the chondrogenesis progress of cells in these groups were analyzed. Compared with CM and GM, IM promoted the proliferation of cells significantly. CM was effective for enhancement of cartilage specific markers, while IM induced the cells to express endochondral ossification related genes. Although GAG deposition per cell in CM group was significantly higher than that in IM and GM groups, the total GAG contents in IM group were the most. This study demonstrated that CM focused on induction of chondrogenic differentiation while IM was in favor of promoting proliferation and expression of endochondral ossification related genes. Combinational use of these two media would be more beneficial to bone/cartilage repair.

Evaluation of Insulin Medium or Chondrogenic Medium on Proliferation and Chondrogenesis of ATDC5 Cells

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Yongchang Yao

2014-01-01

Full Text Available Background. The ATDC5 cell line is regarded as an excellent cell model for chondrogenesis. In most studies with ATDC5 cells, insulin medium (IM was used to induce chondrogenesis while chondrogenic medium (CM, which was usually applied in chondrogenesis of mesenchymal stem cells (MSCs, was rarely used for ATDC5 cells. This study was mainly designed to investigate the effect of IM, CM, and growth medium (GM on chondrogenesis of ATDC5 cells. Methods. ATDC5 cells were, respectively, cultured in IM, CM, and GM for a certain time. Then the proliferation and the chondrogenesis progress of cells in these groups were analyzed. Results. Compared with CM and GM, IM promoted the proliferation of cells significantly. CM was effective for enhancement of cartilage specific markers, while IM induced the cells to express endochondral ossification related genes. Although GAG deposition per cell in CM group was significantly higher than that in IM and GM groups, the total GAG contents in IM group were the most. Conclusion. This study demonstrated that CM focused on induction of chondrogenic differentiation while IM was in favor of promoting proliferation and expression of endochondral ossification related genes. Combinational use of these two media would be more beneficial to bone/cartilage repair.

Development of mandible in indigenous sheep fetuses

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N. S. Ahmed

2011-01-01

Full Text Available The aim of this study was to detect the precise sites of the beginning of primary ossification centers of the mandible of sheep fetuses as well as their onset time, to achieve this goal, samples were taken weekly starting from the 7th week up to 20th week of intrauterine life. Sections of the samples were stained by the alizarin red and alcian blue technique. Primary centers appeared at the beginning of 7th week as big red spot on either sides of mesenchyme of first branchial arch (Meckel’s cartilage that developed by intramembranous ossification. The rostral part of the mandible, however, was developed by endochondral ossification. The successive bone development process (7–20 weeks, were moniterd by macerating the mandibles using either potassium hydroxide or fly larvae. Measuring tape and graph papers were employed for measurements and for localization of mandibular angle. The results revealed significant increase of these measurements during the successive weeks of intrauterine life.

Long-Term Expansion, Enhanced Chondrogenic Potential, and Suppression of Endochondral Ossification of Adult Human MSCs via WNT Signaling Modulation

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Roberto Narcisi

2015-03-01

Full Text Available Mesenchymal stem cells (MSCs are a potential source of chondrogenic cells for the treatment of cartilage disorders, but loss of chondrogenic potential during in vitro expansion and the propensity of cartilage to undergo hypertrophic maturation impede their therapeutic application. Here we report that the signaling protein WNT3A, in combination with FGF2, supports long-term expansion of human bone marrow-derived MSCs. The cells retained their chondrogenic potential and other phenotypic and functional properties of multipotent MSCs, which were gradually lost in the absence of WNT3A. Moreover, we discovered that endogenous WNT signals are the main drivers of the hypertrophic maturation that follows chondrogenic differentiation. Inhibition of WNT signals during differentiation prevented calcification and maintained cartilage properties following implantation in a mouse model. By maintaining potency during expansion and preventing hypertrophic maturation following differentiation, the modulation of WNT signaling removes two major obstacles that impede the clinical application of MSCs in cartilage repair.

The ossification principle of the laryngeal skeleton

International Nuclear Information System (INIS)

Glass, W. von.

1981-01-01

In 94 decreased of both sexes aged 15 to 79 who had not has any affections of the larynx itself, the laryngeal skeleton was X-rayed after removing the soft parts, to demonstrate the ossification processes. Furthermore the deformation of the thyroid cartilage caused at the larynx by the laryngopharyngeal muscle in the act of swallowing was experimentally induced and determined with the aid of strain gauges. (orig.) [de

Heterotopic ossification in abdominal incision : a case report

Energy Technology Data Exchange (ETDEWEB)

Yoo, Yoon Sik; Nam, Kung Sook; Hwang, Im Kyung; Kim, Heung Chul [College of Medicine, Hallym Univ., Chuncheon (Korea, Republic of)

2001-08-01

Heterotopic ossification in abdominal incision is a rare post-surgical sequala and a subtype of myositis ossificans traumatica. Recognition of this rare condition is important because it may be misinterpreted as a retained foreign body or incisional neoplastic recurrence. We report a case involving a 59-year-old man who presented with a palpable epigastric mass and pronounced fatigability.

Heterotopic ossification of the elbow after closed reduction and retrograde intramedullary nailing for radial neck fracture treated by anconeus interposition.

Science.gov (United States)

Sreenivas, T; Menon, Jagdish; Nataraj, A R

2013-12-01

Heterotopic ossification around the elbow can lead to considerable functional disability. We describe a case of a 42-year-old man who developed heterotopic ossification of his elbow after closed reduction of the elbow dislocation and radial neck fracture and retrograde intramedullary nailing for radial neck fracture. During the follow-up after initial surgery, movements of the elbow were gradually deteriorated and diagnosed as heterotopic ossification of the elbow. Implant removal, radial head excision along with heterotopic mass, and also interposition of the anconeus muscle resulted in improvement of his elbow mobility. At 18 months of follow-up, patient had elbow flexion arc of 15°-110°, 70° of supination, and 50° of pronation without recurrence of heterotopic ossification. The uniqueness of this case lies in the treatment of heterotopic ossification of the elbow to prevent its recurrence, which was developed after retrograde intramedullary nailing for radial neck fracture following closed reduction.

Hysterescopic management of endometrial ossification as a cause of infertility: case report

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Kubilay Vicdan

2006-12-01

Full Text Available Endometrial ossification is a rare pathology, most commonly caused by retention of fetal bones following termination of pregnancy. The most frequent presentation is abnormal vaginal bleeding and discharge, dismenore, pelvic pain and secondary infertility. Here we present a new case of endometrial ossification. A 25 year old woman had attended to a gynecology clinic with a complaint of menorrhagia and vaginal discharge lasting for 3 months. Her medical history revealed a voluntarily termination of pregnancy at 12 weeks of gestation two years ago. The transvaginal ultrasonographic examination showed increased echogenity of the endometrium and calcified mass and the patient underwent D&C. The patient was referred to our clinic with a histopathological diagnosis of mature bony tissue. Hysterescopic evaluation of the patient confirmed the diagnosis and lameller bone fragments were removed. Pathology of the removed material was reported as thick trabekuller bone within endometrial glands. Posthysterescopic transvaginal sonography was normal. After hysterescopic management, the patient decided to use contraceptive pill for one year. She became pregnant spontaneously within 3 months after quiting contraceptive pill. In conclusion, endometrial ossification is a rare, iatrogenic cause of infertility which can be easily diagnosed and managed by histeroscopy.

Heterotopic Ossification of Brachialis Muscle

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Jacob George

2005-01-01

Full Text Available A 13-year-old girl with seizure disorder presented with 90º fixed flexion deformity of right elbow. She had history of encephalitis, 2 years ago, from which she recovered completely except for the deformity of the elbow. Plain X-ray revealed extensive ossification of the brachialis muscle from its origin at the lower anterior aspect of the humerus to its insertion at the coronoid process of the ulna. The alkaline phosphatase value was 500 IU. The middle segment of the ossified mass was surgically excised. The mobility of the elbow was restored and she achieved a range of movement between 45–120º.

Radiologic evaluation after posterior instrumented surgery for thoracic ossification of the posterior longitudinal ligament: union between rostral and caudal ossifications.

Science.gov (United States)

Ando, Kei; Imagama, Shiro; Ito, Zenya; Kobayashi, Kazuyoshi; Ukai, Junichi; Muramoto, Akio; Shinjo, Ryuichi; Matsumoto, Tomohiro; Nakashima, Hiroaki; Ishiguro, Naoki

2014-05-01

Retrospective clinical study. To investigate, using multislice CT images, how thoracic ossification of the posterior longitudinal ligament (OPLL) changes with time after thoracic posterior fusion surgery. Few studies have evaluated thoracic OPLL preoperatively and post using computed tomography (CT). The subjects included 19 patients (7 men and 12 women) with an average age at surgery of 52 years (38-66 y) who underwent indirect posterior decompression with corrective fusion and instrumentation at our institute. Minimum follow-up period was 1 year, and averaged 3 years 10 months (12-120 mo). Using CT images, we investigated fusion range, preoperative and postoperative Cobb angles of thoracic fusion levels, intraoperative and postoperative blood loss, operative time, hyperintense areas on preoperative MRI of thoracic spine and thickness of the OPLL on the reconstructed sagittal, multislice CT images taken before the operation and at 3 months, 6 months and 1 year after surgery. The basic fusion area was 3 vertebrae above and below the OPLL lesion. The mean operative time was 7 hours and 48 min (4 h 39 min-10 h 28 min), and blood loss was 1631 mL (160-11,731 mL). Intramedullary signal intensity change on magnetic resonance images was observed at the most severe ossification area in 18 patients. Interestingly, the rostral and caudal ossification regions of the OPLLs, as seen on sagittal CT images, were discontinuous across the disk space in all patients. Postoperatively, the discontinuous segments connected in all patients without progression of OPLL thickness by 5.1 months on average. All patients needing surgery had discontinuity across the disk space between the rostral and caudal ossified lesions as seen on CT. This discontinuity was considered to be the main reason for the myelopathy because a high-intensity area on magnetic resonance imaging was seen in 18 of 19 patients at the same level. Rigid fixation with instrumentation may allow the discontinuous segments

Association of achondroplasia with sagittal synostosis and scaphocephaly in two patients, an underestimated condition?

Science.gov (United States)

Accogli, Andrea; Pacetti, Mattia; Fiaschi, Pietro; Pavanello, Marco; Piatelli, Gianluca; Nuzzi, Daniele; Baldi, Maurizia; Tassano, Elisa; Severino, Maria Savina; Allegri, Anna; Capra, Valeria

2015-03-01

We report on two patients with an unusual combination of achondroplasia and surgically treated sagittal synostosis and scaphocephaly. The most common achondroplasia mutation, p.Gly380Arg in fibroblast growth factor receptor 3 (FGFR3), was detected in both patients. Molecular genetic testing of FGFR1, FGFR2, FGFR3 and TWIST1 genes failed to detect any additional mutations. There are several reports of achondroplasia with associated craniosynostosis, but no other cases of scaphocephaly in children with achondroplasia have been described. Recently it has been demonstrated that FGFR3 mutations affect not only endochondral ossification but also membranous ossification, providing new explanations for the craniofacial hallmarks in achondroplasia. Our report suggests that the association of isolated scaphocephaly and other craniosynostoses with achondroplasia may be under recognized. © 2015 Wiley Periodicals, Inc.

The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs.

Science.gov (United States)

Sun, Yubo; Kiraly, Alex J; Cox, Michael; Mauerhan, David R; Hanley, Edward N

2018-04-01

Phosphocitrate (PC) and its analogue, PC-β ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (Pguinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program.

Recapitulation of physiological spatiotemporal signals promotes in vitro formation of phenotypically stable human articular cartilage

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Wei, Yiyong; Zhou, Bin; Bernhard, Jonathan; Robinson, Samuel; Burapachaisri, Aonnicha; Guo, X. Edward

2017-01-01

Standard isotropic culture fails to recapitulate the spatiotemporal gradients present during native development. Cartilage grown from human mesenchymal stem cells (hMSCs) is poorly organized and unstable in vivo. We report that human cartilage with physiologic organization and in vivo stability can be grown in vitro from self-assembling hMSCs by implementing spatiotemporal regulation during induction. Self-assembling hMSCs formed cartilage discs in Transwell inserts following isotropic chondrogenic induction with transforming growth factor β to set up a dual-compartment culture. Following a switch in the basal compartment to a hypertrophic regimen with thyroxine, the cartilage discs underwent progressive deep-zone hypertrophy and mineralization. Concurrent chondrogenic induction in the apical compartment enabled the maintenance of functional and hyaline cartilage. Cartilage homeostasis, chondrocyte maturation, and terminal differentiation markers were all up-regulated versus isotropic control groups. We assessed the in vivo stability of the cartilage formed under different induction regimens. Cartilage formed under spatiotemporal regulation in vitro resisted endochondral ossification, retained the expression of cartilage markers, and remained organized following s.c. implantation in immunocompromised mice. In contrast, the isotropic control groups underwent endochondral ossification. Cartilage formed from hMSCs remained stable and organized in vivo. Spatiotemporal regulation during induction in vitro recapitulated some aspects of native cartilage development, and potentiated the maturation of self-assembling hMSCs into stable and organized cartilage resembling the native articular cartilage. PMID:28228529

Prevalence and distribution of ossification of the supra/interspinous ligaments in symptomatic patients with cervical ossification of the posterior longitudinal ligament of the spine: a CT-based multicenter cross-sectional study.

Science.gov (United States)

Mori, Kanji; Yoshii, Toshitaka; Hirai, Takashi; Iwanami, Akio; Takeuchi, Kazuhiro; Yamada, Tsuyoshi; Seki, Shoji; Tsuji, Takashi; Fujiyoshi, Kanehiro; Furukawa, Mitsuru; Nishimura, Soraya; Wada, Kanichiro; Koda, Masao; Furuya, Takeo; Matsuyama, Yukihiro; Hasegawa, Tomohiko; Takeshita, Katsushi; Kimura, Atsushi; Abematsu, Masahiko; Haro, Hirotaka; Ohba, Tetsuro; Watanabe, Masahiko; Katoh, Hiroyuki; Watanabe, Kei; Ozawa, Hiroshi; Kanno, Haruo; Imagama, Shiro; Ito, Zenya; Fujibayashi, Shunsuke; Yamazaki, Masashi; Matsumoto, Morio; Nakamura, Masaya; Okawa, Atsushi; Kawaguchi, Yoshiharu

2016-12-01

Supra/interspinous ligaments connect adjacent spinous processes and act as a stabilizer of the spine. As with other spinal ligaments, it can become ossified. However, few report have discussed ossification supra/interspinous ligaments (OSIL), so its epidemiology remains unknown. We therefore aimed to investigate the prevalence and distribution of OSIL in symptomatic patients with cervical ossification of the posterior longitudinal ligament (OPLL). The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. The whole spine CT data as well as clinical parameters such as age and sex were obtained from 20 institutions belong to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament (JOSL). The prevalence and distribution of OSIL and the association between OSIL and clinical parameters were reviewed. The sum of the levels involved by OPLL (OP-index) and OSIL (OSI-index) as well as the prevalence of ossification of the nuchal ligament (ONL) were also investigated. A total of 234 patients with a mean age of 65 years was recruited. The CT-based evidence of OSIL was noted in 68 (54 males and 14 females) patients (29%). The distribution of OSIL showed a significant thoracic preponderance. In OSIL-positive patients, single-level involvement was noted in 19 cases (28%), whereas 49 cases (72%) presented multi-level involvement. We found a significant positive correlation between the OP-index grade and OSI-index. ONL was noted at a significantly higher rate in OSIL-positive patients compared to negative patients. The prevalence of OSIL in symptomatic patients with cervical OPLL was 29%. The distribution of OSIL showed a significant thoracic preponderance.

Regulation of extracellular matrix vesicles via rapid responses to steroid hormones during endochondral bone formation.

Science.gov (United States)

Asmussen, Niels; Lin, Zhao; McClure, Michael J; Schwartz, Zvi; Boyan, Barbara D

2017-12-09

Endochondral bone formation is a precise and highly ordered process whose exact regulatory framework is still being elucidated. Multiple regulatory pathways are known to be involved. In some cases, regulation impacts gene expression, resulting in changes in chondrocyte phenotypic expression and extracellular matrix synthesis. Rapid regulatory mechanisms are also involved, resulting in release of enzymes, factors and micro RNAs stored in extracellular matrisomes called matrix vesicles. Vitamin D metabolites modulate endochondral development via both genomic and rapid membrane-associated signaling pathways. 1α,25-dihydroxyvitamin D3 [1α,25(OH) 2 D 3 ] acts through the vitamin D receptor (VDR) and a membrane associated receptor, protein disulfide isomerase A3 (PDIA3). 24R,25-dihydroxyvitamin D3 [24R,25(OH) 2 D 3 ] affects primarily chondrocytes in the resting zone (RC) of the growth plate, whereas 1α,25(OH) 2 D 3 affects cells in the prehypertrophic and upper hypertrophic cell zones (GC). This includes genomically directing the cells to produce matrix vesicles with zone specific characteristics. In addition, vitamin D metabolites produced by the cells interact directly with the matrix vesicle membrane via rapid signal transduction pathways, modulating their activity in the matrix. The matrix vesicle payload is able to rapidly impact the extracellular matrix via matrix processing enzymes as well as providing a feedback mechanism to the cells themselves via the contained micro RNAs. Copyright © 2017. Published by Elsevier Inc.

Constitutive stimulatory G protein activity in limb mesenchyme impairs bone growth.

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Karaca, Anara; Malladi, Vijayram Reddy; Zhu, Yan; Tafaj, Olta; Paltrinieri, Elena; Wu, Joy Y; He, Qing; Bastepe, Murat

2018-05-01

GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsα) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsα, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsα activity also impairs bone growth. Here we generated mice expressing a constitutively active Gsα mutant (Gsα-R201H) conditionally upon Cre recombinase (cGsα R201H mice). Gsα-R201H was expressed in cultured bone marrow stromal cells from cGsα R201H mice upon adenoviral-Cre transduction. When crossed with mice in which Cre is expressed in a tamoxifen-regulatable fashion (CAGGCre-ER™), tamoxifen injection resulted in mosaic expression of the transgene in double mutant offspring. We then crossed the cGsα R201H mice with Prx1-Cre mice, in which Cre is expressed in early limb-bud mesenchyme. The double mutant offspring displayed short limbs at birth, with narrow hypertrophic chondrocyte zones in growth plates and delayed formation of secondary ossification center. Consistent with enhanced Gsα signaling, bone marrow stromal cells from these mice demonstrated increased levels of c-fos mRNA. Our findings indicate that constitutive Gsα activity during limb development disrupts endochondral ossification and bone growth. Given that Gsα haploinsufficiency also leads to short bones, as in patients with Albright's hereditary osteodystrophy, these results suggest that a tight control of Gsα activity is essential for normal growth plate physiology. Copyright © 2018 Elsevier Inc. All rights reserved.

Femoral Head Bone Loss Following Short and Long-Duration Spaceflight

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Blaber, Elizabeth A.; Cheng-Campbell, Margareth A.; Almeida, Eduardo A. C.

2016-01-01

Exposure to mechanical unloading during spaceflight is known to have significant effects on the musculoskeletal system. Our ongoing studies with the mouse bone model have identified the failure of normal stem cell-based tissue regeneration, in addition to tissue degeneration, as a significant concern for long-duration spaceflight, especially in the mesenchymal and hematopoietic tissue lineages. The 30-day BionM1 and the 37-day Rodent Research 1 (RR1) missions enabled the possibility of studying these effects in long-duration microgravity experiments. We hypothesized that the inhibition of stem cell-based tissue regeneration in short-duration spaceflight would continue during long-duration spaceflight and furthermore would result in significant tissue alterations. MicroCT analysis of BionM1 femurs revealed 31 decrease in bone volume ratio, a 14 decrease in trabecular thickness, and a 20 decrease in trabecular number in the femoral head of space-flown mice. Furthermore, high-resolution MicroCT and immunohistochemical analysis of spaceflight tissues revealed a severe disruption of the epiphyseal boundary, resulting in endochondral ossification of the femoral head and perforation of articular cartilage by bone. This suggests that spaceflight in microgravity may cause rapid induction of an aging-like phenotype with signs of osteoarthritic disease in the hip joint. However, mice from RR1 exhibited significant bone loss in the femoral head but did not exhibit the severe aging and disease-like phenotype observed during BionM1. This may be due to increased physical activity in the RH hardware. Immunohistochemical analysis of the epiphyseal plate and investigation of cellular proliferation and differentiation pathways within the marrow compartment and whole bone tissue is currently being conducted to determine alterations in stem cell-based tissue regeneration between these experiments. Our results show that the observed inhibition of stem cell-based tissue regeneration

Physiologic and pathologic calcifications and ossifications in the face and neck

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Keberle, M. [Medizinische Hochschule Hannover, Diagnostische Radiologie, Hannover (Germany); Robinson, S. [DiagnoseZentrumUrania, Wien (Austria)

2007-08-15

The aim was to give a systematic presentation of physiologic and pathologic calcifications and ossifications in the face and neck with a special emphasis on clinical relevance. In a sometimes subacute setting one should recognize specific calcifications which often lead to important diagnoses such as fungal sinusitis or sclerosing labyrinthitis. In a more chronic situation intraocular calcifications in small children are pathognomonic for retinoblastoma. Juxtatumoral sclerosis of the laryngeal cartilage in laryngopharyngeal carcinoma is usually caused by tumor infiltration of the cartilage resulting in a higher tumor stage and, this way, has a major impact on the therapeutical strategy. Calcified lymph nodes are mainly unspecific but can be the result of tuberculosis or metastases of thyroid cancer. Cross-sectional imaging methods, most of all computed tomography, are ideally suited to reveal head and neck calcifications and ossifications, especially those which are clinically relevant. (orig.)

Ossificação pulmonar dendriforme Dendriform pulmonary ossification

Directory of Open Access Journals (Sweden)

Andrezza Araújo de Oliveira Duarte

2006-06-01

Full Text Available A ossificação pulmonar difusa é uma condição rara, de etiologia desconhecida, na qual osso maduro é encontrado no parênquima pulmonar. É quase sempre descoberta como um achado incidental de autópsias. Freqüentemente afeta homens de meia-idade e é assintomática. Relata-se o caso de um paciente de 75 anos, que apresentou uma radiografia torácica com comprometimento pulmonar difuso e cujo diagnóstico foi baseado no exame histopatológico de fragmento pulmonar obtido através da biópsia a céu aberto, o qual demonstrou fibrose intersticial acentuada com ossificação do parênquima pulmonar.Diffuse pulmonary ossification is a rare condition of unknown pathogenesis in which mature bone is found in the pulmonary parenchyma. It is almost invariably discovered as an incidental finding at autopsy. Most commonly, it affects middle-aged men and is asymptomatic. We present the case of a 75-year-old man in which the chest X-ray showed diffuse interstitial infiltrate. Diagnosis was based on histopathological examination by open-lung biopsy, which revealed interstitial fibrosis with pulmonary ossification.

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification.

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Yamashita, Kyoko; Kohashi, Kenichi; Yamada, Yuichi; Ishii, Takeaki; Nishida, Yoshihiro; Urakawa, Hiroshi; Ito, Ichiro; Takahashi, Mitsuru; Inoue, Takeshi; Ito, Masafumi; Ohara, Yuuki; Oda, Yoshinao; Toyokuni, Shinya

2018-04-01

Ossification is found occasionally in dedifferentiated liposarcoma (DDLPS). The aims of this study were to elucidate whether the formed bone tissue is usually produced by tumour cells or by reactive non-neoplastic cells, and to reveal the clinicopathological characteristics of DDLPS with ossification. We examined 36 cases of ossified DDLPS by comparing them to 31 cases of non-ossified DDLPS. MDM2 amplification was confirmed in osteocytes and/or osteoblastic cells in all but one ossified DDLPS cases (27 of 28) using fluorescence in-situ hybridisation, although the morphological impression of ossification appeared to be mainly metaplastic (27 of 36) or high-grade osteosarcoma-like (six of 36). The bone tissue was often formed predominantly at the periphery of the DDLPS area near the well-differentiated liposarcoma component (18 of 36), and an organised structure such as bone marrow-like differentiation was not uncommon (12 of 36). According to a modified French Fédération Nationale des Centers de Lutte Contre le Cancer (FNCLCC) grading system, ossified DDLPS tended to be lower grade than non-ossified DDLPS (mean grade: 1.88 and 2.15, respectively). Ossification in DDLPS was associated significantly with shorter local recurrence-free survival by multivariate analysis (P = 0.02347), but metaplastic-appearing ossification tended to be associated with longer overall survival (P = 0.1400). The bone tissue formed in DDLPS was mainly neoplastic regardless of its morphology and maturity, which highlighted the osteogenic differentiation of the tumour cells. DDLPS patients with osteogenic differentiation tended to suffer from earlier local recurrences, which did not necessarily lead to poor life outcomes. © 2017 John Wiley & Sons Ltd.

CT and MRI characteristics of ossification of the ligamenta flava in the thoracic spine

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Xiong, L. [Dept. of Radiology, University of Texas Health Science Center, San Antonio, TX (United States); Zeng, Q.Y. [Dept. of Radiology, General Coal Hospital, Beijing (China); Jinkins, J.R. [Dept. of Radiology, School of Medicine, Philadelphia, PA (United States)

2001-09-01

The purpose of this study was to compare MRI findings with CT findings of mass-forming calcification/ossification of the thoracic ligamenta flava (OTLF). Twenty-one Chinese patients presented with clinical evidence of chronic and progressive thoracic spinal cord compression which included: difficulty in walking; weakness; and/or numbness of the extremities, back pain, and lower extremity paresthesias. Axial and sagittal T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) were performed through the thoracic spine on a 1.0-T Impact unit (Siemens, Erlangen, Germany). Axial CT was obtained with 5-mm contiguous sections through the thoracic region. Decompressive surgery with resection of the OTLF were carried out in all patients. Low signal intensity of the mass-forming OTLF was demonstrated at a single level (n=1) or at multiple levels (n=20) on both T1WI and T2WI. The distribution of OTLF was bilateral at all levels identified in 6 cases, unilateral at all levels in 5 patients, and both unilateral and bilateral at different levels in 10 cases. Ossification of the thoracic ligamenta flava involved the upper thoracic spine (T1-4) in 3 cases, midthoracic spine (T5-8) in 3 cases, lower thoracic spine (T9-12) in 10 cases, and more than one thoracic spinal subregion in 5 cases. Computed tomography confirmed the MR findings regarding the location and distribution of OTLF in all cases, as well as the associated evidence of central spinal canal stenosis. In addition, 5 patients revealed associated ossification of the posterior longitudinal ligament. All patients demonstrated gradual, but incomplete, clinical improvement of the radiculomyelopathy following decompressive surgery. Ossification of the posterior longitudinal ligament resulting in thoracic central spinal canal stenosis and clinical radiculomyelopathy is not uncommon in the Asian people. Ossification of the thoracic ligamenta flava can be accurately evaluated equally well by CT and MR with regard to level

CT and MRI characteristics of ossification of the ligamenta flava in the thoracic spine

International Nuclear Information System (INIS)

Xiong, L.; Zeng, Q.Y.; Jinkins, J.R.

2001-01-01

The purpose of this study was to compare MRI findings with CT findings of mass-forming calcification/ossification of the thoracic ligamenta flava (OTLF). Twenty-one Chinese patients presented with clinical evidence of chronic and progressive thoracic spinal cord compression which included: difficulty in walking; weakness; and/or numbness of the extremities, back pain, and lower extremity paresthesias. Axial and sagittal T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) were performed through the thoracic spine on a 1.0-T Impact unit (Siemens, Erlangen, Germany). Axial CT was obtained with 5-mm contiguous sections through the thoracic region. Decompressive surgery with resection of the OTLF were carried out in all patients. Low signal intensity of the mass-forming OTLF was demonstrated at a single level (n=1) or at multiple levels (n=20) on both T1WI and T2WI. The distribution of OTLF was bilateral at all levels identified in 6 cases, unilateral at all levels in 5 patients, and both unilateral and bilateral at different levels in 10 cases. Ossification of the thoracic ligamenta flava involved the upper thoracic spine (T1-4) in 3 cases, midthoracic spine (T5-8) in 3 cases, lower thoracic spine (T9-12) in 10 cases, and more than one thoracic spinal subregion in 5 cases. Computed tomography confirmed the MR findings regarding the location and distribution of OTLF in all cases, as well as the associated evidence of central spinal canal stenosis. In addition, 5 patients revealed associated ossification of the posterior longitudinal ligament. All patients demonstrated gradual, but incomplete, clinical improvement of the radiculomyelopathy following decompressive surgery. Ossification of the posterior longitudinal ligament resulting in thoracic central spinal canal stenosis and clinical radiculomyelopathy is not uncommon in the Asian people. Ossification of the thoracic ligamenta flava can be accurately evaluated equally well by CT and MR with regard to level

Characterization of ossification of the posterior rim of acetabulum in the developing hip and its impact on the assessment of femoroacetabular impingement.

Science.gov (United States)

Morris, William Z; Chen, Jason Y; Cooperman, Daniel R; Liu, Raymond W

2015-02-04

Many radiographic indices that are used to assess adolescents for femoroacetabular impingement rely on an ossified posterior acetabular wall. A recent study identified a secondary ossification center in the posterior rim of the acetabulum, the ossification of which may affect perceived acetabular coverage. The purpose of this study was to characterize ossification of the posterior rim of the acetabulum with use of a longitudinal radiographic study and quantify its impact on the radiographic assessment of femoroacetabular impingement. In this study, we utilized a historical collection of annual radiographs made in a population of healthy adolescents. Six hundred and twelve anteroposterior radiographs of the left hip of ninety-eight patients were reviewed to identify the appearance, duration, and fusion of the secondary ossification center in the posterior rim of the acetabulum. The center-edge angle was then measured before appearance and after fusion of the secondary ossification center in a subset of ten patients who had 40°), the use of radiographs in adolescents with incompletely ossified hips may lead to misinterpretation of acetabular coverage. In patients with open triradiate cartilage, magnetic resonance imaging may be considered for the assessment of femoroacetabular impingement. The posterior rim ossification sign is a normal finding in adolescent hip development and has important implications for the proper evaluation of femoroacetabular impingement. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.

Does Excision of Heterotopic Ossification of the Elbow Result in Satisfactory Patient-Rated Outcomes?

Science.gov (United States)

Sandeep, K N; Suresh, G; Gopisankar, B; Abhishek, N; Sujiv, A

2017-03-01

Treatment of heterotopic ossification (HO) of the elbow is challenging and fraught with complications. Patients who sustain direct trauma to the elbow joint, the central nervous system, and thermal burns are at increased risk for development of HO. There is a paucity of studies and reports on patient's self-evaluation after the excision of the heterotopic ossification. This retrospective study assessed outcomes after excision of heterotopic ossification around the elbow in a cohort of ten patients operated from 2012 to 2015. The outcome assessment was done by the Mayo Elbow Performance index (MEPI) and the American Shoulder and Elbow Surgeons-Elbow score (ASES-E scores). The mean follow-up was 18.11 months after the operation. The Mayo Elbow Performance Score was excellent in two elbows, good in six and fair in two. The mean gain in flexion-extension arc after excision of HO was 80 degrees. All of the patients had residual flexion deformity postoperatively. Eight of the nine patients were able to do activities requiring flexion at final follow-up. Excision of HO around the elbow is associated with satisfactory patient-rated outcomes in spite of failure to regain full range of motion.

Pseudo-Acetabulum due to Heterotopic Ossification in a Child with Post Traumatic Neglected Posterior Hip Dislocation.

Science.gov (United States)

Pathak, Aditya C; Patil, Atul K; Sheth, Binoti; Bansal, Rohan

2012-01-01

Traumatic neglected dislocations of hip in children are rare entity. Neglected traumatic dislocations of hip in children along with heterotopic ossification are still rare. Post traumatic neglected hip dislocations are to be diagnosed as early as possible and have to be treated with precision and aggression as the outcome of treatment for the same is not predictable. 5 year female with post-traumatic neglected hip dislocation with heterotopic ossification forming a pseudoacetabulum postero-superiorly in which femur head was lodged. The girl was operated by open reduction using Moore's Posterior approach and showed good results. Here is a mention of a rare case with a good 18 months follow up with no complication. Post-traumatic neglected posterior hip dislocation mostly requires open reduction and relocation of femoral head in original acetabulum with concentric reduction. Heterotopic ossification is a rare but known complication of traumatic dislocation of hip in children. Good results can be achieved in such cases and regular follow-up of patient is required post-operatively.

Gender-specific pattern differences of the ossification centers in the pediatric elbow

International Nuclear Information System (INIS)

Patel, Bijal; Reed, Martin; Patel, Shamir

2009-01-01

Only a limited number of studies have investigated the age ranges in which the secondary centers of the elbow appear and ossify. Knowledge of sequence, gender differences and age ranges can aid in accurate assessment of radiographs, especially in cases of injury. To determine the sequence and general age ranges in which each ossification center both appears and fuses, and also to identify differences between genders. This study included 412 sets of radiographs of children's elbows that were analyzed prospectively by a single experienced pediatric radiologist. The presence as well as state of fusion of each ossification center was noted. The ages of the children ranged from 2 months to 17 years. In girls, the radial head and medial epicondyle appeared at the same age. In boys, there was a trend towards the radial head appearing earlier than the medial epicondyle. There was no statistically significant difference between the age at which the trochlea and olecranon appeared. Our results demonstrate a statistically significant difference between genders in both appearance and fusion. All centers both appeared and fused earlier in girls, with the exception of the appearance of the capitellum. The sequence of appearance and fusion was similar between genders. Ossification centers at the elbow both appear and fuse earlier in females but the normal range in age for the times of appearance and fusion of these centers is quite wide for both sexes. (orig.)

Radiation therapy of hyperplastic heterotopic ossifications in osteogenesis imperfecta; Two case reports. Strahlentherapie hyperplastischer heterotoper Ossifikationen bei Osteogenesis imperfecta; Zwei Falldarstellungen

Energy Technology Data Exchange (ETDEWEB)

Micke, O. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Strahlentherapie - Radioonkologie); Wagner, W. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Strahlentherapie - Radioonkologie); Poetter, R. (Allgemeines Krankenhaus der Stadt Wien, Vienna (Austria). Universitaetsklinik fuer Strahlentherapie und Strahlenbiologie); Prott, F.J. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Strahlentherapie - Radioonkologie); Karbowski, A. (Muenster Univ. (Germany). Klinik und Poliklinik fuer Allgemeine Orthopaedie)

1994-06-01

Purpose: Osteogenesis imperfecta is a rare hereditary disease of connective tissue with a genetic defect in collagen synthesis. In osteogenesis imperfecta hyperplastic heterotopic ossification can be induced by hyperplastic callus formation caused by trauma or operation. Heterotopic ossifications can be found in numerous benign diseases. The successful use of low dose radiotherapy in the treatment of heterotopic ossifications in well-known from the literature. Patients and Methods: We treated two children (a 13-year old girl and a ten-year old boy) with heterotopic ossifications of the lower extremities in osteogenesis imperfecta type IV (Lobstein) with a low dose irradiation (10x1 Gy, respectively 6x1 Gy) under megavoltage conditions. Results: After radiotherapy the children were painfree and the hyperplastic callus was considerably reduced. The previously immobilized patients could partly be mobilized. Thereby it could be contributed to the rehabilitation of the patients. New hyperplastic callus formation was not observed in the irradiated areas so far. Conclusion: Analogous to the successful radiation of heterotopic ossifications in other benign diseases radiation therapy seems to be a successful treatment of hyperplastic callus formation in osteogenesis imperfecta. Despite the late risks of radiotherapy radiation treatment of benign diseases in children might be indicated. (orig.)

Effects of a 4.7 T static magnetic field on fetal development in ICR mice

International Nuclear Information System (INIS)

Okazaki, Ryuji; Ootsuyama, Akira; Uchida, Soshi; Norimura, Toshiyuki

2001-01-01

In order to determine the effects of a 4.7 T static magnetic field (SMF) on fetal development in mice, we evaluated fetal teratogenesis and endochondral ossification following exposure in utero. Pregnant ICR mice were exposed to a 4.7 T SMF from day 7.5 to 9.5 of gestation in a whole-body dose, and sacrificed on day 18.5 of gestation. We examined with incidence of prenatal death, external malformations and fetal skeletal malformations. There were no significant differences observed in the incidence of prenatal death and/or malformations between SMF-exposed mice and control mice. Further, we evaluated the immunoreactivity for the vascular endothelial growth factor (VEGF), which is implicated in angiogenesis and osteogenesis, in the sternum of fetal mice following magnetic exposure. Our studies also indicated that on day 16.5 of gestation following SMF exposure, the immunoreactivity for VEGF was increased compared to unexposed controls. However, it was decreased in the exposed group compared to the control group on day 18.5 of gestation. DNA and proteoglycan (PG) synthesis were also measured in rabbit costal growth plate chondrocytes in vitro. No significant differences were observed in DNA synthesis between the SMF exposed chondrocytes and the control chondrocytes; however, PG synthesis in SMF exposed chondrocytes increased compared to the controls. Based on these results, we suggest that while SMF exposure promoted the endochondral ossification of chondrocytes, it did not induce any harmful effects on fetal development in ICR mice. (author)

Effects of a 4.7 T static magnetic field on fetal development in ICR mice

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Okazaki, Ryuji; Ootsuyama, Akira; Uchida, Soshi; Norimura, Toshiyuki [Univ. of Occupational and Environmental Health, Kitakyushu, Fukuoka (Japan). School of Medicine

2001-09-01

In order to determine the effects of a 4.7 T static magnetic field (SMF) on fetal development in mice, we evaluated fetal teratogenesis and endochondral ossification following exposure in utero. Pregnant ICR mice were exposed to a 4.7 T SMF from day 7.5 to 9.5 of gestation in a whole-body dose, and sacrificed on day 18.5 of gestation. We examined with incidence of prenatal death, external malformations and fetal skeletal malformations. There were no significant differences observed in the incidence of prenatal death and/or malformations between SMF-exposed mice and control mice. Further, we evaluated the immunoreactivity for the vascular endothelial growth factor (VEGF), which is implicated in angiogenesis and osteogenesis, in the sternum of fetal mice following magnetic exposure. Our studies also indicated that on day 16.5 of gestation following SMF exposure, the immunoreactivity for VEGF was increased compared to unexposed controls. However, it was decreased in the exposed group compared to the control group on day 18.5 of gestation. DNA and proteoglycan (PG) synthesis were also measured in rabbit costal growth plate chondrocytes in vitro. No significant differences were observed in DNA synthesis between the SMF exposed chondrocytes and the control chondrocytes; however, PG synthesis in SMF exposed chondrocytes increased compared to the controls. Based on these results, we suggest that while SMF exposure promoted the endochondral ossification of chondrocytes, it did not induce any harmful effects on fetal development in ICR mice. (author)

Circulating osteogentic precursor cells in non-hereditary heterotopic ossification.

Science.gov (United States)

Egan, Kevin P; Duque, Gustavo; Keenan, Mary Ann; Pignolo, Robert J

2018-04-01

Non-hereditary heterotopic ossification (NHHO) may occur after musculoskeletal trauma, central nervous system (CNS) injury, or surgery. We previously described circulating osteogenic precursor (COP) cells as a bone marrow-derived type 1 collagen + CD45 + subpopulation of mononuclear adherent cells that are able of producing extraskeletal ossification in a murine in vivo implantation assay. In the current study, we performed a tissue analysis of COP cells in NHHO secondary to defined conditions, including traumatic brain injury, spinal cord injury, cerebrovascular accident, trauma without neurologic injury, and joint arthroplasty. All bone specimens revealed the presence of COP cells at 2-14 cells per high power field. COP cells were localized to early fibroproliferative and neovascular lesions of NHHO with evidence for their circulatory status supported by their presence near blood vessels in examined lesions. This study provides the first systematic evaluation of COP cells as a contributory histopathological finding associated with multiple forms of NHHO. These data support that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites, such as those subject to soft tissue injury, and due to their migratory nature, may likely be involved in seeding sites distant to CNS injury. Copyright © 2018 Elsevier Inc. All rights reserved.

The Nuclear Factor of Activated T Cells (Nfat) Transcription Factor Nfatp (Nfatc2) Is a Repressor of Chondrogenesis

Science.gov (United States)

Ranger, Ann M.; Gerstenfeld, Louis C.; Wang, Jinxi; Kon, Tamiyo; Bae, Hyunsu; Gravallese, Ellen M.; Glimcher, Melvin J.; Glimcher, Laurie H.

2000-01-01

Nuclear factor of activated T cells (NFAT) transcription factors regulate gene expression in lymphocytes and control cardiac valve formation. Here, we report that NFATp regulates chondrogenesis in the adult animal. In mice lacking NFATp, resident cells in the extraarticular connective tissues spontaneously differentiate to cartilage. These cartilage cells progressively differentiate and the tissue undergoes endochondral ossification, recapitulating the development of endochondral bone. Proliferation of already existing articular cartilage cells also occurs in some older animals. At both sites, neoplastic changes in the cartilage cells occur. Consistent with these data, NFATp expression is regulated in mesenchymal stem cells induced to differentiate along a chondrogenic pathway. Lack of NFATp in articular cartilage cells results in increased expression of cartilage markers, whereas overexpression of NFATp in cartilage cell lines extinguishes the cartilage phenotype. Thus, NFATp is a repressor of cartilage cell growth and differentiation and also has the properties of a tumor suppressor. PMID:10620601

Noonan syndrome-causing SHP2 mutants impair ERK-dependent chondrocyte differentiation during endochondral bone growth.

Science.gov (United States)

Tajan, Mylène; Pernin-Grandjean, Julie; Beton, Nicolas; Gennero, Isabelle; Capilla, Florence; Neel, Benjamin G; Araki, Toshiyuki; Valet, Philippe; Tauber, Maithé; Salles, Jean-Pierre; Yart, Armelle; Edouard, Thomas

2018-04-12

Growth retardation is a constant feature of Noonan syndrome (NS) but its physiopathology remains poorly understood. We previously reported that hyperactive NS-causing SHP2 mutants impair the systemic production of insulin-like growth factor 1 (IGF1) through hyperactivation of the RAS/extracellular signal-regulated kinases (ERK) signalling pathway. Besides endocrine defects, a direct effect of these mutants on growth plate has not been explored, although recent studies have revealed an important physiological role for SHP2 in endochondral bone growth. We demonstrated that growth plate length was reduced in NS mice, mostly due to a shortening of the hypertrophic zone and to a lesser extent of the proliferating zone. These histological features were correlated with decreased expression of early chondrocyte differentiation markers, and with reduced alkaline phosphatase staining and activity, in NS murine primary chondrocytes. Although IGF1 treatment improved growth of NS mice, it did not fully reverse growth plate abnormalities, notably the decreased hypertrophic zone. In contrast, we documented a role of RAS/ERK hyperactivation at the growth plate level since 1) NS-causing SHP2 mutants enhance RAS/ERK activation in chondrocytes in vivo (NS mice) and in vitro (ATDC5 cells) and 2) inhibition of RAS/ERK hyperactivation by U0126 treatment alleviated growth plate abnormalities and enhanced chondrocyte differentiation. Similar effects were obtained by chronic treatment of NS mice with statins.In conclusion, we demonstrated that hyperactive NS-causing SHP2 mutants impair chondrocyte differentiation during endochondral bone growth through a local hyperactivation of the RAS/ERK signalling pathway, and that statin treatment may be a possible therapeutic approach in NS.

The Contribution of Genotype to Heterotopic Ossification after Orthopaedic Trauma

Science.gov (United States)

2010-05-01

examine the  relationship  of genetics to the Heterotopic Ossification phenotype  To date, we have accrued 6000 patients with specimens in our genetics...Haque S, Ahmad M, et al. Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial

Intracapsular and para-articular chondroma adjacent to large joints: report of three cases and review of the literature

International Nuclear Information System (INIS)

Gonzalez-Lois, C.; Garcia-de-la-Torre, J.P.; SantosBriz-Terron, A.; Martinez-Tello, F.J.; Vila, J.; Manrique-Chico, J.

2001-01-01

Para-articular chondroma is a rare tumor that has been reported in only 30 cases adjacent to large joints in the Anglo-Saxon literature. We report three new cases of this entity, describe its clinical, radiological and pathological features, and review the previous literature. Para-articular chondromas have an insidious clinical presentation and on radiographs show a large soft tissue mass with variable ossification. They appear as a lobulated mass of hyaline cartilage with variable endochondral ossification in the central area. These rare benign tumors arise from the capsule or the para-articular connective tissue of a large joint (mainly the knee), which suffers cartilaginous metaplasia and subsequent ossification. Cases 1 and 2 of this presentation fit all the features described previously. Case 3 has identical clinical features but differs from the former two cases in its microscopic appearance, being composed almost entirely of fibrocartilage and myxoid areas within the fibroadipose tissue of the joint instead of mature trabecular bone surrounded by hyaline cartilage. To the best of our knowledge this is the first description of this histological variant of para-articular chondroma. (orig.)

Intracapsular and para-articular chondroma adjacent to large joints: report of three cases and review of the literature

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Gonzalez-Lois, C.; Garcia-de-la-Torre, J.P.; SantosBriz-Terron, A.; Martinez-Tello, F.J. [Dept. of Pathology, University Hospital ' ' Doce de Octubre' ' , Madrid (Spain); Vila, J. [Dept. of Orthopedics and Traumatology, University Hospital ' ' Doce de Octubre' ' , Madrid (Spain); Manrique-Chico, J. [Dept. of Radiology, University Hospital ' ' Doce de Octubre' ' , Madrid (Spain)

2001-12-01

Para-articular chondroma is a rare tumor that has been reported in only 30 cases adjacent to large joints in the Anglo-Saxon literature. We report three new cases of this entity, describe its clinical, radiological and pathological features, and review the previous literature. Para-articular chondromas have an insidious clinical presentation and on radiographs show a large soft tissue mass with variable ossification. They appear as a lobulated mass of hyaline cartilage with variable endochondral ossification in the central area. These rare benign tumors arise from the capsule or the para-articular connective tissue of a large joint (mainly the knee), which suffers cartilaginous metaplasia and subsequent ossification. Cases 1 and 2 of this presentation fit all the features described previously. Case 3 has identical clinical features but differs from the former two cases in its microscopic appearance, being composed almost entirely of fibrocartilage and myxoid areas within the fibroadipose tissue of the joint instead of mature trabecular bone surrounded by hyaline cartilage. To the best of our knowledge this is the first description of this histological variant of para-articular chondroma. (orig.)

Risk of symptomatic heterotopic ossification following plate osteosynthesis in multiple trauma patients: an analysis in a level-1 trauma centre

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Pape Hans-Christoph

2009-10-01

Full Text Available Abstract Background Symptomatic heterotopic ossification (HO in multiple trauma patients may lead to follow up surgery, furthermore the long-term outcome can be restricted. Knowledge of the effect of surgical treatment on formation of symptomatic heterotopic ossification in polytrauma is sparse. Therefore, we test the effects of surgical treatment (plate osteosynthesis or intramedullary nailing on the formation of heterotopic ossification in the multiple trauma patient. Methods We retrospectively analysed prospectively documented data of blunt multiple trauma patients with long bone fractures which were treated at our level-1 trauma centre between 1997 and 2005. Patients were distributed to 2 groups: Patients treated by intramedullary nails (group IMN or plate osteosynthesis (group PLATE were compared. The expression and extension of symptomatic heterotopic ossifications on 3-6 months follow-up x-rays in antero-posterior (ap and lateral views were classified radiologically and the maximum expansion was measured in millimeter (mm. Additionally, ventilation time, prophylactic medication like indomethacine and incidence and correlation of head injuries were analysed. Results 101 patients were included in our study, 79 men and 22 women. The fractures were treated by intramedullary nails (group IMN n = 50 or plate osteosynthesis (group PLATE n = 51. Significantly higher radiologic ossification classes were detected in group PLATE (2.9 ± 1.3 as compared to IMN (2.2 ± 1.1; p = 0.013. HO size in mm ap and lateral showed a tendency towards larger HOs in the PLATE group. Additionally PLATE group showed a higher rate of articular fractures (63% vs. 28% in IMN while IMN demonstrated a higher rate of diaphyseal fractures (72% vs. 37% in PLATE; p = 0.003. Ventilation time, indomethacine and incidence of head injuries showed no significant difference between groups. Conclusion Fracture care with plate osteosynthesis in polytrauma patients is associated with

Surgical excision of heterotopic ossification of hip in a rare case of Moyamoya disease with extra articular ankylosis

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Dhanasekararaja Palanisami

2012-01-01

Full Text Available We report a case of isolated ossification of iliopsoas with ankylosis of the left hip in a 27-year-old female. The patient was diagnosed to have Moyamoya disease, a rare chronic occlusive disorder of cerebrovascular circulation following an acute onset of hemiplegia. The patient presented 9 months later to us with ankylosis of left hip which was successfully treated by surgical excision of the heterotopic bone and there was no recurrence at the end of 5 years. A review of literature failed to reveal a similar case with isolated and complete ossification of iliopsoas muscle associated with Moyamoya disease which required surgical intervention. Surgical excision resulted in dramatic improvement in the quality of life. Surgical excision of neurogenic type of heterotopic ossification is a very successful procedure and timely intervention after maturity of mass is very important to prevent the onset of secondary complications and to avoid recurrence.

Wrist ultrasonography of ossification centers during the adolescent growth spurt

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Nessi, Renato; Zaffaroni, Roberto; Lazzerini, Francesco; Garattini, Giovanna; Bazzini, Elena

1997-01-01

High-resolution ultrasound (US) of the hand and wrist was compared with radiography in 26 patients (mean age: 11.4 years) to be submitted to orthodontic therapy. US scans were targeted on the ossification centers critical for the growth spurt, namely the pisiform and abductor sesamoid bones of the metacarpophalaneal joint of the thumb and the cartilage of the distal phalanx of the third finger. All images were retrospectively reviewed on a double-blind basis by two independent observers who gave a conspicuity score to each structure of interest. All the scores were submitted to statistical analysis with the Wilcoxon test. US images clearly demonstrated the initial appearance of the ossification centers of the pisiform and sesamoid bones. These structures appeared as hyperechoic spots causing marked acoustic shadowing. The persistence of the phalangeal cartilage was depicted as a thin rim interrupting the hyperechoic cortical profile of the bone. Us results were statistically equivalent to radiographic findings in the pisiform. A statistically significant difference between the two techniques was found in the third finger cartilage because its profile was poorly depicted on some US images. To conclude, wrist US is proposed as a simple and valuable radiation-free support examination for the follow-up of skeletal maturation in adolescents to be submitted to orthodontic therapy

Bone marrow blood vessel ossification and "microvascular dead space" in rat and human long bone.

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Prisby, Rhonda D

2014-07-01

Severe calcification of the bone microvascular network was observed in rats, whereby the bone marrow blood vessels appeared ossified. This study sought to characterize the magnitude of ossification in relation to patent blood vessels and adipocyte content in femoral diaphyses. Additionally, this study confirmed the presence of ossified vessels in patients with arteriosclerotic vascular disease and peripheral vascular disease and cellulitis. Young (4-6 month; n=8) and old (22-24 month; n=8) male Fischer-344 rats were perfused with barium sulfate to visualize patent bone marrow blood vessels. Femoral shafts were processed for bone histomorphometry to quantify ossified (Goldner's Trichrome) and calcified (Alizarin Red) vessels. Adipocyte content was also determined. Additional femora (n=5/age group) were scanned via μCT to quantify microvascular ossification. Bone marrow blood vessels from the rats and the human patients were also isolated and examined via microscopy. Ossified vessels (rats and humans) had osteocyte lacunae on the vessel surfaces and "normal" vessels were transitioning into bone. The volume of ossified vessels was 4800% higher (pnecrosis. Progression of bone microvascular ossification may provide the common link associated with age-related changes in bone and bone marrow. The clinical implications may be evident in the difficulties treating bone disease in the elderly. Copyright © 2014 Elsevier Inc. All rights reserved.

Pannus inflammation in sacroiliitis following immune pathological injury and radiological structural damage: a study of 193 patients with spondyloarthritis.

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Wang, Dan Min; Lin, Ling; Peng, Jian Hua; Gong, Yao; Hou, Zhi Duo; Chen, Su Biao; Xiao, Zheng Yu

2018-06-08

The pathogenesis of sacroiliitis is unclear; therefore, we aimed to systematically study the immunopathology of sacroiliitis in patients with axial spondyloarthritis (axSpA), and explore the relationship between pannus formation, inflammation, and the structural damage caused by sacroiliitis. Fine needle aspiration biopsy of the sacroiliac joint (SIJ) was performed in 193 patients with axSpA. Clinical, laboratory, and imaging data were collected at baseline and during the follow up. Immunohistochemistry analysis was performed to detect CD34+ microvessels, CD68+ osteoclasts/macrophages, vascular endothelial growth factor (VEGF), metalloproteinase-3 (MMP-3), tumor necrosis factor-α (TNF-α), and caspase-3. Autopsy subjects were used as controls. In early sacroiliitis (grade 0-1) all pathological features could be observed, with the most common being subchondral pannus formation. Among the 193 patients, 98 were followed up for 1-13 years (mean 3.6 years); 63.3% had radiological progression at the endpoint. Multiple regression analysis showed that cartilage pannus invasion (OR 2.99, P = 0.010) and endochondral ossification (OR 3.97, P = 0.049) at baseline were risk factors for radiological structural damage. Compared to SIJ controls, the subchondral microvessel density, number of CD68+ multinuclear osteoclasts, and the levels of VEGF, caspase-3, MMP-3, and TNF-α expressed at the interface of the bone and cartilage were significantly higher in patients with sacroiliitis. Subchondral fibrovascular tissue formation is the most important pathological feature in early sacroiliitis. The existence of cartilage pannus invasion or endochondral ossification at baseline can predict radiological structural damage during the follow up.

Endogenously produced Indian Hedgehog regulates TGFβ-driven chondrogenesis of human bone marrow stromal/stem cells.

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Handorf, Andrew M; Chamberlain, Connie S; Li, Wan-Ju

2015-04-15

Human bone marrow stromal/stem cells (hBMSCs) have an inherent tendency to undergo hypertrophy when induced into the chondrogenic lineage using transforming growth factor-beta 1 (TGFβ) in vitro, reminiscent of what occurs during endochondral ossification. Surprisingly, Indian Hedgehog (IHH) has received little attention for its role during hBMSC chondrogenesis despite being considered a master regulator of endochondral ossification. In this study, we investigated the role that endogenously produced IHH plays during hBMSC chondrogenesis. We began by analyzing the expression of IHH throughout differentiation using quantitative polymerase chain reaction and found that IHH expression was upregulated dramatically upon chondrogenic induction and peaked from days 9 to 12 of differentiation, which coincided with a concomitant increase in the expression of chondrogenesis- and hypertrophy-related markers, suggesting a potential role for endogenously produced IHH in driving hBMSC chondrogenesis. More importantly, pharmacological inhibition of Hedgehog signaling with cyclopamine or knockdown of IHH almost completely blocked TGFβ1-induced chondrogenesis in hBMSCs, demonstrating that endogenously produced IHH is necessary for hBMSC chondrogenesis. Furthermore, overexpression of IHH was sufficient to drive chondrogenic differentiation, even when TGFβ signaling was inhibited. Finally, stimulation with TGFβ1 induced a significant and sustained upregulation of IHH expression within 3 h that preceded an upregulation in all cartilage-related genes analyzed, and knockdown of IHH blocked the effects of TGFβ1 entirely, suggesting that the effects of TGFβ1 are being mediated through endogenously produced IHH. Together, our findings demonstrate that endogenously produced IHH is playing a critical role in regulating hBMSC chondrogenesis.

Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis.

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Occhetta, Paola; Pigeot, Sebastien; Rasponi, Marco; Dasen, Boris; Mehrkens, Arne; Ullrich, Thomas; Kramer, Ina; Guth-Gundel, Sabine; Barbero, Andrea; Martin, Ivan

2018-05-01

It is generally accepted that adult human bone marrow-derived mesenchymal stromal cells (hMSCs) are default committed toward osteogenesis. Even when induced to chondrogenesis, hMSCs typically form hypertrophic cartilage that undergoes endochondral ossification. Because embryonic mesenchyme is obviously competent to generate phenotypically stable cartilage, it is questioned whether there is a correspondence between mesenchymal progenitor compartments during development and in adulthood. Here we tested whether forcing specific early events of articular cartilage development can program hMSC fate toward stable chondrogenesis. Inspired by recent findings that spatial restriction of bone morphogenetic protein (BMP) signaling guides embryonic progenitors toward articular cartilage formation, we hypothesized that selective inhibition of BMP drives the phenotypic stability of hMSC-derived chondrocytes. Two BMP type I receptor-biased kinase inhibitors were screened in a microfluidic platform for their time- and dose-dependent effect on hMSC chondrogenesis. The different receptor selectivity profile of tested compounds allowed demonstration that transient blockade of both ALK2 and ALK3 receptors, while permissive to hMSC cartilage formation, is necessary and sufficient to maintain a stable chondrocyte phenotype. Remarkably, even upon compound removal, hMSCs were no longer competent to undergo hypertrophy in vitro and endochondral ossification in vivo, indicating the onset of a constitutive change. Our findings demonstrate that adult hMSCs effectively share properties of embryonic mesenchyme in the formation of transient but also of stable cartilage. This opens potential pharmacological strategies to articular cartilage regeneration and more broadly indicates the relevance of developmentally inspired protocols to control the fate of adult progenitor cell systems.

Bone Marrow Blood Vessel Ossification and “Microvascular Dead Space” in Rat and Human Long Bone

Science.gov (United States)

Prisby, Rhonda D.

2014-01-01

Severe calcification of the bone microvascular network was observed in rats, whereby the bone marrow blood vessels appeared ossified. This study sought to characterize the magnitude of ossification in relation to patent blood vessels and adipocyte content in femoral diaphyses. Additionally, this study confirmed the presence of ossified vessels in patients with arteriosclerotic vascular disease and peripheral vascular disease and cellulitis. Young (4–6 mon; n=8) and old (22–24 mon; n=8) male Fischer-344 rats were perfused with barium sulfate to visualize patent bone marrow blood vessels. Femoral shafts were processed for bone histomorphometry to quantify ossified (Goldner’s Trichrome) and calcified (Alizarin Red) vessels. Adipocyte content was also determined. Additional femora (n=5/age group) were scanned via µCT to quantify microvascular ossification. Bone marrow blood vessels from rats and the human patients were also isolated and examined via microscopy. Ossified vessels (rats and humans) had osteocyte lacunae on the vessel surfaces and “normal” vessels were transitioning into bone. The volume of ossified vessels was 4800% higher (p necrosis. The progression of bone microvascular ossification may provide the common link associated with age-related changes in bone and bone marrow. The clinical implications may be evident in the difficulties treating bone disease in the elderly. PMID:24680721

MicroCT and microMRI imaging of a prenatal mouse model of increased brain size

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López, Elisabeth K. N.; Stock, Stuart R.; Taketo, Makoto M.; Chenn, Anjen; Ravosa, Matthew J.

2008-08-01

There are surprisingly few experimental models of neural growth and cranial integration. This and the dearth of information regarding fetal brain development detract from a mechanistic understanding of cranial integration and its relevance to the patterning of skull form, specifically the role of encephalization on basicranial flexion. To address this shortcoming, our research uses transgenic mice expressing a stabilized form of β-catenin to isolate the effects of relative brain size on craniofacial development. These mice develop highly enlarged brains due to an increase in neural precursors, and differences between transgenic and wild-type mice are predicted to result solely from variation in brain size. Comparisons of wild-type and transgenic mice at several prenatal ages were performed using microCT (Scanco Medical MicroCT 40) and microMRI (Avance 600 WB MR spectrometer). Statistical analyses show that the larger brain of the transgenic mice is associated with a larger neurocranium and an altered basicranial morphology. However, body size and postcranial ossification do not seem to be affected by the transgene. Comparisons of the rate of postcranial and cranial ossification using microCT also point to an unexpected effect of neural growth on skull development: increased fetal encephalization may result in a compensatory decrease in the level of cranial ossification. Therefore, if other life history factors are held constant, the ontogeny of a metabolically costly structure such as a brain may occur at the expense of other cranial structures. These analyses indicate the benefits of a multifactorial approach to cranial integration using a mouse model.

Neural crest does not contribute to the neck and shoulder in the axolotl (Ambystoma mexicanum).

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Epperlein, Hans-Henning; Khattak, Shahryar; Knapp, Dunja; Tanaka, Elly M; Malashichev, Yegor B

2012-01-01

A major step during the evolution of tetrapods was their transition from water to land. This process involved the reduction or complete loss of the dermal bones that made up connections to the skull and a concomitant enlargement of the endochondral shoulder girdle. In the mouse the latter is derived from three separate embryonic sources: lateral plate mesoderm, somites, and neural crest. The neural crest was suggested to sustain the muscle attachments. How this complex composition of the endochondral shoulder girdle arose during evolution and whether it is shared by all tetrapods is unknown. Salamanders that lack dermal bone within their shoulder girdle were of special interest for a possible contribution of the neural crest to the endochondral elements and muscle attachment sites, and we therefore studied them in this context. We grafted neural crest from GFP+ fluorescent transgenic axolotl (Ambystoma mexicanum) donor embryos into white (d/d) axolotl hosts and followed the presence of neural crest cells within the cartilage of the shoulder girdle and the connective tissue of muscle attachment sites of the neck-shoulder region. Strikingly, neural crest cells did not contribute to any part of the endochondral shoulder girdle or to the connective tissue at muscle attachment sites in axolotl. Our results in axolotl suggest that neural crest does not serve a general function in vertebrate shoulder muscle attachment sites as predicted by the "muscle scaffold theory," and that it is not necessary to maintain connectivity of the endochondral shoulder girdle to the skull. Our data support the possibility that the contribution of the neural crest to the endochondral shoulder girdle, which is observed in the mouse, arose de novo in mammals as a developmental basis for their skeletal synapomorphies. This further supports the hypothesis of an increased neural crest diversification during vertebrate evolution.

Neural crest does not contribute to the neck and shoulder in the axolotl (Ambystoma mexicanum.

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Hans-Henning Epperlein

Full Text Available BACKGROUND: A major step during the evolution of tetrapods was their transition from water to land. This process involved the reduction or complete loss of the dermal bones that made up connections to the skull and a concomitant enlargement of the endochondral shoulder girdle. In the mouse the latter is derived from three separate embryonic sources: lateral plate mesoderm, somites, and neural crest. The neural crest was suggested to sustain the muscle attachments. How this complex composition of the endochondral shoulder girdle arose during evolution and whether it is shared by all tetrapods is unknown. Salamanders that lack dermal bone within their shoulder girdle were of special interest for a possible contribution of the neural crest to the endochondral elements and muscle attachment sites, and we therefore studied them in this context. RESULTS: We grafted neural crest from GFP+ fluorescent transgenic axolotl (Ambystoma mexicanum donor embryos into white (d/d axolotl hosts and followed the presence of neural crest cells within the cartilage of the shoulder girdle and the connective tissue of muscle attachment sites of the neck-shoulder region. Strikingly, neural crest cells did not contribute to any part of the endochondral shoulder girdle or to the connective tissue at muscle attachment sites in axolotl. CONCLUSIONS: Our results in axolotl suggest that neural crest does not serve a general function in vertebrate shoulder muscle attachment sites as predicted by the "muscle scaffold theory," and that it is not necessary to maintain connectivity of the endochondral shoulder girdle to the skull. Our data support the possibility that the contribution of the neural crest to the endochondral shoulder girdle, which is observed in the mouse, arose de novo in mammals as a developmental basis for their skeletal synapomorphies. This further supports the hypothesis of an increased neural crest diversification during vertebrate evolution.

Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function.

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Kwok Yeung Tsang

2007-03-01

Full Text Available In protein folding and secretion disorders, activation of endoplasmic reticulum (ER stress signaling (ERSS protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del, misfolded alpha1(X chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Thyroid hormone receptor-β1 signaling is critically involved in regulating secondary ossification via promoting transcription of the Ihh gene in the epiphysis.

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Xing, Weirong; Aghajanian, Patrick; Goodluck, Helen; Kesavan, Chandrasekhar; Cheng, Shaohong; Pourteymoor, Sheila; Watt, Heather; Alarcon, Catrina; Mohan, Subburaman

2016-05-15

Thyroid hormone (TH) action is mediated through two nuclear TH receptors, THRα and THRβ. Although the role of THRα is well established in bone, less is known about the relevance of THRβ-mediated signaling in bone development. On ther basis of our recent finding that TH signaling is essential for initiation and formation of secondary ossification center, we evaluated the role of THRs in mediating TH effects on epiphysial bone formation. Two-day treatment of TH-deficient Tshr(-/-) mice with TH increased THRβ1 mRNA level 3.4-fold at day 7 but had no effect on THRα1 mRNA level at the proximal tibia epiphysis. Treatment of serum-free cultures of tibias from 3-day-old mice with T3 increased THRβ1 expression 2.1- and 13-fold, respectively, at 24 and 72 h. Ten-day treatment of Tshr(-/-) newborns (days 5-14) with THRβ1 agonist GC1 at 0.2 or 2.0 μg/day increased BV/TV at day 21 by 225 and 263%, respectively, compared with vehicle treatment. Two-day treatment with GC1 (0.2 μg/day) increased expression levels of Indian hedgehog (Ihh) 100-fold, osterix 15-fold, and osteocalcin 59-fold compared with vehicle at day 7 in the proximal tibia epiphysis. Gel mobility shift assay demonstrated that a putative TH response element in the distal promoter of mouse Ihh gene interacted with THRβ1. GC1 treatment (1 nM) increased Ihh distal promoter activity 20-fold after 48 h in chondroctyes. Our data suggest a novel role for THRβ1 in secondary ossification at the epiphysis that involves transcriptional upregulation of Ihh gene.

Disseminated dendriform pulmonary ossification associated with usual interstitial pneumonia: incidence and thin-section CT-pathologic correlation

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Kim, Tae Sung; Chung, Myung Jin [Sungkyunkwan University School of Medicine, Department of Radiology and Center for Imaging Science, Seoul (Korea); Han, Joungho [Sungkyunkwan University School of Medicine, Department of Pathology, Seoul (Korea); Chung, Man Pyo [Sungkyunkwan University School of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Seoul (Korea); Choi, Yong Soo [Sungkyunkwan University School of Medicine, Division of Thoracic Surgery, Seoul (Korea)

2005-08-01

The aim of this work was to assess the incidence of disseminated pulmonary dendriform ossification in usual interstitial pneumonia and nonspecific interstitial pneumonia, and to correlate thin-section computed tomography (CT) and histopathologic findings. We retrospectively reviewed thin-section CT and pathologic specimens of biopsy-proven usual interstitial pneumonia (75 patients, 57 men and 18 women, mean age 60 years, range 29-83 years) and nonspecific interstitial pneumonia (44 patients, 9 men and 35 women, mean age 55 years, range 20-73 years). On review of CT and histopathologic specimens, diffuse dendriform ossification was identified in five (four men and one woman, age range 41-68 years, mean 58 years) of 75 patients (6.7%) with usual interstitial pneumonia. It was not seen in any of 44 patients with nonspecific interstitial pneumonia. With thin-section CT (osteoporosis window; window width 818, level 273), disseminated dendriform pulmonary ossification was detected as multiple tiny calcifications in bibasilar subpleural lungs (100% sensitive and 100% specific when compared with histopathologic findings as the gold standard). The thin-section CT finding of multiple tiny calcifications in bibasilar subpleural lungs might be of some help in the differential diagnosis between usual interstitial pneumonia and nonspecific interstitial pneumonia, considering they were not seen in any patients with nonspecific interstitial pneumonia (0%, 0/44) in our series. (orig.)

Disseminated dendriform pulmonary ossification associated with usual interstitial pneumonia: incidence and thin-section CT-pathologic correlation

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Kim, Tae Sung; Chung, Myung Jin; Han, Joungho; Chung, Man Pyo; Choi, Yong Soo

2005-01-01

The aim of this work was to assess the incidence of disseminated pulmonary dendriform ossification in usual interstitial pneumonia and nonspecific interstitial pneumonia, and to correlate thin-section computed tomography (CT) and histopathologic findings. We retrospectively reviewed thin-section CT and pathologic specimens of biopsy-proven usual interstitial pneumonia (75 patients, 57 men and 18 women, mean age 60 years, range 29-83 years) and nonspecific interstitial pneumonia (44 patients, 9 men and 35 women, mean age 55 years, range 20-73 years). On review of CT and histopathologic specimens, diffuse dendriform ossification was identified in five (four men and one woman, age range 41-68 years, mean 58 years) of 75 patients (6.7%) with usual interstitial pneumonia. It was not seen in any of 44 patients with nonspecific interstitial pneumonia. With thin-section CT (osteoporosis window; window width 818, level 273), disseminated dendriform pulmonary ossification was detected as multiple tiny calcifications in bibasilar subpleural lungs (100% sensitive and 100% specific when compared with histopathologic findings as the gold standard). The thin-section CT finding of multiple tiny calcifications in bibasilar subpleural lungs might be of some help in the differential diagnosis between usual interstitial pneumonia and nonspecific interstitial pneumonia, considering they were not seen in any patients with nonspecific interstitial pneumonia (0%, 0/44) in our series. (orig.)

An analysis of cervical myelopathy due to cervical spondylosis or ossification of posterior longitudinal ligament by CT myelography

International Nuclear Information System (INIS)

Fujiwara, Keiju; Yonenobe, Sakuo; Ebara, Sohei; Yamashita, Kazuo; Ono, Keiro

1988-01-01

CT-myelographic (CTM) findings of 20 patients with ossification of posterior longitudinal ligament (OPLL) and 24 patients with cervical spondylotic myelopathy (CSM) were reviewed for the evaluation of (1) contributing factors to preoperative neurologic symptoms and therapeutic prognosis in OPLL, and (2) differences in pathology between OPLL and CSM. In OPLL, the severity of preoperative neurologic symptoms was not related to the degree of deformed spinal cord - as expressed by the transverse area of the spinal cord and the rate of flatness - nor the degree of ossification - as expressed by the rate of stricture, and the transverse areas of the effective spinal canal and ossification. The transverse areas of the spinal cord and effective spinal canal were correlated with both postoperative scores for neurologic symptoms and the recovery rate. Osseous compression to the spinal cord was severer in OPLL than OSM. Regarding other factors, such as size and shape of the spinal cord and therapeutic prognosis, there was no difference between the two diseases. This implied the association of dynamic compression to the spinal cord that resulted from the unstable cervical spine in the case of CSM. (Namekawa, K.)

The ossification pattern in paediatric occipito-cervical spine: is it possible to estimate real age?

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Lee, H.J.; Kim, J.T.; Shin, M.H.; Choi, D.Y.; Park, Y.S.; Hong, J.T.

2015-01-01

Aim: To retrospectively analyse the synchondrosis from the occipital bone to the whole cervical spine and determine the feasibility and validity of age estimation using computed tomography (CT) images. Material and methods: A total of 231 cervical spine or neck CT images of young children (<7 years of age) were examined. Twelve ossification centres were assessed (occiput: n = 2; atlas: n = 2; axis, n = 6; whole sub-axial vertebra: n = 2), and the ossification process was graded as open (O, fully lucent), osseous bridging (B, partially ossified), and fusion (F, totally ossified). After the first analysis was completed, the resulting chronological chart was used to estimate the age of 10 new cases in order to confirm the usefulness of the chart. Results: Infancy was easily estimated using the sub-axial or C2 posterior ossification centres, while the posterior occipital regions provided good estimation of age between 1–2 years. The most difficult period for accurate age estimation was between 2–4 years. However, the C2 anterior (neurocentral ossification) and C1 posterior regions did yield information to help determine the age around 3 years. The anterior occipital region was useful for age estimation between 4–5 years, and the C1-anterior region was potentially useful to help decide among the other parameters. The test for age estimation (TAE) had a very high ICC score (0.973) among the three observers. Conclusion: Segmentalised analysis can enhance the ability to estimate real age, at least by the year. The analysis of the occipital bone made a strong contribution to the usefulness of the chorological chart. An organised chronological chart can provide readily available information for age estimation, and the primary application of the above data (TAE) demonstrated the validity of this approach. -- Highlights: •Subaxial or C2 posterior regions was useful for age estimation between 0–1 year. •Posterior occipital regions provided good estimation of

Postoperative radiotherapy prophylaxis of periarticular ossification after total hip replacement

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Sauer, R.; Seegenschmiedt, M.H.; Andreas, P.; Goldmann, A.; Beck, H.

1992-01-01

Since June 1988, we have treated 77 patients or 80 hips respectively with prophylactic irradiation. Individual risk factors included severe coxarthrosis grade IV, ipsi- or contralateral heterotopic ossification and severe hip trauma. As of July 1991 60 patients with a minimum follow-up of six months could be analyzed using clinical and radiological scoring systems. The patients had been prospectively randomized in two different treatment arms: 32 patients were treated with low dose (LD), five times 2 Gy daily fractions to a total dose of 10 Gy, whereas 28 patients were treated with high dose (HD), ten times 2 Gy (eight patients) or five times 3.5 Gy (20 patients). Operative procedures and individual risk factors were equally distributed in both groups. 23 patients (38% received indometacin three times 25 mg for six weeks, 19 patients (32%) diphosphonate EHDP 20 mg/kg body weight and 18 patients (30%) had no additional medication. 56/60 (93%) patients developed no significant heterotopic ossification and/or remained without impairment of their postoperative radiological and clinical hip status according to the applied Brooker and Harris Scores. Only 4/60 (7%) patients demonstrated treatment failures developing postoperative worsening one grade of Brooker score in two patients and two and three grades of Brooker score in the two others. Only 1/49 patients experienced a treatment failure, when radiotherapy had been initiated before and at postoperative day 4 compared to 3/11 patients initiated after postoperative day 4 (p [de

Ossification of the stylohyoid chain on computed tomograms - Eagle syndrome

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Lugmayr, H.; Krennmair, G.; Lenglinger, F.

1997-01-01

The computed tomographic morphology of a typical Eagle syndrome is presented on the basis of a case history. In a 40-year-old female patient presenting with bilateral tinnitus, globus hystericus, and increasing hoarseness computed tomography revealed bilateral ossification of the stylohyoid ligament. The incidence of stylalgia is very low in comparison to the occurrence of a elongated styloid process or an ossified stylohyoid ligament. However, in cases of unexplained complaints in the head and neck region it should be considered in the differential diagnosis as it has therapeutic consequences. (orig.) [de

The role of Matrix Gla Protein in ossification and recovery of the avian growth plate

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Harel eDan

2012-07-01

Full Text Available ECM mineralization is an essential physiologic process in bone, teeth, and hypertrophic cartilage. Matrix Gla Protein (MGP, an inhibitor of mineralization, is expressed by chondrocytes and vascular smooth muscle cells to inhibit calcification of those soft tissues.Tibial Dyschondroplasia (TD, a skeletal abnormality apparent as a plug of non-vascularized, non-mineralized, white opaque cartilage in the tibial growth plate of avian species can serve as a good model for studying process and genes involved in matrix mineralization and calcification. In this work, we studied the involvement of MGP in the development of TD, as well as in the processes of spontaneous and induced recovery from this syndrome. First, we found that during normal bone development, MGP is expressed in specific time and locations, starting from wide spread expression in the yet un-ossified diaphysis during embryonic development, to specific expression in hypertrophic chondrocytes adjacent to the chondro-osseous junction and the secondary ossification center just prior to calcification. In addition, we show that MGP is not expressed in the impaired TD lesion, however when the lesion begins to heal, it strongly express MGP prior to its calcification. Moreover, we show that when calcification is inhibited, a gap is formed between the expression zones of MGP and BMP2 and that this gap is closed during the healing process. To conclude, we suggest that MGP, directly or through interaction with BMP2, plays a role as ossification regulator, rather then simple inhibitor that acts prior to ossification.

Influence of shape and dispersion media of titanium dioxide nanostructures on microvessel network and ossification.

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Freyre-Fonseca, Verónica; Medina-Reyes, Estefany I; Téllez-Medina, Darío I; Paniagua-Contreras, Gloria L; Monroy-Pérez, Eric; Vaca-Paniagua, Felipe; Delgado-Buenrostro, Norma L; Flores-Flores, José O; López-Villegas, Edgar O; Gutiérrez-López, Gustavo F; Chirino, Yolanda I

2018-02-01

Titanium dioxide nanoparticles (TiO 2 NPs) production has been used for pigment, food and cosmetic industry and more recently, shaped as belts for treatment of contaminated water, self-cleaning windows and biomedical applications. However, the toxicological data have demonstrated that TiO 2 NPs inhalation induce inflammation in in vivo models and in vitro exposure leads to cytotoxicity and DNA damage. Dermal exposure has limited adverse effects and the possible risks for implants used for tissue regeneration is still under research. Then, it has been difficult to establish a straight statement about TiO 2 NPs toxicity since route of exposure and shapes of nanoparticles play an important role in the effects. In this study we aimed to investigate the effect of three different types of TiO 2 NPs (industrial, food-grade and belts) dispersed in fetal bovine serum (FBS) and saline solution (SS) on microvessel network, angiogenesis gene expression and femur ossification using a chick embryo model after an acute exposure of NPs on the day 7 after eggs fertilization. Microvascular density of chorioallantoic membrane (CAM) was analyzed after 7days of NPs injection and vehicles induced biological effects per se. NPs dispersed in FBS or SS have slight differences in microvascular density, mainly opposite effect on angiogenesis gene expression and no effects on femur ossification for NPs dispersed in SS. Interestingly, NPs shaped as belts dramatically prevented the alterations in ossification induced by FBS used as vehicle. Copyright © 2017 Elsevier B.V. All rights reserved.

A new computed tomography method to identify meningitis-related cochlear ossification and fibrosis before cochlear implantation.

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Ichikawa, Kazunori; Kashio, Akinori; Mori, Harushi; Ochi, Atushi; Karino, Shotaro; Sakamoto, Takashi; Kakigi, Akinobu; Yamasoba, Tatsuya

2014-04-01

To develop a new method to determine the presence of intracochlear ossification and/or fibrosis in cochlear implantation candidates with bilateral profound deafness following meningitis. Diagnostic test assessment. A university hospital. This study involved 15 ears from 13 patients with profound deafness following meningitis who underwent cochlear implantation. These ears showed normal structures, soft tissue, partial bony occlusion, and complete bony occlusion in 4, 3, 2, and 6 ears, respectively. We measured radiodensity in Hounsfield units (HU) using 0.5-mm-thick axial high-resolution computed tomography image slices at 3 different levels in the basal turn, the fenestration, and inferior and ascending segment sites, located along the electrode-insertion path. Pixel-level analysis on the DICOM viewer yielded actual computed tomography values of intracochlear soft tissues by eliminating the partial volume effect. The values were compared with the intraoperative findings. Values for ossification (n = 12) ranged from +547 HU to +1137 HU; for fibrosis (n = 11), from +154 HU to +574 HU; and for fluid (n = 22), from -49 HU to +255 HU. From these values, we developed 2 presets of window width (WW) and window level (WL): (1) WW: 1800, WL: 1100 (200 HU to 2000 HU) and (2) WW: 1500, WL: 1250 (500 HU to 2000 HU). The results using these 2 presets corresponded well to the intraoperative findings. Our new method is easy and feasible for preoperative determination of the presence of cochlear ossification and/or fibrosis that develops following meningitis.

Growth recovery lines are more common in infants at high vs. low risk for abuse

International Nuclear Information System (INIS)

Zapala, Matthew A.; Tsai, Andy; Kleinman, Paul K.

2016-01-01

Growth recovery lines, also known as growth arrest lines, are transverse radiodense metaphyseal bands that develop due to a temporary arrest of endochondral ossification caused by local or systemic insults. To determine if growth recovery lines are more common in infants at high risk versus low risk for abuse. Reports of American College of Radiology compliant skeletal surveys (1999-2013) were reviewed with clinical records. Infants at low risk for abuse had a skull fracture without significant intracranial injury, history of a fall and clinical determination of low risk (child protection team/social work assessment). Infants at high risk had significant intracranial injury, retinal hemorrhages, other skeletal injuries and clinical determination of high risk. There were 52 low-risk infants (mean: 4.7 months, range: 0.4-12 months) and 21 high-risk infants (mean: 4.2 months, range: 0.8-9.1 months). Two blinded radiologists independently evaluated the skeletal survey radiographs of the knees/lower legs for the presence of at least one growth recovery line. When growth recovery lines are scored as probably present or definitely present, their prevalence in the low-risk group was 38% (standard deviation [SD] = 8%; reader 1 = 17/52, reader 2 = 23/52) vs. 71% (SD = 7%; reader 1 = 16/21, reader 2 = 14/21) in the high-risk group (P < 0.001; odds ratio 4.0, 95% CI: 1.7-9.5). Growth recovery lines are encountered at a significantly higher rate in infants at high risk vs. low risk for abuse. This suggests that abused infants are prone to a temporary disturbance in endochondral ossification as a result of episodic physiological stresses. (orig.)

Chronic psychosocial stress disturbs long-bone growth in adolescent mice

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Sandra Foertsch

2017-12-01

Full Text Available Although a strong association between psychiatric and somatic disorders is generally accepted, little is known regarding the interrelationship between mental and skeletal health. Although depressive disorders have been shown to be strongly associated with osteoporosis and increased fracture risk, evidence from post-traumatic stress disorder (PTSD patients is less consistent. Therefore, the present study investigated the influence of chronic psychosocial stress on bone using a well-established murine model for PTSD. C57BL/6N mice (7 weeks old were subjected to chronic subordinate colony housing (CSC for 19 days, whereas control mice were singly housed. Anxiety-related behavior was assessed in the open-field/novel-object test, after which the mice were euthanized to assess endocrine and bone parameters. CSC mice exhibited increased anxiety-related behavior in the open-field/novel-object test, increased adrenal and decreased thymus weights, and unaffected plasma morning corticosterone. Microcomputed tomography and histomorphometrical analyses revealed significantly reduced tibia and femur lengths, increased growth-plate thickness and reduced mineral deposition at the growth plate, suggesting disturbed endochondral ossification during long-bone growth. This was associated with reduced Runx2 expression in hypertrophic chondrocytes in the growth plate. Trabecular thicknesses and bone mineral density were significantly increased in CSC compared to singly housed mice. Tyrosine hydroxylase expression was increased in bone marrow cells located at the growth plates of CSC mice, implying that local adrenergic signaling might be involved in the effects of CSC on the skeletal phenotype. In conclusion, chronic psychosocial stress negatively impacts endochondral ossification in the growth plate, affecting both longitudinal and appositional bone growth in adolescent mice.

Heterotopic mesenteric ossification: Report of two cases with review of the literature

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Mussatto J

2016-02-01

Full Text Available Very few cases of heterotopic mesenteric ossification (HMO have been reported in the literature. We describe two cases, one at an early phase and the other at a more advanced stage of the disease. Both patients developed HMO after multiple major abdominal surgeries. The value of monitoring serum alkaline phosphatase and calcium in a setting of previous abdominal surgery or trauma along with other clinical, radiological and pathologic findings is discussed.

Heterotopic ossification associated with myelopathy following cervical disc prosthesis implantation.

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Wenger, Markus; Markwalder, Thomas-Marc

2016-04-01

This case report presents a 37-year-old man with clinical signs of myelopathy almost 9 years after implantation of a Bryan disc prosthesis (Medtronic Sofamor Danek, Memphis, TN, USA) for C5/C6 soft disc herniation. As demonstrated on MRI and CT scan, spinal cord compression was caused by bony spurs due to heterotopic ossification posterior to the still moving prosthesis. The device, as well as the ectopic bone deposits, had to be removed because of myelopathy and its imminent aggravation. Conversion to anterior spondylodesis was performed. Copyright © 2015 Elsevier Ltd. All rights reserved.

High-frequency spectral ultrasound imaging (SUSI) visualizes early post-traumatic heterotopic ossification (HO) in a mouse model.

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Ranganathan, Kavitha; Hong, Xiaowei; Cholok, David; Habbouche, Joe; Priest, Caitlin; Breuler, Christopher; Chung, Michael; Li, John; Kaura, Arminder; Hsieh, Hsiao Hsin Sung; Butts, Jonathan; Ucer, Serra; Schwartz, Ean; Buchman, Steven R; Stegemann, Jan P; Deng, Cheri X; Levi, Benjamin

2018-04-01

Early treatment of heterotopic ossification (HO) is currently limited by delayed diagnosis due to limited visualization at early time points. In this study, we validate the use of spectral ultrasound imaging (SUSI) in an animal model to detect HO as early as one week after burn tenotomy. Concurrent SUSI, micro CT, and histology at 1, 2, 4, and 9weeks post-injury were used to follow the progression of HO after an Achilles tenotomy and 30% total body surface area burn (n=3-5 limbs per time point). To compare the use of SUSI in different types of injury models, mice (n=5 per group) underwent either burn/tenotomy or skin incision injury and were imaged using a 55MHz probe on VisualSonics VEVO 770 system at one week post injury to evaluate the ability of SUSI to distinguish between edema and HO. Average acoustic concentration (AAC) and average scatterer diameter (ASD) were calculated for each ultrasound image frame. Micro CT was used to calculate the total volume of HO. Histology was used to confirm bone formation. Using SUSI, HO was visualized as early as 1week after injury. HO was visualized earliest by 4weeks after injury by micro CT. The average acoustic concentration of HO was 33% more than that of the control limb (n=5). Spectroscopic foci of HO present at 1week that persisted throughout all time points correlated with the HO present at 9weeks on micro CT imaging. SUSI visualizes HO as early as one week after injury in an animal model. SUSI represents a new imaging modality with promise for early diagnosis of HO. Copyright © 2018 Elsevier Inc. All rights reserved.

Complete absence of rib ossification, micrognathia and ear anomalies: extreme expression of cerebro-costo-mandibular syndrome?

NARCIS (Netherlands)

Hennekam, R. C.; Goldschmeding, R.

1998-01-01

We describe a newborn with complete absence of ossification of the ribs, extreme micrognathia, absence of external ear canals and the inner ears, and diminished mobility in the upper extremities. It is suggested that this represents an unusually severe expression of the cerebro-costo-mandibular

Interaction of TGFβ and BMP signaling pathways during chondrogenesis.

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Bettina Keller

2011-01-01

Full Text Available TGFβ and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFβ signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage-specific loss of BMP and TGFβ signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFβ signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFβ signaling that was generated by expressing a dominant negative form of the TGFβ receptor I (ΔTβRI in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFβ was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFβ signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro.

Cartilage-Specific and Cre-Dependent Nkx3.2 Overexpression In Vivo Causes Skeletal Dwarfism by Delaying Cartilage Hypertrophy.

Science.gov (United States)

Jeong, Da-Un; Choi, Je-Yong; Kim, Dae-Won

2017-01-01

Nkx3.2, the vertebrate homologue of Drosophila bagpipe, has been implicated as playing a role in chondrogenic differentiation. In brief, Nkx3.2 is initially expressed in chondrocyte precursor cells and later during cartilage maturation, its expression is diminished in hypertrophic chondrocytes. In addition to Nkx3.2 expression analyses, previous studies using ex vivo chick embryo cultures and in vitro cell cultures have suggested that Nkx3.2 can suppress chondrocyte hypertrophy. However, it has never been demonstrated that Nkx3.2 functions in regulating chondrocyte hypertrophy during cartilage development in vivo. Here, we show that cartilage-specific and Cre-dependent Nkx3.2 overexpression in mice results in significant postnatal dwarfism in endochondral skeletons, while intramembranous bones remain unaltered. Further, we observed significant delays in cartilage hypertrophy in conditional transgenic ciTg-Nkx3.2 mice. Together, these findings confirm that Nkx3.2 is capable of controlling hypertrophic maturation of cartilage in vivo, and this regulation plays a significant role in endochondral ossification and longitudinal bone growth. J. Cell. Physiol. 232: 78-90, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Roentgenographic appearance of ossification centers in the Japanese fetus, stillborn and neonatal death infants, Hiroshima and Nagasaki

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Kawamoto, Sadahisa

1964-01-01

A roentgenographic study of the presence of the ossification centers has been made on a total of 235 cases of miscarriage, therapeutic abortion, stillbirth and neonatal death according to criteria of sex, length of gestational age, and weight at birth. The cases were aged from 16 to 42 gestational weeks. The weight of the cases ranged from 110 g to 3780 g at birth. The order of appearance of the eight centers in fetal life was as follows: Ischium, pubis, calcaneus, talus, distal epiphysis of femur, hyoid, proximal epiphysis of tibia, and cuboid bone. Some of the eight ossification centers appeared earlier in girls than in boys of the same gestational age and birth weight. The osseous development of Japanese fetuses and infants weighing over 2000 g was judged less mature than in similar Caucasian and Negro subjects. 10 references, 1 figure, 6 tables.

Mesenteric ossification in CT indicates sclerosing peritonitis in chronic bacterial infection and pancreatitis

International Nuclear Information System (INIS)

Kirchner, J.; Kirchner, E.M.; Kickuth, R.; Stein, A.

2004-01-01

Sclerosing peritonitis already has been described as a serious complication of the continuous ambulatory peritoneal dialysis. But different other affections of the pertioneum such as chronic bacterial peritonitis and pancreatitis may result in sclerosing peritonitis, too. The symptom is characterised by thickened small bowel walls and periotoneal membranes as well as peritoneal calcifications which can be shown in computed tomography. We demonstrate two cases of peritoneal ossifications due to peritonitis and pancreatitis. (orig.) [de

Preliminary results of a randomized trial comparing 400 cGy vs 700 cGy as an adjuvant to prevent heterotopic ossification after total hip arthroplasty

International Nuclear Information System (INIS)

Nguyen, Cam; Gupta-Burt, Shalina; Silverton, Craig; Cummings, Marilyn; Galante, Jorge O.

1997-01-01

Purpose/Objective: We report our preliminary results of a randomized trial comparing one single dose of 400 cGy versus 700 cGy given postoperatively in an attempt to prevent heterotopic ossification after total hip arthroplasty. Materials and Methods: From 09/1993 and 05/1996, over 800 total hip replacements were performed at our hospital. From this group of patients, 120 hips in 114 high-risk patients (14%) were enrolled in a randomized trial to determine if 400 cGy (Group A) is as efficacious as 700 cGy (Group B) in preventing heterotopic ossification. In Group A, there were 42 males (46 hips) and 12 females (12 hips) with a mean age of 60 (range 41-79); with 18 primary cementless femoral components (33%), 30 primary cemented stems (55%) and 10 revisions. In Group B, there were 30 males (32 hips) and 30 females (31 hips) with a median age of 59 (range 41-85); with 12 primary cementless femoral components (20%), 44 primary cemented stems (73%) and 6 revisions. All acetabular components were of the cementless type. Patients were randomized to receive either 400 cGy or 700 cGy in one fraction. Radiotherapy is given within 48 hours post-operatively using paired anterior and posterior fields, with blocking of the cementless acetabular component and the femoral component. Results: All 114 patients were available for a minimum follow-up of 6 months (range 6-30 months). None of the arthroplasties has failed at the latest follow-up. There were no radiation therapy complications noted. Statistical analysis revealed no difference in the distribution of patients in either group according to age, sex, primary or revision arthroplasty, cemented or cementless femoral component fixation, preoperative heterotopic ossification risk, or surgical approach. Of the 58 hips in Group A, heterotopic ossification was graded as Grade 0 in 24 hips, Grade I in 10 hips, Grade II in 18 hips, Grade III in 6 hips, with no cases of Grade IV. Of the 63 hips in Group B, heterotopic ossification was

Expression of non-neuronal cholinergic system in maxilla of rat in vivo

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Jie Guo

2014-01-01

Full Text Available BACKGROUND: Acetylcholine (ACh is known to be a key neurotransmitter in the central and peripheral nervous systems, which is also produced in a variety of non-neuronal tissues and cell. The existence of ACh in maxilla in vivo and potential regulation role for osteogenesis need further study. RESULTS: Components of the cholinergic system (ACh, esterase, choline acetyltransferase, high-affinity choline uptake, n- and mAChRs were determined in maxilla of rat in vivo, by means of Real-Time PCR and immunohistochemistry. Results showed RNA for CarAT, carnitine/acylcarnitine translocase member 20 (Slc25a20, VAChT, OCTN2, OCT1, OCT3, organic cation transporter member 4 (Slc22a4, AChE, BChE, nAChR subunits α1, α2, α3, α5, α7, α10, β1, β2, β4, γ and mAChR subunits M1, M2, M3, M4, M5 were detected in rat's maxilla. RNA of VAChT, AChE, nAChR subunits α2, β1, β4 and mAChR subunits M4 had abundant expression (2-ΔCt > 0.03. Immunohistochemical staining was conducted for ACh, VAChT, nAChRα7 and AChE. ACh was expressed in mesenchymal cells, chondroblast, bone and cartilage matrix and bone marrow cells, The VAChT expression was very extensively while ACh receptor α7 was strongly expressed in newly formed bone matrix of endochondral and bone marrow ossification, AchE was found only in mesenchymal stem cells, cartilage and bone marrow cells. CONCLUSIONS: ACh might exert its effect on the endochondral and bone marrow ossification, and bone matrix mineralization in maxilla.

A hypothesis on the formation of the primary ossification centers in the membranous neurocranium: a mathematical and computational model.

Science.gov (United States)

Garzón-Alvarado, Diego A

2013-01-21

This article develops a model of the appearance and location of the primary centers of ossification in the calvaria. The model uses a system of reaction-diffusion equations of two molecules (BMP and Noggin) whose behavior is of type activator-substrate and its solution produces Turing patterns, which represents the primary ossification centers. Additionally, the model includes the level of cell maturation as a function of the location of mesenchymal cells. Thus the mature cells can become osteoblasts due to the action of BMP2. Therefore, with this model, we can have two frontal primary centers, two parietal, and one, two or more occipital centers. The location of these centers in the simplified computational model is highly consistent with those centers found at an embryonic level. Copyright © 2012 Elsevier Ltd. All rights reserved.

Osteochondritis dissecans (OCD), an endoplasmic reticulum storage disease?

DEFF Research Database (Denmark)

Skagen, Peter Storgaard; Horn, T; Kruse, H A

2011-01-01

Osteochondritis dissecans (OCD) fragments, cartilage and blood from four patients were used for morphological and molecular analysis. Controls included articular cartilage and blood samples from healthy individuals. Light microscopy and transmission electron microscopy (TEM) showed abnormalities...... in chondrocytes and extracellular matrix of cartilage from OCD patients. Abnormal type II collagen heterofibrils in "bundles" and chondrocytes with abnormal accumulation of matrix proteins in distended rough endoplasmic reticulum were typical findings. Further, Von Kossa staining and TEM showed empty lacunae...... polymorphism was found within the COL2A1 gene for one patient. We suggest that OCD lesions are caused by an alteration in chondrocyte matrix synthesis causing an endoplasmic reticulum storage disease phenotype, which disturbs or abrupts endochondral ossification....

Inhalant abuse of 1,1-difluoroethane (DFE) leading to heterotopic ossification: a case report

OpenAIRE

Little, Jill; Hileman, Barbara; Ziran, Bruce H

2008-01-01

Abstract Background Heterotopic ossification (HO) is the formation of mature, lamellar bone within soft tissues other than the periosteum. There are three recognized etiologies of HO: traumatic, neurogenic, and genetic. Presently, there are no definitively documented causal factors of HO. The following factors are presumed to place a patient at higher risk: 60 years of age or older, male, previous HO, hypertrophic osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosi...

Influence of Bone and Muscle Injuries on the Osteogenic Potential of Muscle Progenitors: Contribution of Tissue Environment to Heterotopic Ossification.

Science.gov (United States)

Molligan, Jeremy; Mitchell, Reed; Schon, Lew; Achilefu, Samuel; Zahoor, Talal; Cho, Young; Loube, Jeffery; Zhang, Zijun

2016-06-01

: By using surgical mouse models, this study investigated how the tissue environment influences the osteogenic potential of muscle progenitors (m-progenitors) and potentially contributes to heterotopic ossification (HO). Injury was induced by clamping the gluteus maximus and medius (group M) or osteotomy of greater trochanter (group O) on the right hip, as well as combined muscle injury and osteotomy of greater trochanter (group M+O). The gluteus maximus and medius of the operated hips were harvested at days 1, 3, 5, and 10 for isolation of m-progenitors. The cells were cultured in an osteogenic medium for 3 weeks, and osteogenesis was evaluated by matrix mineralization and the expression of osteogenesis-related genes. The expression of type I collagen, RUNX2 (runt-related transcription factor 2), and osteocalcin by the m-progenitors of group M+O was significantly increased, compared with groups M and O. Osteogenic m-progenitors in group O increased the expression of bone morphogenetic protein 2 and also bone morphogenetic protein antagonist differential screening-selected gene aberrative in neuroblastoma. On histology, there was calcium deposition mostly in the muscles of group M+O harvested at day 10. CD56, representing myogenic progenitors, was highly expressed in the m-progenitors isolated from group M (day 10), but m-progenitors of group M+O (day 10) exhibited the highest expression of platelet-derived growth factor receptor α (PDGFR-α), a marker of muscle-derived mesenchymal stem cells (M-MSCs). The expressions of PDGFR-α and RUNX2 were colocalized in osteogenic m-progenitors. The data indicate that the tissue environment simulated in the M+O model is a favorable condition for HO formation. Most likely, M-MSCs, rather than myogenic progenitors, in the m-progenitors participate in HO formation. The prevalence of traumatic heterotopic ossification (HO) is high in war injury. The pathogenesis of HO is still unknown. This study clarified the contribution of a

The difference in the appearance of proximal humeral epiphyseal ossification center on chest radiograph between the preterm and full-term infants

International Nuclear Information System (INIS)

Park, Hee Hong; Kim, Seung Cheol; Chang, Young Pyo; Park, Jin Young; Kwon, Ho Jang; Lee, Jee Young; Yoo, Dong Soo; Kim, You Me; Jeong, Chun Keun; Lee, Young Seok

1997-01-01

To assess the difference in the appearance of the proximal humeral epiphyseal ossification center, as seen on chest radiograph, between preterm and full-term infants at the same corrected ages. Forty two preterm infants born at 26--35 weeks of gestational age and 218 normal full-term infants born at 38-42 weeks were investigated. Because of various perinatal problems, the preterm infants were treated at a neonatal intensive care unit. Proximal humeral epiphyseal ossification centers were evaluated from chest radiographs, and in cases of preterm infants, the corrected age of 0 month was defined as postconceptional 40 weeks. In preterm infants, the numbers of chest radiographs obtained were 42 at 0 month, 40 at 1 month, 37 at 2 months and 36 at 3 months of corrected age, while in those who were full-term, the numbers were 103 cases at 0 month, 42 at 1 month, 42 at 2 months and 31 at 3 months of age In the preterm group, alkaline phosphatase, calcium, phosphorus levels and simple wrist radiographs were checked. We then evaluated the difference of appearance of the proximal humeral epiphyseal ossification center between preterm and full-term infants at the same corrected ages, as well as the difference between causative diseases, between the normal and abnormal serologic group and between the normal and abnormal wrist group in preterm infants at the same corrected ages. Using Fisher's exact test, the data were analysed. The incidences of the proximal humeral epiphyseal ossification center in preterm infants were 2.4% (1/42) at 0 month, 20.0% (8/40) at 1 month, 43.2% (16/37) at 2 months and 69.4%(25/36) at 3 months; in full-term infants, the figures were 24.3% (25/103) at 0 month, 66.7%(28/42) at 1 month, 83.3% (35/42) at 2 months and 90.3% (28/31) at 3 months. At 0, 1, and 2 months, the incidences were thus seen to be lower in preterm than in full-term infants(p 0.05). In preterm infants, there were no statistical differences between causative diseases, between the

Preoperative radiotherapy (RT) for prevention of heterotopic ossification (HO) after total hip replacement

International Nuclear Information System (INIS)

Heyd, R.; Schopohl, B.; Boettcher, H.D.; Kirchner, J.

1997-01-01

Preliminary results of a prospective study which investigates the efficacy of preoperative radiotherapy (RT) for prevention of heterotopic ossification (HO) after total hip arthroplasty are summarized. A total number of 20 hip joints (18 patients) were irradiated with a single dose of 6.0 Gy Brooker grade II). The functional outcome quantified with the Harris score was improved by an average of 37.9 points. The authors conclude that preoperative RT is an effective alternative for postoperative irradiation. (orig.) [de

Two new risk factors for heterotopic ossification development after severe burns.

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Laurent Thefenne

Full Text Available Life after severe burns is conditioned by the remaining sequelae. The pathophysiology and risk factors of Heterotopic Ossification (HO after burns are still poorly understood. The aim of this study was to determine: 1 the incidence of HO after burns and 2 the risk factors associated with HO development, in a large retrospective study.A case-control study of patients admitted to the burns intensive care unit of Percy Hospital, Paris, from the 1st January 2009 to the 31st December 2013 and then admitted to one of three centres specialised in the rehabilitation of patients with burns. Multivariate analysis was carried out to analyse the relationship between HO development and demographic and clinical data.805 patients were included. 32 patients (4.0% developed a total of 74 heterotopic ossifications, that is a little higher incidence than the incidence found in the literature. The epidemiological characteristics of the population studied was similar to the literature. HOs were mainly localized around the elbows, followed by the hips, shoulders and knees. Each case-patient was paired with 3 control-patients. There were significant associations between HO development and the length of stay in the burns intensive care unit, the extent and depth of the burns, the occurrence of pulmonary or cutaneous infections, use of curare and use of an air-fluidized bed.In addition to recognized risk factors (duration of stay in the intensive care burns unit, extent and depth of burns, pulmonary and cutaneous infections, the use of curare and the use of a fluidized bed (with the duration of use were significantly associated with HO formation.

Heterotopic ossification - a domain of radiotherapy

International Nuclear Information System (INIS)

Gocheva, L.

2002-01-01

The radiotherapy (RT) in the case of non-malignant diseases is a subject of controversial standpoints. If founds increasingly restricted application in the English-American countries, while it is quite frequently applied treatment in other countries. At the present stage the indications for RT for non-malignant diseases are rather diverse. The heterotopic ossification (HO) refers to the clearly established in clinical practice cases. The present review considers in detail the frequency of HO development after endo-prosthetics, traumas in the area of the cerebrum and the spinal cord, cauterization. The aetiology, pathogenesis and early diagnostics as well as the basic therapeutic possibilities (non-steroid and anti-inflammatory remedies and radiotherapy) have been considered. The radiobiological mechanism of RT action, the type of the used radiation, the time of application (prior-to and post operation RT), doses and schemes of treatment have been analyzed in detail. The use of RT is recommended as a simple for performance and effective local treatment of HO, with absent or negligible side effects. The one-time prior-to and post operation irradiation is more preferable than the fractionated prior-to and post operation one, taking under consideration the comfort of the patients and the possible post operation complications.(author)

Prevention of heterotopic ossification about the hip: final results of two randomized trials in 410 patients using either preoperative or postoperative radiation therapy

International Nuclear Information System (INIS)

Seegenschmiedt, M. Heinrich; Keilholz, Ludwig; Martus, Peter; Goldmann, Axel; Woelfel, Rainer; Henning, Friedrich; Sauer, Rolf

1997-01-01

Purpose: Experimental and clinical data support effectiveness of perioperative radiotherapy to prevent heterotopic ossification after hip surgery or trauma. Since 1987, two prospectively randomized trials were performed in patients with high-risk factors to develop heterotopic ossification: the first (HOP 1) to assess the prophylactic efficacy of postoperative low vs. medium dose radiotherapy, and the second (HOP 2) to assess the prophylactic efficacy of pre vs. postoperative radiotherapy. Methods and Material: 410 patients with high risk to develop heterotopic ossifications about the hip following hip surgery were recruited. Between June 1987 and June 1992, 249 patients were randomized in HOP 1 to postoperative 'low dose' (5 x 2 Gy; total: 10 Gy) or 'medium dose' (5 x 3.5 Gy; total: 17.5 Gy) radiotherapy. Between July 1992 and December 1995, 161 patients were randomized in HOP 2 to either 1 x 7 Gy preoperatively (≤4 h before surgery) or 5 x 3.5 Gy (total: 17.5 Gy) postoperatively (≤96 h after surgery). With exception of age and type of implant (cemented vs. uncemented prosthesis) all confounding patient variables (gender, prior surgery) and predisposing risk factors were similarly distributed between both trials and treatment arms. Portals encompassed the peri acetabular and intertrochanteric soft tissues. Radiographs were obtained prior and immediately after surgery and at least 6 months after surgery to assess the extent of ectopic bone formation about the hip. Modified Brooker grading was used to score the extent of heterotopic ossification. Harris scoring was applied to evaluate the functional hip status. If the scores decreased from immediate post or preoperative status, respectively, to the last follow-up, radiological or functional failures were assumed. Results: Effective prophylaxis was achieved in 227 (91%) hips of HOP 1 and in 142 (88%) of HOP 2. In HOP 1, 15 (11%) radiological failures were observed in the low-dose group compared to 7 (6%) in the

Combined spinal epidural anesthesia in achondroplastic dwarf for femur surgery

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Rochana Girish Bakhshi

2011-11-01

Full Text Available Achondroplasia is the commonest form of short-limbed dwarfism and occurs in 1:26,000- 40,000 live births. This is an autosomal dominant disorder with abnormal endochondral ossification whereas periosteal and intramembranous ossification are normal. The basic abnormality is a disturbance of cartilage formation mainly at the epiphyseal growth plates and at the base of the skull. The anesthetic management of achondroplastic dwarfs is a challenge to the anesthesiologist. Both regional as well as general anesthesia have their individual risks and consequences. We report a case of an achondroplastic dwarf in whom combined spinal epidural anesthesia was used for fixation of a fractured femur. The patient had undergone previous femur surgery under general anesthesia since he had been informed that spinal anesthesia could be very problematic. There was no technical difficulty encountered during the procedure and an adequate level was achieved with low-dose local anesthetics without any problem. Postoperative pain relief was offered for three consecutive postoperative days using epidural tramadol. We discuss the anesthetic issues and highlight the role of combined spinal epidural anesthesia with low-dose local anesthetics in this patient. This approach also helped in early ambulation and postoperative pain relief.

Apophyseal Ossification of the Iliac Crest in Forensic Age Estimation: Computed Tomography Standards for Modern Australian Subadults.

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Lottering, Nicolene; Alston-Knox, Clair L; MacGregor, Donna M; Izatt, Maree T; Grant, Caroline A; Adam, Clayton J; Gregory, Laura S

2017-03-01

This study contrasts the ontogeny of the iliac crest apophysis using conventional radiography and multislice computed tomography (MSCT), providing probabilistic information for age estimation of modern Australian subadults. Retrospective abdominopelvic MSCT data acquired from 524 Australian individuals aged 7-25 and surveillance radiographs of adolescent idiopathic scoliosis patients included in the Paediatric Spine Research Group Progression Study (n = 531) were assessed. Ossification scoring of pseudo-radiographs and three-dimensional (3D) volume-rendered reconstructions using Risser (1958) quantitative descriptors indicate discrepancies in age estimates, stage allocation, and conflicting morphological progression. To mitigate visualization limitations associated with two-dimensional radiographs, we provide and validate a modified 3D-MSCT scoring tier of ossification, demonstrating complete fusion between 17.3-19.2 and 17.1-20.1 years in males and females. Legal demarcation for doli incapax presumption and age of majority (18 years) can be achieved using probability estimates from a fitted cumulative probit model for apophyseal fusion using the recalibrated standards. © 2016 American Academy of Forensic Sciences.

Significance of radiological diagnosis in complex investigation of necroses of femoral head ossification centers. Pt. 2

Energy Technology Data Exchange (ETDEWEB)

Siegling, C.W.; Endert, G.; Ritter, H.; Schumann, E.

1984-07-01

101 scintigraphic investigations and 42 angiograms show that the vascular tamponade is the decisive factor for the beginning of necrosis of the femoral head ossification center. Plain films, scintigraphy and angiography give information of the duration of the disease. Extent and localisation of the circulatory disturbance are important for the prognosis of the disease. From stage classification and prognostic factors the conclusions for therapy can be drawn.

Expression of interleukin-17B in mouse embryonic limb buds and regulation by BMP-7 and bFGF

International Nuclear Information System (INIS)

You Zongbing; DuRaine, Grayson; Tien, Janet Y.L.; Lee, Corinne; Moseley, Timothy A.; Reddi, A. Hari

2005-01-01

Interleukin-17B (IL-17B) is a member of interleukin-17 family that displays a variety of proinflammatory and immune modulatory activities. In this study, we found that IL-17B mRNA was maximally expressed in the limb buds of 14.5 days post coitus (dpc) mouse embryo and declined to low level at 19.5 dpc. By immunohistochemical staining, the strongest IL-17B signals were observed in the cells of the bone collar in the primary ossification center. The chondrocytes in the resting and proliferative zones were stained moderately, while little staining was seen in the hypertrophic zone. Furthermore, in both C3H10T1/2 and MC3T3-E1 cells, the IL-17B mRNA was up-regulated by recombinant human bone morphogenetic protein-7, but down-regulated by basic fibroblast growth factor via the extracellular signal-regulated kinase pathway. This study provides the first evidence that IL-17B is expressed in the mouse embryonic limb buds and may play a role in chondrogenesis and osteogenesis

Osteochondritis dissecans (OCD), an endoplasmic reticulum storage disease?

DEFF Research Database (Denmark)

Skagen, Peter Storgaard; Horn, T; Kruse, H A

2011-01-01

in chondrocytes and extracellular matrix of cartilage from OCD patients. Abnormal type II collagen heterofibrils in "bundles" and chondrocytes with abnormal accumulation of matrix proteins in distended rough endoplasmic reticulum were typical findings. Further, Von Kossa staining and TEM showed empty lacunae...... close to mineralized "islands" in the cartilage and hypertrophic chondrocytes containing accumulated matrix proteins. Immunostaining revealed: (1) that types I, II, VI and X collagens and aggrecans were deposited intracellulary and (2) co-localization within the islands of types I, II, X collagens...... and aggrecan indicating that hypertrophic chondrocytes express a phenotype of bone cells during endochondral ossification. Types I, VI and X collagens were also present across the entire dissecates suggesting that chondrocytes were dedifferentiated. DNA sequencings were non-conclusive, only single nucleotide...

Aspects of gorgonopsian paleobiology and evolution: insights from the basicranium, occiput, osseous labyrinth, vasculature, and neuroanatomy

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Ricardo Araújo

2017-04-01

Full Text Available Synapsida, the clade including therapsids and thus also mammals, is one of the two major branches of amniotes. Organismal design, with modularity as a concept, offers insights into the evolution of therapsids, a group that experienced profound anatomical transformations throughout the past 270 Ma, eventually leading to the evolution of the mammalian bauplan. However, the anatomy of some therapsid groups remains obscure. Gorgonopsian braincase anatomy is poorly known and many anatomical aspects of the brain, cranial nerves, vasculature, and osseous labyrinth, remain unclear. We analyzed two gorgonopsian specimens, GPIT/RE/7124 and GPIT/RE/7119, using propagation phase contrast synchrotron micro-computed tomography. The lack of fusion between many basicranial and occipital bones in GPIT/RE/7124, which is an immature specimen, allowed us to reconstruct its anatomy and ontogenetic sequence, in comparison with the mature GPIT/RE/7119, in great detail. We explored the braincase and rendered various skull cavities. Notably, we found that there is a separate ossification between what was previously referred to as the “parasphenoid” and the basioccipital. We reinterpreted this element as a posterior ossification of the basisphenoid: the basipostsphenoid. Moreover, we show that the previously called “parasphenoid” is in fact the co-ossification of the dermal parasphenoid and the endochondral basipresphenoid. In line with previous descriptions, the anatomy of the osseous labyrinth is rendered in detail, revealing a unique discoid morphology of the horizontal semicircular canal, rather than toroidal, probably due to architectural constraints of the ossification of the opisthotic and supraoccipital. In addition, the orientation of the horizontal semicircular canal suggests that gorgonopsians had an anteriorly tilted alert head posture. The morphology of the brain endocast is in accordance with the more reptilian endocast shape of other non

Early Identification of Molecular Predictors of Heterotopic Ossification Following Extremity Blast Injury with a Biomarker Assay

Science.gov (United States)

2018-03-01

Charleston SC, 29425 REPORT DATE: March 2018 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick...does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE March 2018 2. REPORT...ossification (HO), characterized by the pathologic formation of mature bone in the soft tissues, is a frequent complication following high energy orthopaedic

Systematic procedure for identifying the five main ossification stages of the medial clavicular epiphysis using computed tomography: a practical proposal for forensic age diagnostics.

Science.gov (United States)

Wittschieber, Daniel; Schulz, Ronald; Pfeiffer, Heidi; Schmeling, Andreas; Schmidt, Sven

2017-01-01

In forensic age estimations of living individuals, computed tomography of the clavicle is widely used for determining the age of majority. To this end, the degree of ossification of the medial clavicular epiphysis can be determined by means of two classification systems complementing each other: a 5-stage system and an additional 6-stage system that further sub-classifies the stages 2 and 3. In recent years, practical experience and new data revealed that difficulties and even wrong stage determinations may occur especially when following the short descriptions of the fundamental 5-stage system only. Based on current literature, this article provides a systematic procedure for identifying the five main ossification stages by listing important preconditions and presenting an algorithm that is comprised of four specific questions. Each question is accompanied by comprehensive and detailed descriptions which specify the criteria used for differentiation. The information is subdivided into "single-slice view" and "multi-slice view." In addition, illustrative case examples and schematic drawings facilitate application of the procedure in forensic practice. The pitfalls associated with the criteria of stage determination will be discussed in detail. Eventually, two general rules will be inferred to assign correct ossification stages of the medial clavicular epiphysis by means of computed tomography.

Quantitative description of the morphology and ossification center in the axial skeleton of 20-week gestation formalin-fixed human fetuses using magnetic resonance images.

Science.gov (United States)

Chabert, Steren; Villalobos, Manuel; Ulloa, Patricia; Salas, Rodrigo; Tejos, Cristian; San Martin, Sebastian; Pereda, Jaime

2012-03-01

Human tissues are usually studied using a series of two-dimensional visualizations of in vivo or cutout specimens. However, there is no precise anatomical description of some of the processes of human fetal development. The purpose of our study is to develop a quantitative description of the normal axial skeleton by means of high-resolution three-dimensional magnetic resonance (MR) images, collected from six normal 20-week-old human fetuses fixed in formaldehyde. Fetuses were collected after spontaneous abortion and subsequently fixed with formalin. They were imaged using a 1.5 T MR scanner with an isotropic spatial resolution of 200 µm. The correct tissue discrimination between ossified and cartilaginous bones was confirmed by comparing the images achieved by MR scans and computerized axial tomographies. The vertebral column was segmented out from each image using a specially developed semi-automatic algorithm. Vertebral body dimensions and inter-vertebral distances were larger in the lumbar region, in agreement with the beginning of the ossification process from the thoracolumbar region toward the sacral and cephalic ends. In this article, we demonstrate the feasibility of using MR images to study the ossification process in formalin-fixed fetal tissues. A quantitative description of the ossification centers of vertebral bodies and arches is presented. © 2012 John Wiley & Sons, Ltd.

Regulation of α5 and αV Integrin Expression by GDF-5 and BMP-7 in Chondrocyte Differentiation and Osteoarthritis.

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David Garciadiego-Cázares

Full Text Available The Integrin β1 family is the major receptors of the Extracellular matrix (ECM, and the synthesis and degradation balance of ECM is seriously disrupted during Osteoarthritis (OA. In this scenario, integrins modify their pattern expression and regulate chondrocyte differentiation in the articular cartilage. Members of the Transforming growth factor beta (Tgf-β Superfamily, such as Growth differentiation factor 5 (Gdf-5 and Bone morphogenetic protein 7 (Bmp-7, play a key role in joint formation and could regulate the integrin expression during chondrocyte differentiation and osteoarthritis progression in an experimental OA rat model. Decrease of α5 integrin expression in articular cartilage was related with chondrocyte dedifferentiation during OA progression, while increase of α1, α2, and α3 integrin expression was related with fibrous areas in articular cartilage during OA. Hypertrophic chondrocytes expressed αV integrin and was increased in the articular cartilage of rats with OA. Integrin expression during chondrocyte differentiation was also analyzed in a micromass culture system of mouse embryo mesenchymal cells, micromass cultures was treated with Gdf-5 or Bmp-7 for 4 and 6 days, respectively. Gdf-5 induced the expression of the α5 sub-unit, while Bmp-7 induced the expression of the αV sub-unit. This suggests a switch in signaling for prehypertrophic chondrocyte differentiation towards hypertrophy, where Gdf-5 could maintain the articular chondrocyte phenotype and Bmp-7 would induce hypertrophy. Decrease of Ihh expression during late stages of OA in rat model suggest that the ossification in OA rat knees and endochondral ossification could be activated by Bmp-7 and αV integrin in absence of Ihh. Thus, chondrocyte phenotype in articular cartilage is similar to prehypetrophic chondrocyte in growth plate, and is preserved due to the presence of Indian hedgehog (Ihh, Gdf-5 and α5 integrin to maintain articular cartilage and prevent

Unusual fan shaped ossification in a female fetus with radiological features of boomerang dysplasia

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Odent, S.; Loget, P.; Le Marec, B.; Delezoide, A.; Maroteaux, P.

1999-01-01

We report on a female fetus of 24 weeks whose clinical and radiological findings were compatible with boomerang dysplasia (BD). However, histopathology was unusual with a lateral fan shaped diaphyseal ossification. This has never been described either in typical atelosteogenesis I (AT-I) or in BD. The purpose of this report is to find out if this condition is a separate lethal bone dysplasia or another histological feature of the nosological group of AT-I and BD. 


Keywords: boomerang dysplasia; atelosteogenesis; lethal chondrodysplasia; lethal dwarfism PMID:10227404

Reliability of Schmeling's stages of ossification of medial clavicular epiphyses and its validity to assess 18 years of age in living subjects.

Science.gov (United States)

Cameriere, R; De Luca, S; De Angelis, D; Merelli, V; Giuliodori, A; Cingolani, M; Cattaneo, C; Ferrante, L

2012-11-01

Nowadays, due to the global increase in migration movements, forensic age estimation of living young adults has become an important focus of interest. Minors often have no identification documents providing their correct birth dates. Establishing the age of majority is therefore fundamental in order to determine whether juvenile penal systems or penal systems in force for adults are to be applied. Radiological examination of the clavicles is one of the methods recommended by the Study Group on Forensic Age Diagnostics. In this retrospective study, a sample of chest radiographs of 274 subjects, aged between 12 and 25 years, was studied according to Schmeling's method in order to examine the ossification of both medial clavicular epiphyses. All stage classifications were evaluated by five examiners. Intra- and inter-examiner reliability was analysed by Cohen's K statistic. Intra-examiner agreement was insufficient for two of the experts. Inter-examiner agreement, among the other three operators, was moderate (K = 0.509). Study of reliability highlighted difficulties in interpretation, the need to select qualified personnel and choice of the best radiographic image in order to reduce any anatomic overlaps. Although ossification of the medial clavicular epiphyses is recommended to assess whether an individual has already reached the age of majority or not, these results suggested that it is very difficult to clearly identify the five stages of ossification by using conventional chest radiography.

Separated centers of ossification caudal to the wing of the pedal bone in horses - a help [to] rule out fractures of the wings and ossification in the accessory cartilages

International Nuclear Information System (INIS)

Hertsch, B.; Neuberth, M.

1991-01-01

Radiographic evaluation of a lat-med. x-ray of the digits of 278 normal three year old standard bred stallions (group I) and of 300 mares and geldings over the age of six years (group II) was made in view of frequency and clinical relevance of a separated center of ossification caudal to each wing of the pedal bone. The material served both age associated judgement and localisation dependant morphological description of these separated ossified bone piece. Through comparative measurements of the angle of the dorsal hoof wall in the two groups of horses, a possible etiological aspect especially concerning the hoof form is discussed, to true nature of this small separated ossified bone piece

Condylar cartilaginous changes after mandibular distraction osteogenesis in rabbits.

Science.gov (United States)

Ahn, Sin-Young; Kim, Su-Gwan

2011-10-01

The purpose of this study was to evaluate histologic and immunohistochemical changes in the condylar articular surface in response to distraction osteogenesis (DO) of the mandibular body in rabbits. A unilateral osteotomy of the mandible at the premolar area was performed in 16 rabbits. The animals were divided into 4 groups based on different distraction parameters (rate and rhythm). After a 5-day latency, the mandible was lengthened by 0.5 mm daily for 6 days (group 1); 0.5 mm twice daily for 3 days (group 2); 0.5 mm once daily for 10 days (group 3); or 0.5 mm twice daily for 5 days (group 4). All 4 groups underwent a 14-day consolidation period. Four rabbits were included in the control group. The specimens were stained with hematoxylin-eosin for histologic examination. Immunohistochemical analysis was performed to evaluate the expression of growth factors. None of the groups demonstrated any degenerative changes in the temporomandibular joint (TMJ). On the distraction side in all groups, the histopathological examination revealed a hypertrophic thickening of the cartilage zone. Prominent endochondral ossification and high active osteoblasts were observed in groups 3 and 4. On the nondistraction side, no major changes were observed excluding the appearance of osteoclasts in groups 3 and 4. The immunohistochemical analysis revealed tenascin immunoreactivity in bone marrow mesenchymal cells on the distraction side in group 4. Connexin immunoreactivity did not display a marked change in any of the groups. Osteocalcin was observed on the distraction side in group 2, which suggested that bone formation is increased. Nitric oxide synthase 2 immunoreactivity was observed on the distraction side in group 2, which is associated with stress and inflammation. The results indicated that the hypertrophy of the cartilage zone and endochondral ossification became more pronounced as the extent and rate of distraction increased. Copyright © 2011 Mosby, Inc. All rights reserved.

Role of c-Myb in chondrogenesis

Czech Academy of Sciences Publication Activity Database

Oralová, Veronika; Matalová, Eva; Janečková, Eva; Drobná Krejčí, E.; Knopfová, L.; Šnajdr, P.; Tucker, A. S.; Veselá, I.; Šmarda, J.; Buchtová, Marcela

2015-01-01

Roč. 76, č. 1 (2015), s. 97-106 ISSN 8756-3282 R&D Projects: GA ČR GCP302/12/J059; GA ČR GB14-37368G Institutional support: RVO:67985904 Keywords : micromass cultures * mouse limbs * endochondral bone Subject RIV: EA - Cell Biology Impact factor: 3.736, year: 2015

Failed rapid sequence induction in an achondroplastic dwarf

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Jasleen Kaur

2011-01-01

Full Text Available Achondroplasia, a common cause of short limbed type of dwarfism is due to quantitative decrease in rate of endochondral ossification. This abnormal bone growth leads to disproportionate body and head structure, thus placing them under high risk for anaesthetic management. There is paucity in literatures, regarding appropriate drug dosage selection in these patients. Use of drugs as per standard dosage recommendations based on body weight or body surface area, may not be adequate in these patients owing to discrepancies in overall body weight and lean body weight, especially during rapid sequence induction. Here, we report a case of failed rapid sequence induction due to abnormal response to administered drugs in an adult achondroplastic dwarf. Standard doses of thiopentone and rocuronium had to be repeated thrice to achieve adequate conditions for intubation.

Urethral dysontogenic metaplasia in cat with bilateral renal dysplasia

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Carolina da Fonseca Sapin

2017-10-01

Full Text Available This paper to describe a case of dysontogenic urethral metaplasia in a one month old mongrel feline who also had bilateral renal dysplasia. Dysontogenic metaplasia in cats are scarce and this change may be associated with renal dysplasia and/or lower urinary tract. The animal had history of abdominal enlargement since birth and dysuria, eliminating urine only dropwise. Due to the poor prognosis we opted for euthanasia. At necropsy was observed enlarged and distended bladder, reduced kidneys and dilated and tortuous ureters. The urethra was thickened, hard to cut, and histologically, was replacing the connective tissue, cartilage and endochondral ossification areas, which features dysontogenic metaplasia. Both kidneys presented primitive appearance featuring dysplasia. Dysontogenic metaplasia in urinary tract feline with renal dysplasia, has not been described.

Heterotopic ossification in civilians with lower limb amputations.

Science.gov (United States)

Matsumoto, Mary E; Khan, Mohammed; Jayabalan, Prakash; Ziebarth, Jessica; Munin, Michael C

2014-09-01

To report the incidence of symptomatic heterotopic ossification (HO) in a defined civilian amputee population, describe its characteristics, and compare these findings to published data in military amputees. Retrospective chart analysis from July 1998 to July 2009. Ambulatory amputee clinic within a large university medical center. Adults with lower limb amputation (N=158). Not applicable. Patients with symptomatic HO confirmed by radiographs. A total of 261 patients were evaluated; 158 met inclusion criteria, with 59% having traumatic etiology, 18% vascular etiology, 22% infection, and 1% tumor. Symptomatic HO was diagnosed in 36 (22.8%) patients, and 94% patients had mild HO on radiographic scoring. Rate of HO in amputations related to trauma was not increased compared with those of other etiologies. Surgical resection of the ectopic bone was required in 4 (11%) patients. HO is seen commonly after civilian lower limb amputation regardless of etiology. The prevalence was less than that observed in previous reports from military populations. This is the first report estimating the prevalence of HO in adult civilian amputees. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Interleukin-6 inhibits early differentiation of ATDC5 chondrogenic progenitor cells.

Science.gov (United States)

Nakajima, Shoko; Naruto, Takuya; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Nishimaki, Shigeru; Yokota, Shumpei

2009-08-01

Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.

Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis.

Science.gov (United States)

Später, Daniela; Hill, Theo P; O'sullivan, Roderick J; Gruber, Michaela; Conner, David A; Hartmann, Christine

2006-08-01

Joints, which separate skeleton elements, serve as important signaling centers that regulate the growth of adjacent cartilage elements by controlling proliferation and maturation of chondrocytes. Accurate chondrocyte maturation is crucial for endochondral ossification and for the ultimate size of skeletal elements, as premature or delayed maturation results predominantly in shortened elements. Wnt9a has previously been implicated as being a player in joint induction, based on gain-of function experiments in chicken and mouse. We show that loss of Wnt9a does not affect joint induction, but results to synovial chondroid metaplasia in some joints. This phenotype can be enhanced by removal of an additional Wnt gene, Wnt4, suggesting that Wnts are playing a crucial role in directing bi-potential chondro-synovioprogenitors to become synovial connective tissue, by actively suppressing their chondrogenic potential. Furthermore, we show that Wnt9a is a temporal and spatial regulator of Indian hedgehog (Ihh), a central player of skeletogenesis. Loss of Wnt9a activity results in transient downregulation of Ihh and reduced Ihh-signaling activity at E12.5-E13.5. The canonical Wnt/beta-catenin pathway probably mediates regulation of Ihh expression in prehypertrophic chondrocytes by Wnt9a, because embryos double-heterozygous for Wnt9a and beta-catenin show reduced Ihh expression, and in vivo chromatin immunoprecipitation demonstrates a direct interaction between the beta-catenin/Lef1 complex and the Ihh promoter.

BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation.

Science.gov (United States)

Minina, E; Wenzel, H M; Kreschel, C; Karp, S; Gaffield, W; McMahon, A P; Vortkamp, A

2001-11-01

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of IHH: Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This

In Vivo Evaluation of Fracture Callus Development During Bone Healing in Mice Using an MRI-compatible Osteosynthesis Device for the Mouse Femur.

Science.gov (United States)

Haffner-Luntzer, Melanie; Müller-Graf, Fabian; Matthys, Romano; Abaei, Alireza; Jonas, René; Gebhard, Florian; Rasche, Volker; Ignatius, Anita

2017-11-14

Endochondral fracture healing is a complex process involving the development of fibrous, cartilaginous, and osseous tissue in the fracture callus. The amount of the different tissues in the callus provides important information on the fracture healing progress. Available in vivo techniques to longitudinally monitor the callus tissue development in preclinical fracture-healing studies using small animals include digital radiography and µCT imaging. However, both techniques are only able to distinguish between mineralized and non-mineralized tissue. Consequently, it is impossible to discriminate cartilage from fibrous tissue. In contrast, magnetic resonance imaging (MRI) visualizes anatomical structures based on their water content and might therefore be able to noninvasively identify soft tissue and cartilage in the fracture callus. Here, we report the use of an MRI-compatible external fixator for the mouse femur to allow MRI scans during bone regeneration in mice. The experiments demonstrated that the fixator and a custom-made mounting device allow repetitive MRI scans, thus enabling longitudinal analysis of fracture-callus tissue development.

Msx2 Stimulates Chondrocyte Maturation by Controlling Ihh Expression*

OpenAIRE

Amano, Katsuhiko; Ichida, Fumitaka; Sugita, Atsushi; Hata, Kenji; Wada, Masahiro; Takigawa, Yoko; Nakanishi, Masako; Kogo, Mikihiko; Nishimura, Riko; Yoneda, Toshiyuki

2008-01-01

Several studies indicated that a homeobox gene, Msx2, is implicated in regulation of skeletal development by controlling enchondral ossification as well as membranous ossification. However, the molecular basis by which Msx2 conducts chondrogenesis is currently unclear. In this study, we examined the role of Msx2 in chondrocyte differentiation using mouse primary chondrocytes and embryonic metatarsal explants. Treatment with BMP2 up-regulated the expression of Msx2 mRNA...

Hormones and growth factors in the pathogenesis of spinal ligament ossification.

Science.gov (United States)

Li, Hai; Jiang, Lei-Sheng; Dai, Li-Yang

2007-08-01

Ossification of the spinal ligaments (OSL) is a pathologic condition that causes ectopic bone formation and subsequently results in various degrees of neurological deficit, but the etiology of OSL remains almost unknown. Some systemic hormones, such as 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), insulin and leptin, and local growth factors, such as transforming growth factor-beta (TGF-beta), and bone morphogenetic protein (BMP), have been studied and are thought to be involved in the initiation and development of OSL. This review article summarizes these studies, delineates the possible mechanisms, and puts forward doubts and new questions. The related findings from studies of genes and target cells in the ligament of OSL are also discussed. Although these findings may be helpful in understanding the pathogenesis of OSL, much more research needs to be conducted in order to investigate the nature of OSL.

Differentiating os acromiale from normally developing acromial ossification centers using magnetic resonance imaging

Energy Technology Data Exchange (ETDEWEB)

Winfeld, Matthew [Children' s National Medical Center, Department of Radiology, Washington, DC (United States); Rosenberg, Zehava Sadka; Wang, Annie; Bencardino, Jenny [New York University School of Medicine, New York, NY (United States)

2015-05-01

Acromial fusion may not be complete until age 18-25, making it questionable to diagnose os acromiale in adolescents. Os acromiale may exist in adolescents and can be differentiated from a developing acromial ossification center based on MRI findings. A total of 128 MRIs of the shoulder were randomly and blindly reviewed retrospectively by two musculoskeletal radiologists. The MRIs consisted of two groups: (1) 56 of os acromiale in adults (25-74 years old, mean, 50) and (2) 72 consecutive of adolescents (12-17 years old, mean, 14.5). The following were assessed at the interface between the distal acromion and os acromiale/developing ossification center(s): presence of os acromiale vs. developing acromion, orientation, margins, and edema within and adjacent to it. Fifty-one adults and 49 adolescents were included. Exclusions were due to poor image quality or confounding findings (n = 7) or complete acromial fusion (n = 21 adolescents). Utilizing accepted definitions of os acromiale, all adult cases (100 %) were accurately diagnosed as os acromiale, with transverse interface orientation and irregular margins (94 %, R = 0.86, p < 0.00001). Forty-five (92 %) adolescent cases were accurately diagnosed as normally developing acromion with arched interface and lobulated margins (92 %, R = 0.92, p < 0.000001). Four (8 %) adolescent cases were diagnosed as having os acromiale, with transverse orientation and irregular margins. Thirty-five (69 %) and 46 (90 %) adults had marrow and interface edema, respectively. Six (12 %) and eight (16 %) adolescents had marrow and interface edema, respectively, including the four concluded to be os acromiale. Adolescents may have imaging findings consistent with os acromiale. The diagnosis of os acromiale should be based on imaging features and not limited by age. (orig.)

Differentiating os acromiale from normally developing acromial ossification centers using magnetic resonance imaging

International Nuclear Information System (INIS)

Winfeld, Matthew; Rosenberg, Zehava Sadka; Wang, Annie; Bencardino, Jenny

2015-01-01

Acromial fusion may not be complete until age 18-25, making it questionable to diagnose os acromiale in adolescents. Os acromiale may exist in adolescents and can be differentiated from a developing acromial ossification center based on MRI findings. A total of 128 MRIs of the shoulder were randomly and blindly reviewed retrospectively by two musculoskeletal radiologists. The MRIs consisted of two groups: (1) 56 of os acromiale in adults (25-74 years old, mean, 50) and (2) 72 consecutive of adolescents (12-17 years old, mean, 14.5). The following were assessed at the interface between the distal acromion and os acromiale/developing ossification center(s): presence of os acromiale vs. developing acromion, orientation, margins, and edema within and adjacent to it. Fifty-one adults and 49 adolescents were included. Exclusions were due to poor image quality or confounding findings (n = 7) or complete acromial fusion (n = 21 adolescents). Utilizing accepted definitions of os acromiale, all adult cases (100 %) were accurately diagnosed as os acromiale, with transverse interface orientation and irregular margins (94 %, R = 0.86, p < 0.00001). Forty-five (92 %) adolescent cases were accurately diagnosed as normally developing acromion with arched interface and lobulated margins (92 %, R = 0.92, p < 0.000001). Four (8 %) adolescent cases were diagnosed as having os acromiale, with transverse orientation and irregular margins. Thirty-five (69 %) and 46 (90 %) adults had marrow and interface edema, respectively. Six (12 %) and eight (16 %) adolescents had marrow and interface edema, respectively, including the four concluded to be os acromiale. Adolescents may have imaging findings consistent with os acromiale. The diagnosis of os acromiale should be based on imaging features and not limited by age. (orig.)

Heterotopic ossification resection after open periarticular combat-related elbow fractures.

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Wilson, Kevin W; Dickens, Jonathan F; Heckert, Reed; Tintle, Scott M; Keeling, John J; Andersen, Romney C; Potter, Benjamin K

2013-01-01

A retrospective review was performed to evaluate the outcomes and complications following heterotopic ossification (HO) resection and lysis of adhesion procedures for posttraumatic contracture, after combat-related open elbow fractures. From 2004 to 2011, HO resection was performed on 30 blast-injured elbows at a mean 10 months after injury. Injuries included 8 (27%) Gustilo-Anderson type II fractures, 8 (27%) type III-A, 10 (33%) III-B, and 4 (13%) III-C. Mean preoperative flexion-extension range of motion (ROM) was 36.4°, compared with mean postoperative ROM of 83.6°. Mean gain of motion was 47.2°. Traumatic brain injury, need for flap, and nerve injury did not appear to have a significant effect on preoperative or postoperative ROM. Complications included one fracture, six recurrent contractures, and one nerve injury. The results and complications of HO resection for elbow contracture following high-energy, open injuries from blast trauma are generally comparable to those reported for HO resection following lower energy, closed injuries.

Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism.

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Zhang, Xinxin; Xing, Xuesha; Liu, Xing; Hu, Yu; Qu, Shengqiang; Wang, Heyi; Luo, Yang

2017-12-26

Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusions of the proximal phalanges of the hands and feet. GDF5 and NOG were identified to be responsible for SYM1. We have previously reported on a p.Leu373Arg mutation in the GDF5 proregion present in a Chinese family with SYM1. Here, we investigated the effects of the GDF-L373R mutation. The variant caused proteolysis efficiency of GDF5 increased in ATDC5 cells. The variant also caused upregulation of SMAD1/5/8 phosphorylation and increased expression of target genes SMURF1 , along with COL2A1 and SOX9 which are factors associated with chondrosis. Furthermore, we developed a human-relevant SYM1 mouse model by making a Gdf5 L367R (the orthologous position for L373R in humans) knock-in mouse. Gdf5 L367R/+ and Gdf5 L367R/L367R mice displayed stiffness and adhesions across the proximal phalanx joint which were in complete accord with SYM1. It was also confirmed the joint formation and development was abnormal in Gdf5 L367R/+ and Gdf5 L367R/L367R mice, including the failure to develop the primary ossification center and be hypertrophic chondrocytes during embryonic development. This knock-in mouse model offers a tool for assessing the pathogenesis of SYM1 and the function of the GDF5 proregion.

Adverse Effect of Trauma on Neurologic Recovery for Patients with Cervical Ossification of the Posterior Longitudinal Ligament

OpenAIRE

Lee, Soo Eon; Jahng, Tae-Ahn; Kim, Hyun-Jib

2015-01-01

Study Design?Retrospective study. Objective?Minor trauma, even from a simple fall, can often cause cervical myelopathy, necessitating surgery in elderly patients who may be unaware of their posterior longitudinal ligament ossification (OPLL). The aim of this study is to determine the influence of trauma on the neurologic course in patients who have undergone surgery for cervical OPLL. Methods?Patients who underwent surgery due to OPLL were divided by trauma history and compared (34 in the tra...

The predisposing factors for the heterotopic ossification after cervical artificial disc replacement.

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Yi, Seong; Shin, Dong Ah; Kim, Keung Nyun; Choi, Gwihyun; Shin, Hyun Chul; Kim, Keun Su; Yoon, Do Heum

2013-09-01

Heterotopic ossification (HO) is defined as a formation of bone outside the skeletal system. The reported HO occurrence rate in cervical artificial disc replacement (ADR) is unexpectedly high and is known to vary. However, the predisposing factors for HO in cervical ADR have not yet been elucidated. Investigation of the predisposing factors of HO in cervical arthroplasty and the relationship between degeneration of the cervical spine and HO occurrence. Retrospective study to discover predisposing factors of HO in cervical arthroplasty. A total of 170 patients who underwent cervical ADR were enrolled including full follow-up clinical and radiologic data. Radiologic outcomes were assessed by identification of HOs according to McAfee's classifications. This study enrolled a total of 170 patients who underwent cervical ADR. Pre-existing degenerative change included anterior or posterior osteophytes, ossification of the anterior longitudinal ligament, posterior longitudinal ligament, or ligamentum nuchae. The relationships between basic patient data, pre-existing degenerative change, and HO were investigated using linear logistic regression analysis. Among all 170 patients, HO was found in 69 patients (40.6%). Among the postulated predisposing factors, only male gender and artificial disc device type were shown to be statistically significant. Unexpectedly, preoperative degenerative changes in the cervical spine exerted no significant influence on the occurrence of HOs. The odds ratio of male gender compared with female gender was 2.117. With regard to device type, the odds ratios of Mobi-C (LDR medical, Troyes, France) and ProDisc-C (Synthes, Inc., West Chester, PA, USA) were 5.262 and 7.449, respectively, compared with the Bryan disc. Definite differences in occurrence rate according to the gender of patients and the prosthesis type were identified in this study. Moreover, factors indefinably expected to influence HO in the past were not shown to be risk factors

Thoracic posterior longitudinal ligament ossification in a fixed population; longitudinal radiological observations

International Nuclear Information System (INIS)

Ono, Minoru; Russell, W.J.; Kudo, Sho.

1984-05-01

All lateral chest radiographs of 34 persons with posterior longitudinal ligament ossification (PLLO) in the thoracic spine were reviewed for date of its onset and its progress. These observations spanned as long as 18 years. Upper mid-thoracic PLLO first appeared under the age of 40, then increased in extent in the vertical axis until the age of 50. Lower thoracic PLLO occurred later than upper mid-thoracic PLLO. In the lower thoracic and lumbar regions, degeneration of the vertebrae and discs apparently were focal factors which triggered the development of thoracic PLLO. PLLO apparently developed in a different way in the upper and mid-thoracic regions, where the vertebrae and discs were unremarkable at the time of its initial appearance, and degenerative abnormalities did not predispose to it. (author)

PIXE study of the kinetics of biomaterials ossification

Science.gov (United States)

Weber, G.; Robaye, G.; Braye, F.; Oudadesse, H.; Irigaray, J. L.

1994-05-01

Biomaterials are frequently implanted in bones. This implantation is followed by a phenomenon of ossification. The purpose of this work was to study the time evolution of the gradient of characteristic atomic element's concentrations in the bone, the implant and the bone-implant interface. We have studied two types of neutral biomaterials: pure synthetic hydroxyapatite and porite's asteroid coral. The animal implantations have been made on sheep of the same age and sex having received the same basic diet. The implantations have been made in the cortical femur. On both sides of the implant, at the same distance, two screws were placed to allow further determination of the position of the implant. The PIXE method is particularly suitable here because of the possibility to analyze directly the samples without any preparation and to choose easily the dimensions of beam used for the gradient study. The X-rays have been detected with an ultra LEGe instead of the usual Si(Li) device to avoid the Si escape peak associated with the K α X-ray of calcium, the major constituent of bone. This peak is particularly disturbing here because its energy corresponds to the K α line of phosphorus, an important constituent of bone. The results of these determinations are presented and discussed.

Solitary Osteochondroma of the Ventral Scapula Associated with Large Bursa Formation and Pseudowinging of the Scapula: A Case Report and Literature Review

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Kiyohisa Ogawa

2018-01-01

Full Text Available Osteochondroma (OC is the most common benign bone tumor and may occur on any bone in which endochondral ossification develops. Although scapular OC accounts for less than 5% of the cases of solitary OC, OC is the most common lesion among the tumors and tumor-like lesions of the scapula. OC that develops near the medial scapular border easily causes friction with the ribcage; hence, almost half the number of cases of OC associated with marked bursa formation develops in the ventral scapula. We report a case of a 27-year-old female with a painful OC of the ventral scapular surface associated with large bursa formation and pseudowinging of the scapula. After l2 years of follow-up with magnetic resonance imaging, we confirm that the accompanied bursa left at surgery disappears.

Osteochondroma in a young cat infected by feline leukemia virus

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Matheus de Oliveira Reis

Full Text Available ABSTRACT: Osteochondromas are primary bone tumors characterized by cartilage-covered bone projections involving single or multiple masses (osteochondromatosis. This study reports the clinical and pathological findings from a young domestic cat with osteochondroma in the humerus. During the clinical evaluation, the animal had pronounced right forelimb musculature atrophy and an increased distal humeral volume. Histopathological examination of the neoplasm revealed a proliferative lesion characterized mostly by endochondral ossification and peripheral foci of proliferating cartilage tissue. Further testing using immunohistochemical staining and polymerase chain reaction revealed the presence of feline leukemia virus antigens in the hematopoietic cells of the bone marrow and FeLV proviral DNA in the peripheral blood lymphocytes. Clinical and pathological findings are consistent with osteochondroma. This neoplasm occurred in an eight-month-old feline with humeral enlargement that had been present since two months old.

Sutura palatina mediana: avaliação do grau de ossificação em crânios humanos Mid-palatal suture: evaluation of the ossification degree in human skulls

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Jussara Ennes

2004-10-01

Full Text Available OBJETIVOS: Avaliar o grau de ossificação da sutura palatina mediana em crânios humanos de diferentes grupos etários. AMOSTRA: Crânios humanos (28 divididos em quatro grupos de acordo com a fase do desenvolvimento cronológico: crianças, adultos jovens, adultos e idosos. MATERIAL: Radiografias Oclusais Totais da Maxila dos crânios dos diferentes grupos (28. Imagens digitalizadas das Radiografias Oclusais Totais da Maxila (28. MÉTODOS: A presença de pontes de ossificação na sutura palatina mediana foi identificada macroscópica e estereomicroscopicamente, registrada e quantificada. Os crânios foram radiografados pela Técnica Oclusal total da Maxila, com modificação na posição do filme, no eixo horizontal. As imagens radiográficas obtidas foram digitalizadas e submetidas à variação de tons claros e escuros e ao ajuste de contraste e brilho para a investigação do grau de ossificação da sutura palatina mediana. CONCLUSÃO: Concluiu-se que a ossificação da sutura palatina mediana inicia-se principalmente na fase adulta e no segmento posterior. A técnica Radiográfica Oclusal Total da Maxila não proporciona imagem adequada à identificação do grau de ossificação na sutura palatina mediana.OBJECTIVES: To analyze the mid-palatal suture ossification rate on human skulls. SAMPLE: Human skulls (28 divided among four groups according to chronological developmental phases: child, teen-ager, adult and elderly. MATERIAL: Maxillary Total Occlusal radiographs from different groups of skulls (28. Digitalized images from Maxillary Total Occlusal radiographs (28. METHODS: The presence of ossification bridges on the mid-palatal suture were identified, registered and qualified. The radiographs of the skulls were taken using the Maxillary Total Occlusal technique, modifying the horizontal position of the film. These radiograph images were digitalized and submitted to brightness and contrast adjustments to investigate mid-palatal suture

Ossification Pattern of Estuarine Dolphin (Sotalia guianensis Forelimbs, from the Coast of the State of Espírito Santo, Brazil.

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Anna Paula Martins de Carvalho

Full Text Available The estuarine dolphin, Sotalia guianensis, is one of the most abundant cetacean species in Brazil. Determination of age and of aspects associated with the development of this species is significant new studies. Counts of growth layer groups in dentin are used to estimate age of these animals, though other ways to evaluate development are also adopted, like the measurement of total length (TL. This study presents a procedure to evaluate the development of the estuarine dolphin based on the ossification pattern of forelimbs. Thirty-seven estuarine dolphins found in the state of Espírito Santo, Brazil, were examined. Age was estimated, TL was measured and ossification of epiphyses was examined by radiography. We analyzed results using the Spearman correlation. Inspection of radiographs allowed evaluation of the significance of the correlation between age and development of the proximal (r = 0.9109 and distal (r = 0.9092 radial epiphyses, and of the distal ulnar epiphyses (r = 0.9055. Radiographic analysis of forelimbs proved to be an appropriate method to evaluate physical maturity, and may be a helpful tool to estimate age of these animals in ecological and population studies.

Ossification of the Interosseous Membrane of the Leg in a Football Player: Case Report and Review of the Literature

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Roberto Postacchini

2016-01-01

Full Text Available Introduction. We report a case of ossification of the interosseous membrane (OIM of the leg in a football player who had no history of severe local traumas. A review of the literature of the OIM of the leg in athletes was also carried out. Case Report. A 38-year-old Caucasian male patient complained of pain on lateral aspect of the leg when playing football. Pain progressively worsened until he had to stop the sporting activity. Radiographs, and then CT and MRI, showed OIM in the middle third of the left leg. MRI showed inflammation of tibia periosteum and bone adjacent to the ossification, which was then excised. Two months after surgery the patient returned to play football. Conclusion. A thorough analysis of the literature revealed three types of OIM of the leg in athletes. Type I usually occurs after a syndesmosis ankle sprain, Type II appears to result from a tibia fracture, and Type III, of which only one fully recorded case has been published, is probably caused, as in our patient, by repetitive minor traumas to the leg. Awareness of the existence of Type III OIM can avoid erroneous diagnoses leading to useless investigations and treatments.

Delayed ossification of the femoral head in dogs with hip dysplasia

International Nuclear Information System (INIS)

Madsen, J.S.; Reimann, I.; Svalastoga, E.

1991-01-01

In humans, delayed ossification of the caput femoris is often seen associated with hip dysplasia in babies. This phenomenon may possibly exist in dogs. In this study, the radiographic appearance of the caput femoris of 13 German shepherd dogs was examined. The dogs underwent pelvic radiography at the age of 14 to 15 days, six weeks, and 12 months. A significant relationship was shown between hip dysplasia and the late appearance of the epiphysis of the caput femoris (P=0–02). At the age of 14 to 15 days it was not possible to see both epiphyses in 54 per cent of the dogs. All of these dogs had hip dysplasia when they were 12 months old. This was in contrast to the six dogs which had both epiphyses visible when they were 14 to 15 days old. At 12 months of age, four of these dogs (67 per cent) did not show any sign of hip dysplasia

Radiotherapy for the prophylaxis of heterotopic ossification: A systematic review and meta-analysis of published data

International Nuclear Information System (INIS)

Popovic, Marko; Agarwal, Arnav; Zhang, Liying; Yip, Cheryl; Kreder, Hans J.; Nousiainen, Markku T.; Jenkinson, Richard; Tsao, May; Lam, Henry; Milakovic, Milica; Wong, Erin; Chow, Edward

2014-01-01

Introduction: Following surgery, the formation of heterotopic ossification (HTO) can limit mobility and impair quality of life. Radiotherapy has been proven to provide efficacious prophylaxis against HTO, especially in high-risk settings. Purpose: The current review aims to determine the factors influencing HTO formation in patients receiving prophylactic radiotherapy. Methods: A systematic search of the literature was conducted on Ovid Medline, Embase and the Cochrane Central Register of Controlled Trials. Studies were included if they reported the percentage of sites developing heterotopic ossification after receiving a specified dose of prophylactic radiotherapy. Weighted linear regression analysis was conducted for continuous or categorical predictors. Results: Extracted from 61 articles, a total of 5464 treatment sites were included, spanning 85 separate study arms. Most sites were from the hip (97.7%), from United States patients (55.2%), and had radiation prescribed postoperatively (61.6%) at a dose of 700 cGy (61.0%). After adjusting for radiation site, there was no statistically significant relationship between the percentage of sites developing HTO and radiation dose (p = 0.1) or whether radiation was administered preoperatively or postoperatively (p = 0.1). Sites with previous HTO formation were more likely to develop recurrent HTO than those without previous HTO formation (p = 0.04). There was a statistically significant negative relationship between the HTO development and the cohort mean year of treatment (p = 0.007). Conclusion: Decreases in rates of HTO over time in this patient population may be a function of more efficacious surgical regimens and prophylactic radiotherapy

Dorsal resection of a thoracic hemivertebra in a 4-year-old boy with endochondral gigantism. A case report.

Science.gov (United States)

Zarghooni, Kourosh; Sobotrke, Rolf; Schmidt, Heinrich; Rollinghoff, Marc; Siewe, Jan; Eysel, Peer

2010-10-01

The authors present what appears to be the first case of congenital kyphosis due to a T12 hemivertebra in a four-year-old boy with endochondral gigantism syndrome of unknown origin. Because of his overgrowth, the patient had severe medical and orthopaedic problems and was almost immobile. Prior to surgery, he experienced a rapidly progressive thoracolumbar kyphosis to 600 (T10-L2). MRI of the brain and spine showed critical protraction of the spinal cord and myelopathy from compression at T12. Single-stage posterior resection of the hemivertebra with spinal shortening and dorsal transpedicular instrumentation of T10-L2 was performed. Although the bone tissue was cartilaginous and dysplastic, 420 (30%) correction was achieved along with decompression of the spinal canal. The patient experienced no neurological impairment post-operatively. At follow-up examination 1.5 year after surgery, the patient's movement disorder had improved markedly and he was able to stand and walk. This very rare case demonstrates that single-stage posterior hemivertebra resection and transpedicular instrumentation for correction of congenital kyphosis can be a safe and effective procedure even in a very challenging case.

Intraoperative 3-dimensional navigation and ultrasonography during posterior decompression with instrumented fusion for ossification of the posterior longitudinal ligament in the thoracic spine.

Science.gov (United States)

Tian, Wei; Weng, Chong; Liu, Bo; Li, Qin; Sun, Yu-Qing; Yuan, Qiang; Zhang, Bo; Wang, Yong-Qing; He, Da

2013-08-01

A retrospective clinical study was conducted. The purpose of this study was to describe the clinical outcomes of intraoperative 3D navigation (ITN) and ultrasonography during posterior decompression and instrumented fusion for thoracic myelopathy due to ossification of the posterior longitudinal ligament (OPLL). The symptoms caused by thoracic-ossification of the posterior longitudinal ligament (T-OPLL) are usually progressive and do not respond to conservative treatment-surgical intervention is the only effective treatment option. Various methods have been described for the treatment of symptomatic T-OPLL, all of which have limitations. The study included 18 patients with T-OPLL who underwent posterior decompression with instrumented fusion from 2006 to 2011. A staged operative procedure was used. First, pedicle screws were placed with ITN and a wide laminectomy was performed with resection of ossification of the ligamentum flavum (if present). With insufficient decompression on intraoperative ultrasonography, additional circumferential decompression was performed through a transpedicular approach. ITN-guided OPLL resection was performed using a burr attached to a navigational tracker. In all cases, posterior instrumented fusion was performed in situ. The outcomes were evaluated with the modified Japanese Orthopaedic Association scores and recovery rates. Intraoperative ultrasonography showed that posterior laminectomy was sufficient in 6 patients; the remaining 12 were treated with additional circumferential decompression. The follow-up period ranged from 1 to 6 years (mean period, 2.8 y). Postoperative transient neurological deterioration occurred in 1 patient, and cerebrospinal fluid leakage occurred in 4 patients. All patients showed neurological recovery with a mean Japanese Orthopaedic Association score that improved from 5.5 points preoperatively to 8.5 points at the final follow-up and a mean recovery rate of 54.5%. Intraoperative ultrasonography and ITN

The Cross-talk Between TGF-β1 and Dlk1 Mediates Early Chondrogenesis During Embryonic Endochondral Ossification

DEFF Research Database (Denmark)

Taipaleenmaki, Hanna; M, Linda; Chen, Li

2012-01-01

Dlkl/Pref-1/FA1 (delta like-1/preadipocyte factor-1/Fetal Antigen-1) is a novel surface marker for embryonic chondroprogenitor cells undergoing lineage progression from proliferation to prehypertrophic stages. However, mechanisms mediating control of its expression during chondrogenesis...... during mesenchymal condensation and chondrocyte proliferation, in parallel with expression of Sox9 and Col2a1, and was down-regulated upon the expression of Col10a1 by hypertrophic chondrocytes. Among a number of molecules that affected chondrogenesis, TGF-β1-induced proliferation of chondroprogenitors...... was associated with decreased Dlk1 expression. This effect was abolished by TGF-β signalling inhibitor SB431542, suggesting regulation of Dlk1/FA1 by TGF-β1 signalling in chondrogenesis. TGF-β1-induced Smad phosphorylation and chondrogenesis were significantly increased in Dlk1 (-/-) MEF, while they were blocked...

Biomechanical effects of spinal cord compression due to ossification of posterior longitudinal ligament and ligamentum flavum: a finite element analysis.

Science.gov (United States)

Kim, Yoon Hyuk; Khuyagbaatar, Batbayar; Kim, Kyungsoo

2013-09-01

Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) have been recognized as causes of myelopathy due to thickening of the ligaments resulting in narrowing of the spinal canal and compression of the spinal cord. However, few studies have focused on predicting stress distribution under conditions of OPLL and OLF based on clinical aspects such as the relationship between level of stress and severity of neurologic symptoms because direct in vivo measurement of stress is very restrictive. In this study, a three-dimensional finite element model of the spinal cord in T12-L1 was developed based on MR images. The von-Mises stresses in the cord and the cross-sectional area of the cord were investigated for various grades and shapes of spinal cord compression in OPLL and OLF. Substantial increases in maximum stresses resulting in the manifestation of spinal cord symptoms occurred when the cross-sectional area was reduced by 30-40% at 60% compression of the antero-posterior diameter of the cord in OPLL and at 4mm compression in OLF. These results indicate that compression greater than these thresholds may induce spinal symptoms, which is consistent with clinical observations. Copyright © 2013 IPEM. Published by Elsevier Ltd. All rights reserved.

Chondroregulatory action of prolactin on proliferation and differentiation of mouse chondrogenic ATDC5 cells in 3-dimensional micromass cultures

International Nuclear Information System (INIS)

Seriwatanachai, Dutmanee; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2012-01-01

Highlights: ► Mouse chondrogenic ATDC5 cells expressed PRL receptor mRNAs and proteins. ► Low PRL concentration (10 ng/mL) increased chondrocyte viability and differentiation. ► Higher PRL concentrations (⩾100 ng/mL) decreased viability and increased apoptosis. -- Abstract: A recent investigation in lactating rats has provided evidence that the lactogenic hormone prolactin (PRL) increases endochondral bone growth and bone elongation, presumably by accelerating apoptosis of hypertrophic chondrocytes in the growth plate and/or subsequent chondrogenic matrix mineralization. Herein, we demonstrated the direct chondroregulatory action of PRL on proliferation, differentiation and apoptosis of chondrocytes in 3-dimensional micromass culture of mouse chondrogenic ATDC5 cell line. The results showed that ATDC5 cells expressed PRL receptor (PRLR) transcripts, and responded typically to PRL by downregulating PRLR expression. Exposure to a low PRL concentration of 10 ng/mL, comparable to the normal levels in male and non-pregnant female rats, increased chondrocyte viability, differentiation, proteoglycan accumulation, and mRNA expression of several chondrogenic differentiation markers, such as Sox9, ALP and Hspg2. In contrast, high PRL concentrations of ⩾100 ng/mL, comparable to the levels in pregnancy or lactation, decreased chondrocyte viability by inducing apoptosis, with no effect on chondrogenic marker expression. It could be concluded that chondrocytes directly but differentially responded to non-pregnant and pregnant/lactating levels of PRL, thus suggesting the stimulatory effect of PRL on chondrogenesis in young growing individuals, and supporting the hypothesis of hypertrophic chondrocyte apoptosis in the growth plate of lactating rats.

Histological and morphological evaluation of condylar cartilage of young rats in response to stimulation of mandibular protrusion

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Milena Peixoto Nogueira de Sá

2017-08-01

Full Text Available The aim of this study was to evaluate the histogical and morphological aspects of the condyle in response to mandibular protrusion induced by composite resin occlusal planes. Thirty five-week-old male Wistar rats were selected and randomly divided in two groups. One group received a composite resin type of oclusal plane that induced mandibular protrusion, and the other was the control group, without treatment. Animals were euthanized after experimental time intervals of 7, 21 and 30 days. For histological analysis, thickness of the proliferative, serial and hypertrophic layers was measured, as well as each layer separately. The highest difference in cartilage thickness was observed at day 21, showing a significant increase of the proliferative layer. There were also other histomorphological changes related to occlusal plane interference. Condylar forward repositioning induced by composite occlusal planes influenced the endochondral ossification, increasing the proliferative layer.

Continuous and intermittent exposure of neonatal rat calvarial cells to PTHrP (1-36 inhibits bone nodule mineralization in vitro by downregulating bone sialoprotein expression via the cAMP signaling pathway [v2; ref status: indexed, http://f1000r.es/18x

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Suzan A Kamel

2013-06-01

Full Text Available The development and growth of the skeleton in the absence of parathyroid-hormone-related protein (PTHrP is abnormal.  The shortening of appendicular bones in PTHrP gene null mice is explained by an effect of PTHrP on endochondral bone growth.  Whether or not PTHrP influences intramembranous ossification is less clear.  The purpose of this study was to determine the effect of exogenous PTHrP on intramembranous ossification in vitro.  Neonatal rat calvarial cells maintained in primary cell culture conditions that permit spontaneous formation of woven bone nodules by intramembranous ossification were studied. The expression of PTHrP, parathyroid hormone 1 receptor (PTH1R, and alkaline phosphatase (AP by osteogenic cells in developing nodules and the effects of PTHrP (1-36 on nodule development was determined over 3-18 days. PTHrP and PTH1R were detected colonies of osteogenic cells on culture day three, and AP was detected on day six. PTHrP and its receptor were localized in pre-osteoblasts, osteoblasts, and osteocytes, and AP activity was detected in pre-osteoblasts and osteoblasts but not osteocytes. Continuous and intermittent exposure to PTHrP (1-36 decreased the number of mineralized bone nodules and bone sialoprotein (BSP mRNA and protein, but had no effect on the number of AP-positive osteogenic cell colonies, cell proliferation, apoptosis, or osteopontin (OPN mRNA. These results demonstrate that osteogenic cells that participate in the formation of woven bone nodules in vitro exhibit PTHrP and PTH1R before they demonstrate AP activity. Exogenous PTHrP (1-36 inhibits the mineralization of woven bone deposited during bone nodule formation in vitro, possibly by reducing the expression of BSP.

In Vivo Determination of Vitamin D Function Using Transgenic Mice Carrying a Human Osteocalcin Luciferase Reporter Gene

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Tomoko Nakanishi

2013-01-01

Full Text Available Vitamin D is an essential factor for ossification, and its deficiency causes rickets. Osteocalcin, which is a noncollagenous protein found in bone matrix and involved in mineralization and calcium ion homeostasis, is one of the major bone morphogenetic markers and is used in the evaluation of osteoblast maturation and osteogenic activation. We established transgenic mouse line expressing luciferase under the control of a 10-kb osteocalcin enhancer/promoter sequence. Using these transgenic mice, we evaluated the active forms of vitamins D2 and D3 for their bone morphogenetic function by in vivo bioluminescence. As the result, strong activity for ossification was observed with 1α,25-hydroxyvitamin D3. Our mouse system can offer a feasible detection method for assessment of osteogenic activity in the development of functional foods and medicines by noninvasive screening.

Effects of non-steroidal anti-inflammatory drugs on cell proliferation and death in cultured epiphyseal-articular chondrocytes of fetal rats

International Nuclear Information System (INIS)

Chang, J.-K.; Wu, S.-C.; Wang, G.-J.

2006-01-01

Previous reports indicated that non-steroidal anti-inflammatory drugs (NSAIDs) suppress bone repair. Our previous study further found that ketorolac delayed the endochondral bone formation, and the critical effective timing was at the early stage of repair. Furthermore, we found that NSAIDs suppressed proliferation and induced cell death of cultured osteoblasts. In this study, we hypothesized that chondrocytic proliferation and death, which plays an important role at the early stage of endochondral bone formation, might be affected by NSAIDs. Non-selective NSAIDs, indomethacin, ketorolac, diclofenac and piroxicam; cyclooxygenase-2 (COX-2) selective NSAIDs, celecoxib and DFU (an analog of rofecoxib); prostaglandins (PGs), PGE1, PGE2 and PGF2α; and each NSAID plus each PG were tested. The effects of NSAIDs on proliferation, cell cycle kinetics, cytotoxicity and cell death of epiphyseal-articular chondrocytes of fetal rats were examined. The results showed that all the tested NSAIDs, except DFU, inhibited thymidine incorporation of chondrocytes at a concentration range (10 -8 to 10 -4 M) covering the theoretic therapeutic concentrations. Cell cycle was arrested by NSAIDs at the G /G 1 phase. Upon a 24 h treatment, LDH leakage and cell death (both apoptosis and necrosis) were significantly induced by the four non-selective NSAIDs in chondrocyte cultures. However, COX-2 inhibitors revealed non-significant effects on cytotoxicity of chondrocytes except higher concentration of celecoxib (10 -4 M). Replenishments of PGE1, PGE2 or PGF2α could not reverse the effects of NSAIDs on chondrocytic proliferation and cytotoxicity. In this study, we found that therapeutic concentrations of non-selective NSAIDs caused proliferation suppression and cell death of chondrocytes, suggesting these adverse effects may be one of the reasons that NSAIDs delay the endochondral ossification during bone repair found in previous studies. Furthermore, these effects of NSAIDs may act via PG

Comparison of ossification of demineralized bone, hydroxyapatite, Gelfoam, and bone wax in cranial defect repair.

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Papay, F A; Morales, L; Ahmed, O F; Neth, D; Reger, S; Zins, J

1996-09-01

Demineralized bone allografts in the repair of calvarial defects are compared with other common bone fillers. This study uses a video-digitizing radiographic analysis of calvarial defect ossification to determine calcification of bone defects and its relation to postoperative clinical examination and regional controls. The postoperative clinical results at 3 months demonstrated that bony healing was greatest in bur holes filled with demineralized bone and hydroxyapatite. Radiographic analysis demonstrated calcification of demineralized bone-filled defects compared to bone wax- and Gelfoam-filled regions. Hydroxyapatite granules are radiographically dense, thus not allowing accurate measurement of true bone healing. The results suggest that demineralized bone and hydroxyapatite provide better structural support via bone healing to defined calvarial defects than do Gelfoam and bone wax.

A diminutive perinate European Enantiornithes reveals an asynchronous ossification pattern in early birds.

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Knoll, Fabien; Chiappe, Luis M; Sanchez, Sophie; Garwood, Russell J; Edwards, Nicholas P; Wogelius, Roy A; Sellers, William I; Manning, Phillip L; Ortega, Francisco; Serrano, Francisco J; Marugán-Lobón, Jesús; Cuesta, Elena; Escaso, Fernando; Sanz, Jose Luis

2018-03-05

Fossils of juvenile Mesozoic birds provide insight into the early evolution of avian development, however such fossils are rare. The analysis of the ossification sequence in these early-branching birds has the potential to address important questions about their comparative developmental biology and to help understand their morphological evolution and ecological differentiation. Here we report on an early juvenile enantiornithine specimen from the Early Cretaceous of Europe, which sheds new light on the osteogenesis in this most species-rich clade of Mesozoic birds. Consisting of a nearly complete skeleton, it is amongst the smallest known Mesozoic avian fossils representing post-hatching stages of development. Comparisons between this new specimen and other known early juvenile enantiornithines support a clade-wide asynchronous pattern of osteogenesis in the sternum and the vertebral column, and strongly indicate that the hatchlings of these phylogenetically basal birds varied greatly in size and tempo of skeletal maturation.

A novel osteogenic oxysterol compound for therapeutic development to promote bone growth: activation of hedgehog signaling and osteogenesis through smoothened binding.

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Montgomery, Scott R; Nargizyan, Taya; Meliton, Vicente; Nachtergaele, Sigrid; Rohatgi, Rajat; Stappenbeck, Frank; Jung, Michael E; Johnson, Jared S; Aghdasi, Bayan; Tian, Haijun; Weintraub, Gil; Inoue, Hirokazu; Atti, Elisa; Tetradis, Sotirios; Pereira, Renata C; Hokugo, Akishige; Alobaidaan, Raed; Tan, Yanlin; Hahn, Theodor J; Wang, Jeffrey C; Parhami, Farhad

2014-08-01

Osteogenic factors are often used in orthopedics to promote bone growth, improve fracture healing, and induce spine fusion. Osteogenic oxysterols are naturally occurring molecules that were shown to induce osteogenic differentiation in vitro and promote spine fusion in vivo. The purpose of this study was to identify an osteogenic oxysterol more suitable for clinical development than those previously reported, and evaluate its ability to promote osteogenesis in vitro and spine fusion in rats in vivo. Among more than 100 oxysterol analogues synthesized, Oxy133 induced significant expression of osteogenic markers Runx2, osterix (OSX), alkaline phosphatase (ALP), bone sialoprotein (BSP), and osteocalcin (OCN) in C3H10T1/2 mouse embryonic fibroblasts and in M2-10B4 mouse marrow stromal cells. Oxy133-induced activation of an 8X-Gli luciferase reporter, its direct binding to Smoothened, and the inhibition of Oxy133-induced osteogenic effects by the Hedgehog (Hh) pathway inhibitor, cyclopamine, demonstrated the role of Hh pathway in mediating osteogenic responses to Oxy133. Oxy133 did not stimulate osteogenesis via BMP or Wnt signaling. Oxy133 induced the expression of OSX, BSP, and OCN, and stimulated robust mineralization in primary human mesenchymal stem cells. In vivo, bilateral spine fusion occurred through endochondral ossification and was observed in animals treated with Oxy133 at the fusion site on X-ray after 4 weeks and confirmed with manual assessment, micro-CT (µCT), and histology after 8 weeks, with equal efficiency to recombinant human bone morphogenetic protein-2 (rhBMP-2). Unlike rhBMP-2, Oxy133 did not induce adipogenesis in the fusion mass and resulted in denser bone evidenced by greater bone volume/tissue volume (BV/TV) ratio and smaller trabecular separation. Findings here suggest that Oxy133 has significant potential as an osteogenic molecule with greater ease of synthesis and improved time to fusion compared to previously studied oxysterols. Small

The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization.

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Joeng, Kyu Sang; Long, Fanxin

2009-12-01

Indian hedgehog (Ihh) critically regulates multiple aspects of endochondral bone development. Although it is generally believed that all Ihh functions are mediated by the Gli family of transcription activators and repressors, formal genetic proof for this notion has not been provided. Moreover, the extent to which different Gli proteins contribute to Ihh functions is not fully understood. Previous work has shown that de-repression of the Gli3 repressor is the predominant mode through which Ihh controls chondrocyte proliferation and maturation, but that osteoblast differentiation and hypertrophic cartilage vascularization require additional mechanisms. To test the involvement of Gli2 activation in these processes, we have generated a mouse strain that expresses a constitutive Gli2 activator in a Cre-dependent manner, and have attempted to rescue the Ihh-null mouse with the Gli2 activator, either alone or in combination with Gli3 removal. Here, we report that the Gli2 activator alone is sufficient to induce vascularization of the hypertrophic cartilage in the absence of Ihh but requires simultaneous removal of Gli3 to restore osteoblast differentiation. These results therefore provide direct genetic evidence that Gli2 and Gli3 collectively mediate all major aspects of Ihh function during endochondral skeletal development.

The influence of heterotopic ossification on functional status of hip joint following total hip arthroplasty

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Pohl, F.; Seufert, J.; Flentje, M.; Koelbl, O. [Wuerzburg Univ. (Germany). Dept. of Radiotherapy; Tauscher, A.; Springorum, H.W. [Caritas Krankenhaus Bad Mergentheim (Germany). Orthopedic Clinic; Lehmann, H. [Caritas Krankenhaus Bad Mergentheim (Germany). Inst. of Radiology

2005-08-01

Purpose: The functional failure induced by heterotopic ossification (HO) following total hip arthroplasty (THA) was analyzed and correlated to the radiologic failure. Patients and methods: From July 1997 to July 2001, 315 patients (345 hips) received THA indicated by a hypertrophic osteoarthritis of higher degree (Kellgren grade III, IV). All patients were irradiated prophylactically for prevention of HO on the evening before surgery with a 7-Gy single fraction. The patients' median age was 66.3 years. Radiologic failure was assessed by comparison of pre- and postoperative hip X-rays (immediately and 6 months after surgery). Analysis of radiographs was performed according to the Brooker Score. Clinical failure was appraised by measurement of passive range of motion (ROM) of the hip joint with a standard goniometer. The t-test was used for statistical analysis. Results: 281 patients (81.5%) did not develop HO. HO of Brooker grade I or II was found in 58 patients (16.8%). Six patients (1.7%) developed HO Brooker grade III or IV. There was a significant negative correlation between the degree of radiologic and clinical failure. ROM differed significantly between patients with HO Brooker grade 0, I, II and patients with HO Brooker grade III, IV. Comparing the pre- and postoperative ROM, all patients with Brooker grade 0, I and II showed a significant improvement of flexion, internal and external rotation, abduction and adduction movement. Patients with HO Brooker grade III and IV showed no improvement of ROM in the postoperative follow-up. Conclusion: The development of HO following THA influences the physical function of the hip joint dependent on the degree of ossification. HO of lower degree (Brooker I, II) does not influence the clinical outcome, whereas HO of higher degree (Brooker III, IV) reduces the function of hip arthroplasty. Therefore, the purpose of a prophylactic therapy must be to reduce HO of higher degree. (orig.)

Chondroregulatory action of prolactin on proliferation and differentiation of mouse chondrogenic ATDC5 cells in 3-dimensional micromass cultures

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Seriwatanachai, Dutmanee [Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok (Thailand); Krishnamra, Nateetip [Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok (Thailand); Department of Physiology, Faculty of Science, Mahidol University, Bangkok (Thailand); Charoenphandhu, Narattaphol, E-mail: naratt@narattsys.com [Center of Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok (Thailand); Department of Physiology, Faculty of Science, Mahidol University, Bangkok (Thailand)

2012-03-30

Highlights: Black-Right-Pointing-Pointer Mouse chondrogenic ATDC5 cells expressed PRL receptor mRNAs and proteins. Black-Right-Pointing-Pointer Low PRL concentration (10 ng/mL) increased chondrocyte viability and differentiation. Black-Right-Pointing-Pointer Higher PRL concentrations ( Greater-Than-Or-Slanted-Equal-To 100 ng/mL) decreased viability and increased apoptosis. -- Abstract: A recent investigation in lactating rats has provided evidence that the lactogenic hormone prolactin (PRL) increases endochondral bone growth and bone elongation, presumably by accelerating apoptosis of hypertrophic chondrocytes in the growth plate and/or subsequent chondrogenic matrix mineralization. Herein, we demonstrated the direct chondroregulatory action of PRL on proliferation, differentiation and apoptosis of chondrocytes in 3-dimensional micromass culture of mouse chondrogenic ATDC5 cell line. The results showed that ATDC5 cells expressed PRL receptor (PRLR) transcripts, and responded typically to PRL by downregulating PRLR expression. Exposure to a low PRL concentration of 10 ng/mL, comparable to the normal levels in male and non-pregnant female rats, increased chondrocyte viability, differentiation, proteoglycan accumulation, and mRNA expression of several chondrogenic differentiation markers, such as Sox9, ALP and Hspg2. In contrast, high PRL concentrations of Greater-Than-Or-Slanted-Equal-To 100 ng/mL, comparable to the levels in pregnancy or lactation, decreased chondrocyte viability by inducing apoptosis, with no effect on chondrogenic marker expression. It could be concluded that chondrocytes directly but differentially responded to non-pregnant and pregnant/lactating levels of PRL, thus suggesting the stimulatory effect of PRL on chondrogenesis in young growing individuals, and supporting the hypothesis of hypertrophic chondrocyte apoptosis in the growth plate of lactating rats.

The connection between cellular mechanoregulation and tissue patterns during bone healing.

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Repp, Felix; Vetter, Andreas; Duda, Georg N; Weinkamer, Richard

2015-09-01

The formation of different tissues in the callus during secondary bone healing is at least partly influenced by mechanical stimuli. We use computer simulations to test the consequences of different hypotheses of the mechanoregulation at the cellular level on the patterns of tissues formed during healing. The computational study is based on an experiment on sheep, where after a tibial osteotomy, histological sections were harvested at different time points. In the simulations, we used a recently proposed basic phenomenological model, which allows ossification to occur either via endochondral or intramembranous ossification, but tries otherwise to employ a minimal number of simulation parameters. The model was extended to consider also the possibility of bone resorption and consequently allowing a description of the full healing progression till the restoration of the cortex. Specifically, we investigated how three changes in the mechanoregulation influence the resulting tissue patterns: (1) a time delay between stimulation of the cell and the formation of the tissue, (2) a variable mechanosensitivity of the cells, and (3) an independence of long time intervals of the soft tissue maturation from the mechanical stimulus. For all three scenarios, our simulations do not show qualitative differences in the time development of the tissue patterns. Largest differences were observed in the intermediate phases of healing in the amount and location of the cartilage. Interestingly, the course of healing was virtually unaltered in case of scenario (3) where tissue maturation proceeded independent of mechanical stimulation.

Bioburden Increases Heterotopic Ossification Formation in an Established Rat Model.

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Pavey, Gabriel J; Qureshi, Ammar T; Hope, Donald N; Pavlicek, Rebecca L; Potter, Benjamin K; Forsberg, Jonathan A; Davis, Thomas A

2015-09-01

Heterotopic ossification (HO) develops in a majority of combat-related amputations wherein early bacterial colonization has been considered a potential early risk factor. Our group has recently developed a small animal model of trauma-induced HO that incorporates many of the multifaceted injury patterns of combat trauma in the absence of bacterial contamination and subsequent wound colonization. We sought to determine if (1) the presence of bioburden (Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus [MRSA]) increases the magnitude of ectopic bone formation in traumatized muscle after amputation; and (2) what persistent effects bacterial contamination has on late microbial flora within the amputation site. Using a blast-related HO model, we exposed 48 rats to blast overpressure, femur fracture, crush injury, and subsequent immediate transfemoral amputation through the zone of injury. Control injured rats (n = 8) were inoculated beneath the myodesis with phosphate-buffered saline not containing bacteria (vehicle) and treatment rats were inoculated with 1 × 10(6) colony-forming units of A baumannii (n = 20) or MRSA (n = 20). All animals formed HO. Heterotopic ossification was determined by quantitative volumetric measurements of ectopic bone at 12-weeks postinjury using micro-CT and qualitative histomorphometry for assessment of new bone formation in the residual limb. Bone marrow and muscle tissue biopsies were collected from the residual limb at 12 weeks to quantitatively measure the bioburden load and to qualitatively determine the species-level identification of the bacterial flora. At 12 weeks, we observed a greater volume of HO in rats infected with MRSA (68.9 ± 8.6 mm(3); 95% confidence interval [CI], 50.52-85.55) when compared with A baumannii (20.9 ± 3.7 mm(3); 95% CI, 13.61-28.14; p infection but were positive for other strains of bacteria (1.33 × 10(2) ± 0.89 × 10(2); 95% CI, -0.42 × 10(2)-3.08 × 10(2) and 1.25 × 10(6) ± 0

Trauma-Induced Heterotopic Ossification Regulates the Blood-Nerve Barrier

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Zbigniew Gugala

2018-06-01

Full Text Available De novo bone formation can occur in soft tissues as a result of traumatic injury. This process, known as heterotopic ossification (HO, has recently been linked to the peripheral nervous system. Studies suggest that HO may resemble neural crest-derived bone formation and is activated through the release of key bone matrix proteins leading to opening of the blood-nerve barrier (BNB. One of the first steps in this process is the activation of a neuro-inflammatory cascade, which results in migration of chondro-osseous progenitors, and other cells from both the endoneurial and perineurial regions of the peripheral nerves. The perineurial cells undergo brown adipogenesis, to form essential support cells, which regulate expression and activation of matrix metallopeptidase 9 (MMP9 an essential regulatory protein involved in opening the BNB. However, recent studies suggest that, in mice, a key bone matrix protein, bone morphogenetic protein 2 (BMP2 is able to immediately cross the BNB to activate signaling in specific cells within the endoneurial compartment. BMP signaling correlates with bone formation and appears critical for the induction of HO. Surprisingly, several other bone matrix proteins have also been reported to regulate the BNB, leading us to question whether these matrix proteins are important in regulating the BNB. However, this temporary regulation of the BNB does not appear to result in degeneration of the peripheral nerve, but rather may represent one of the first steps in innervation of the newly forming bone.

Postoperative Paralysis From Thoracic Ossification of Posterior Longitudinal Ligament Surgery Risk Factor of Neurologic Injury: Nationwide Multiinstitution Survey.

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Ito, Zenya; Matsuyama, Yukihiro; Ando, Muneharu; Kawabata, Shigenori; Kanchiku, Tsukasa; Kida, Kazunobu; Fujiwara, Yasushi; Yamada, Kei; Yamamoto, Naoya; Kobayashi, Sho; Saito, Takanori; Wada, Kanichiro; Tadokoro, Nobuaki; Takahashi, Masato; Satomi, Kazuhiko; Shinomiya, Kenichi; Tani, Toshikazu

2016-10-01

Retrospective case-control study. The purpose of this study was to examine the factors of postoperative paralysis in patients who have undergone thoracic ossification of posterior longitudinal ligament (OPLL) surgery. A higher percentage of thoracic OPLL patients experience postoperative aggravation of paralysis than cervical OPLL patients, including patients that presented great difficulties in treatment. However, there were a few reports to prevent paralysis thoracic OPLL. The 156 patients who had received thoracic OPLL surgery were selected as the subjects of this study. The items for review were the duration of disease; the preoperative muscle strength (Muscle Manual Testing); OPLL levels (T1/2-4/5: high, T5/6-8/9: middle, and T9/10-11/12: low); the spinal canal occupancy ratio; the ratio of yellow ligament ossification as a complication; the ratio of transcranial-motor evoked potential (Tc-MEP) derivation; the preoperative/postoperative kyphotic angles in the thoracic vertebrae; the correction angle of kyphosis; the duration of surgery; and the amount of bleeding. The subjects were divided into two groups based on the absence or presence of postoperative paralysis to determine the factors of postoperative paralysis. Twenty-three patients (14.7%) exhibited postoperative paralysis. Multivariate analysis identified factors associated with postoperative paralysis: the duration of disease (odds ratio, OR = 3.3); the correction angle of kyphosis (OR = 2.4); and the ratio of Tc-MEP derivation (OR = 2.2). The risk factors of postoperative paralysis are a short duration of disease and a small correction angle of kyphosis. In addition, ratios of Tc-MEP derivation below 50% may anticipate paralysis. 4.

Restricted Mandibular Movement Attributed to Ossification of Mandibular Depressors and Medial Pterygoid Muscles in Patients With Fibrodysplasia Ossificans Progressiva: A Report of 3 Cases.

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Okuno, Tetsuko; Suzuki, Hitoshi; Inoue, Akio; Kusukawa, Jingo

2017-09-01

Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic condition characterized by congenital malformation and progressive heterotopic ossification (HO) caused by a recurrent single nucleotide substitution at position 617 in the ACVR1 gene. As the condition progresses, HO leads to joint ankylosis, breathing difficulties, and mouth-opening restriction, and it can shorten the patient's lifespan. This report describes 3 cases of FOP confirmed by genetic testing in patients with restricted mouth opening. Each patient presented a different onset and degree of jaw movement restriction. The anatomic ossification site of the mandibular joint was examined in each patient using reconstructed computed tomographic (CT) images and 3-dimensional reconstructed CT (3D-CT) images. A 29-year-old woman complained of jaw movement restriction since 13 years of age. 3D-CT image of the mandibular joint showed an osseous bridge, formed by the mandibular depressors that open the mouth, between the hyoid bone and the mentum of the mandible. A 39-year-old man presented with jaw movement restriction that developed at 3 years of age after a mouth injury. 3D-CT image of the jaw showed ankylosis of the jaw from ossification of the mandibular depressors that was worse than in patient 1. CT images showed no HO findings of the masticatory muscles. To the authors' knowledge, these are the first 2 case descriptions of the anatomic site of ankylosis involving HO of the mandibular depressors in the jaw resulting from FOP. In contrast, a 62-year-old bedridden woman with an interincisal distance longer than 10 mm (onset, 39 years of age) had no HO of the mandibular depressors and slight HO of the medial pterygoid muscle on the right and left sides. These findings suggest that restricted mouth opening varies according to the presence or absence of HO of the mandibular depressors. Copyright © 2017. Published by Elsevier Inc.

Distribution of genes for parathyroid hormone (PTH)-related peptide, Indian hedgehog, PTH receptor and patched in the process of experimental spondylosis in mice.

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Nakase, Takanobu; Ariga, Kenta; Meng, Wenxiang; Iwasaki, Motoki; Tomita, Tetsuya; Myoui, Akira; Yonenobu, Kazuo; Yoshikawa, Hideki

2002-07-01

Little is known about the molecular mechanisms underlying the process of spondylosis. The authors determined the extent of genetic localization of major regulators of chondrogenesis such as Indian hedgehog (Ihh) and parathyroid hormone (PTH)-related peptide (PTHrP) and their receptors during the development of spondylosis in their previously established experimental mouse model. Experimental spondylosis was induced in 5-week-old ICR mice. The cervical spines were chronologically harvested, and histological sections were prepared. Messenger (m) RNA for PTHrP, Ihh, PTH receptor (PTHR; a receptor for PTHrP), patched (Ptc; a receptor for Ihh), bone morphogenetic protein (BMP)-6, and collagen type X (COL10; a marker for mature chondrocyte) was localized in the tissue sections by performing in situ hybridization. In the early stage, mRNA for COL10, Ihh, and BMP-6 was absent; however, mRNA for PTHrP, PTHR, and Ptc was detected in the anterior margin of the cervical discs. In the late stage, evidence of COL10 mRNA began to be detected, and transcripts for Ihh, PTHrP, and BMP-6 were localized in hypertrophic chondrocytes adjacent to the bone-forming area in osteophyte. Messenger RNA for Ptc and PTHR continued to localize at this stage. In control mice, expression of these genes was absent. The localization of PTHrP, Ihh, BMP-6, and the receptors PTHR and Ptc demonstrated in the present experimental model indicates the possible involvement of molecular signaling by PTHrP (through the PTHR), Ihh (through the Ptc), and BMP-6 in the regulation of chondrocyte maturation leading to endochondral ossification in spondylosis.

[CHARACTERISTICS OF OSTEOCYTE CELL LINES FROM BONES FORMED AS A RESULT OF MEMBRANOUS (SKULL BONES) AND CHONDRAL (LONG BONES) OSSIFICATION].

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Avrunin, A S; Doktorov, A A

2016-01-01

The aim of this work was to analyze the literature data and the results of authors' own research, to answer the question--if the osteocytes of bone tissues resulting from membranous and chondral ossification, belong to one or to different cell lines. The differences between the cells of osteocyte lines derived from bones resulting from membranous and chondral ossification were established in: 1) the magnitude of the mechanical signal, initiating the development of the process of mechanotransduction; 2) the nature of the relationship between the magnitude of the mechanical signal that initiates the reorganization of the architecture of bone structures and the resource of their strength; in membranous bones significantly lower mechanical signal caused a substantially greater increment of bone strength resource; 3) the biological activity of bone structures, bone fragments formed from membranous tissue were more optimal for transplantation; 4) the characteristics of expression of functional markers of bone cells at different stages of their differentiation; 5) the nature of the reaction of bone cells to mechanical stress; 6) the sensitivity of bone cells to one of the factors controlling the process of mechanotransduction (PGI2); 7) the functioning of osteocytes during lactation. These differences reflect the functional requirements to the bones of the skeleton--the supporting function in the bones of the limbs and the shaping and protection in the bones of the cranial vault. These data suggest that the results of research conducted on the bones of the skull, should not be transferred to the entire skeleton as a whole.

Endurance exercise and growth hormone improve bone formation in young and growth-retarded chronic kidney disease rats.

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Troib, Ariel; Guterman, Mayan; Rabkin, Ralph; Landau, Daniel; Segev, Yael

2016-08-01

Childhood chronic kidney disease (CKD) is associated with both short stature and abnormal bone mineralization. Normal longitudinal growth depends on proper maturation of epiphyseal growth plate (EGP) chondrocytes, leading to the formation of trabecular bone in the primary ossification centre. We have recently shown that linear growth impairment in CKD is associated with impaired EGP growth hormone (GH) receptor signalling and that exercise improved insulin-like growth factor I (IGF-I) signalling in CKD-related muscle atrophy. In this study, 20-day-old rats underwent 5/6 nephrectomy (CKD) or sham surgery (C) and were exercised with treadmill, with or without GH supplementation. CKD-related growth retardation was associated with a widened EGP hypertrophic zone. This was not fully corrected by exercise (except for tibial length). Exercise in CKD improved the expression of EGP key factors of endochondral ossification such as IGF-I, vascular endothelial growth factor (VEGF), receptor activator of nuclear factor kappa-B ligand (RANKL) and osteocalcin. Combining GH treatment with treadmill exercise for 2 weeks improved the decreased trabecular bone volume in CKD, as well as the expression of growth plate runt-related transcription factor 2, RANKL, metalloproteinase 13 and VEGF, while GH treatment alone could not do that. Treadmill exercise improves tibial bone linear growth, as well as growth plate local IGF-I. When combined with GH treatment, running exercise shows beneficial effects on trabecular bone formation, suggesting the potential benefit of this combination for CKD-related short stature and bone disease. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

The Impact of Body Mass Index on Heterotopic Ossification

International Nuclear Information System (INIS)

Mourad, Waleed Fouad; Packianathan, Satya; Shourbaji, Rania A.; Zhang Zhen; Graves, Mathew; Khan, Majid A.; Baird, Michael C.; Russell, George; Vijayakumar, Srinivasan

2012-01-01

Purpose: To analyze the impact of different body mass index (BMI) as a surrogate marker for heterotopic ossification (HO) in patients who underwent surgical repair (SR) for displaced acetabular fractures (DAF) followed by radiation therapy (RT). Methods and Materials: This is a single-institution retrospective study of 395 patients. All patients underwent SR for DAF followed by RT ± indomethacin. All patients received postoperative RT, 7 Gy, within 72 h. The patients were separated into four groups based on their BMI: 30. The end point of this study was to evaluate the efficacy of RT ± indomethacin in preventing HO in patients with different BMI. Results: Analysis of BMI showed an increasing incidence of HO with increasing BMI: 30 (31%), 51 of 167. Chi-square and multivariate logistic regression analysis showed that the correlation between odds of HO and BMI is significant, p < 0.0001. As the BMI increased, the risk of HO and Brooker Classes 3, 4 HO increased. The risk of developing HO is 1.0× (10%) more likely among those with higher BMI compared with those with lower BMI. For a one-unit increase in BMI the log odds of HO increases by 1.0, 95% CI (1.06–1.14). Chi-square test shows no significant difference among all other factors and HO (e.g., indomethacin, race, gender). Conclusions: Despite similar surgical treatment and prophylactic measures (RT ± indomethacin), the risk of HO appears to significantly increase in patients with higher BMI after DAF. Higher single-fraction doses or multiple fractions and/or combination therapy with nonsteroidal inflammatory drugs may be of greater benefit to these patients.

Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

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McIntyre, Rebecca E; Lakshminarasimhan Chavali, Pavithra; Ismail, Ozama; Carragher, Damian M; Sanchez-Andrade, Gabriela; Forment, Josep V; Fu, Beiyuan; Del Castillo Velasco-Herrera, Martin; Edwards, Andrew; van der Weyden, Louise; Yang, Fengtang; Ramirez-Solis, Ramiro; Estabel, Jeanne; Gallagher, Ferdia A; Logan, Darren W; Arends, Mark J; Tsang, Stephen H; Mahajan, Vinit B; Scudamore, Cheryl L; White, Jacqueline K; Jackson, Stephen P; Gergely, Fanni; Adams, David J

2012-01-01

Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm) embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.

Disruption of Mouse Cenpj, a Regulator of Centriole Biogenesis, Phenocopies Seckel Syndrome

Science.gov (United States)

McIntyre, Rebecca E.; Lakshminarasimhan Chavali, Pavithra; Forment, Josep V.; Fu, Beiyuan; Del Castillo Velasco-Herrera, Martin; Edwards, Andrew; van der Weyden, Louise; Yang, Fengtang; Ramirez-Solis, Ramiro; Estabel, Jeanne; Gallagher, Ferdia A.; Logan, Darren W.; Arends, Mark J.; Tsang, Stephen H.; Mahajan, Vinit B.; Scudamore, Cheryl L.; White, Jacqueline K.; Jackson, Stephen P.; Gergely, Fanni; Adams, David J.

2012-01-01

Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpjtm/tm) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpjtm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpjtm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome. PMID:23166506

Spontaneous Cervical Intradural Disc Herniation Associated with Ossification of Posterior Longitudinal Ligament

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Dachuan Wang

2014-01-01

Full Text Available Intradural herniation of a cervical disc is rare; less than 35 cases have been reported to date. A 52-year-old man with preexisting ossification of posterior longitudinal ligament developed severe neck pain with Lt hemiparesis while asleep. Neurological exam was consistent with Brown-Séquard syndrome. Magnetic resonance images showed a C5-6 herniated disc that was adjacent to the ossified ligament and indenting the cord. The mass was surrounded by cerebrospinal fluid signal intensity margin, and caudally the ventral dura line appears divided into two, consistent with the “Y-sign” described by Sasaji et al. Cord edema were noted. Because of preexisting canal stenosis and spinal cord at risk, a laminoplasty was performed, followed by an anterior C6 corpectomy. Spot-weld type adhesions of the posterior longitudinal ligament to the dura was noted, along with a longitudinal tear in the dura. An intradural extra-arachnoid fragment of herniated disc was removed. Clinical exam at 6 months after surgery revealed normal muscle strength but persistent mild paresthesias. It is difficult to make a definite diagnosis of intradural herniation preoperatively; however, the clinical findings and radiographic signs mentioned above are suggestive and should alert the surgeon to look for an intradural fragment.

Clinical outcomes of scala vestibuli cochlear implantation in children with partial labyrinthine ossification.

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Lin, Yung-Song

2009-03-01

Cochlear implantation via the scala vestibuli is a viable approach in those with ossification in the scala tympani. With extended cochlear implant experience, there is no significant difference in the mapping parameters and auditory performance between those implanted via scala vestibuli and via scala tympani. To assess the clinical outcomes of cochlear implantation via scala vestibuli. In a cohort follow-up study, 11 prelingually deafened children who received cochlear implantation between age 3 and 10 years through the scala vestibuli served as participants. The mapping parameters (i.e. comfortable level (C), threshold level (T), dynamic range) and auditory performance of each participant were evaluated following initial cochlear implant stimulation, then at 3 month intervals for 2 years, then semi-annually. The follow-up period lasted for 9 years 9 months on average, with a minimum of 8 years 3 months. The clinical results of the mapping parameters and auditory performance of children implanted via the scala vestibuli were comparative to those who were implanted via the scala tympani. No balance problem was reported by any of these patients. One child exhibited residual low frequency hearing after implantation.

Symptomatic heterotopic ossification after very severe traumatic brain injury in 114 patients: incidence and risk factors

DEFF Research Database (Denmark)

Simonsen, Louise Lau; Sonne-Holm, Stig; Krasheninnikoff, Michael

2007-01-01

The incidence of heterotopic ossification (HO) among patients with traumatic brain injury (TBI) varies in the literature from 11 to 73.3%. The aim of this study was to determine the incidence of HO among patients with very severe TBI treated in a new established intensive rehabilitation Brain...... Injury Unit and to list some of the risk-predicting features. The study comprised an approximately complete, consecutive series of 114 adult patients from a well-defined geographical area, and with a posttraumatic amnesia period of at least 28 days, i.e. very severe TBI. Demographic and functional data...... as well as data about trauma severity and hospital stay of these patients have been registered prospectively in a database (Danish National Head Injury database) at the Brain Injury Unit where the sub acute rehabilitation took place. The present study was based retrospectively on this database, combined...

Deletion of Core-binding factor β (Cbfβ) in mesenchymal progenitor cells provides new insights into Cbfβ/Runxs complex function in cartilage and bone development

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Wu, Mengrui; Li, Chenguan; Zhu, Guochun; Wang, Yiping; Jules, Joel; Lu, Yun; McConnell, Matthew; Wang, Yong-Jun; Shao, Jian-Zhong; Li, Yi-Ping; Chen, Wei

2015-01-01

Core-binding factor β (Cbfβ) is a subunit of the Cbf family of heterodimeric transcription factors which plays a critical role in skeletal development through its interaction with the Cbfα subunits, also known as Runt-related transcription factors (Runxs). However, the mechanism by which Cbfβ regulates cartilage and bone development remains unclear. Existing Cbfβ-deficient mouse models cannot specify the role of Cbfβ in skeletal cell lineage. Herein, we sought to specifically address the role of Cbfβ in cartilage and bone development by using a conditional knockout (CKO) approach. A mesenchymal-specific Cbfβ CKO mouse model was generated by using the Dermo1-Cre mouse line to specifically delete Cbfβ in mesenchymal stem cells, which give rise to osteoblasts and chondrocytes. Surprisingly, the mutant mice had under-developed larynx and tracheal cartilage causing alveolus defects which led to death shortly after birth from suffocation. Also, the mutant mice exhibited severe skeletal deformities from defective intramembranous and endochondral ossification, owing to delayed chondrocyte maturation and impaired osteoblast differentiation. Almost all bones of the mutant mice, including the calvariae, vertebrae, tibiae, femurs, ribs, limbs and sternums were defective. Importantly, we showed that Cbfβ was expressed throughout the skeleton during both embryonic and postnatal development, which explains the multiple-skeletal defects observed in the mutant mice. Consistently, Cbfβ deficiency impaired both chondrocyte proliferation and hypertrophy zone hypertrophy during growth-plate development in the long bones of mutant mice. Notably, Cbfβ, Runx1 and Runx2 displayed different expression patterns in the growth plates of the wildtype mice indicating that Cbfβ/Runx1 complex and Cbfβ/Runx2 complex may regulate chondrocyte proliferation and hypertrophy, respectively, in a spatial and temporal manner. Cbfβ deletion in the mesenchymal progenitors impacted bone

Histone Deacetylases in Bone Development and Skeletal Disorders

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Bradley, Elizabeth W.; Carpio, Lomeli R.; van Wijnen, Andre J.; McGee-Lawrence, Meghan E.; Westendorf, Jennifer J.

2015-01-01

Histone deacetylases (Hdacs) are conserved enzymes that remove acetyl groups from lysine side chains in histones and other proteins. Eleven of the 18 Hdacs encoded by the human and mouse genomes depend on Zn2+ for enzymatic activity, while the other 7, the sirtuins (Sirts), require NAD2+. Collectively, Hdacs and Sirts regulate numerous cellular and mitochondrial processes including gene transcription, DNA repair, protein stability, cytoskeletal dynamics, and signaling pathways to affect both development and aging. Of clinical relevance, Hdacs inhibitors are United States Food and Drug Administration-approved cancer therapeutics and are candidate therapies for other common diseases including arthritis, diabetes, epilepsy, heart disease, HIV infection, neurodegeneration, and numerous aging-related disorders. Hdacs and Sirts influence skeletal development, maintenance of mineral density and bone strength by affecting intramembranous and endochondral ossification, as well as bone resorption. With few exceptions, inhibition of Hdac or Sirt activity though either loss-of-function mutations or prolonged chemical inhibition has negative and/or toxic effects on skeletal development and bone mineral density. Specifically, Hdac/Sirt suppression causes abnormalities in physiological development such as craniofacial dimorphisms, short stature, and bone fragility that are associated with several human syndromes or diseases. In contrast, activation of Sirts may protect the skeleton from aging and immobilization-related bone loss. This knowledge may prolong healthspan and prevent adverse events caused by epigenetic therapies that are entering the clinical realm at an unprecedented rate. In this review, we summarize the general properties of Hdacs/Sirts and the research that has revealed their essential functions in bone forming cells (e.g., osteoblasts and chondrocytes) and bone resorbing osteoclasts. Finally, we offer predictions on future research in this area and the utility of

Crosstalk between Wnt/β-catenin and estrogen receptor signaling synergistically promotes osteogenic differentiation of mesenchymal progenitor cells.

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Yanhong Gao

Full Text Available Osteogenic differentiation from mesenchymal progenitor cells (MPCs are initiated and regulated by a cascade of signaling events. Either Wnt/β-catenin or estrogen signaling pathway has been shown to play an important role in regulating skeletal development and maintaining adult tissue homeostasis. Here, we investigate the potential crosstalk and synergy of these two signaling pathways in regulating osteogenic differentiation of MPCs. We find that the activation of estrogen receptor (ER signaling by estradiol (E2 or exogenously expressed ERα in MPCs synergistically enhances Wnt3A-induced early and late osteogenic markers, as well as matrix mineralization. The E2 or ERα-mediated synergy can be effectively blocked by ERα antagonist tamoxifen. E2 stimulation can enhance endochondral ossification of Wnt3A-transduced mouse fetal limb explants. Furthermore, exogenously expressed ERα significantly enhances the maturity and mineralization of Wnt3A-induced subcutaneous and intramuscular ectopic bone formation. Mechanistically, we demonstrate that E2 does not exert any detectable effect on β-catenin/Tcf reporter activity. However, ERα expression is up-regulated within the first 48h in AdWnt3A-transduced MPCs, whereas ERβ expression is significantly inhibited within 24h. Moreover, the key enzyme for the biosynthesis of estrogens aromatase is modulated by Wnt3A in a biphasic manner, up-regulated at 24h but reduced after 48h. Our results demonstrate that, while ER signaling acts synergistically with Wnt3A in promoting osteogenic differentiation, Wnt3A may crosstalk with ER signaling by up-regulating ERα expression and down-regulating ERβ expression in MPCs. Thus, the signaling crosstalk and synergy between these two pathways should be further explored as a potential therapeutic approach to combating bone and skeletal disorders, such as fracture healing and osteoporosis.

Msh homeobox 1 (Msx1)- and Msx2-overexpressing bone marrow-derived mesenchymal stem cells resemble blastema cells and enhance regeneration in mice.

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Taghiyar, Leila; Hesaraki, Mahdi; Sayahpour, Forough Azam; Satarian, Leila; Hosseini, Samaneh; Aghdami, Naser; Baghaban Eslaminejad, Mohamadreza

2017-06-23

Amputation of the proximal region in mammals is not followed by regeneration because blastema cells (BCs) and expression of regenerative genes, such as Msh homeobox ( Msx ) genes, are absent in this animal group. The lack of BCs and positional information in other cells is therefore the main obstacle to therapeutic approaches for limb regeneration. Hence, this study aimed to create blastema-like cells (BlCs) by overexpressing Msx1 and Msx2 genes in mouse bone marrow-derived mesenchymal stem cells (mBMSCs) to regenerate a proximally amputated digit tip. We transduced mBMSCs with Msx1 and Msx2 genes and compared osteogenic activity and expression levels of several Msx -regulated genes ( Bmp4 , Fgf8 , and keratin 14 ( K14 )) in BlC groups, including MSX1, MSX2, and MSX1/2 (in a 1:1 ratio) with those in mBMSCs and BCs in vitro and in vivo following injection into the amputation site. We found that Msx gene overexpression increased expression of specific blastemal markers and enhanced the proliferation rate and osteogenesis of BlCs compared with mBMSCs and BCs via activation of Fgf8 and Bmp4 Histological analyses indicated full regrowth of digit tips in the Msx -overexpressing groups, particularly in MSX1/2, through endochondral ossification 6 weeks post-injection. In contrast, mBMSCs and BCs formed abnormal bone and nail. Full digit tip was regenerated only in the MSX1/2 group and was related to boosted Bmp4, Fgf8 , and K14 gene expression and to limb-patterning properties resulting from Msx1 and Msx2 overexpression. We propose that Msx -transduced cells that can regenerate epithelial and mesenchymal tissues may potentially be utilized in limb regeneration. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The Impact of Body Mass Index on Heterotopic Ossification

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Mourad, Waleed Fouad, E-mail: Waleed246@gmail.com [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Department of Radiation Oncology, Beth Israel Medical Center, New York, NY (Israel); Department of Radiation Oncology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY (United States); Packianathan, Satya [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Shourbaji, Rania A. [Department of Epidemiology and Biostatistics, Jackson State University, Jackson, MS (United States); Zhang Zhen; Graves, Mathew [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Khan, Majid A. [Department of Radiology, University of Mississippi Medical Center, Jackson, MS (United States); Baird, Michael C. [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Russell, George [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Vijayakumar, Srinivasan [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States)

2012-04-01

Purpose: To analyze the impact of different body mass index (BMI) as a surrogate marker for heterotopic ossification (HO) in patients who underwent surgical repair (SR) for displaced acetabular fractures (DAF) followed by radiation therapy (RT). Methods and Materials: This is a single-institution retrospective study of 395 patients. All patients underwent SR for DAF followed by RT {+-} indomethacin. All patients received postoperative RT, 7 Gy, within 72 h. The patients were separated into four groups based on their BMI: <18.5, 18.5-24.9, 25-29.9, and >30. The end point of this study was to evaluate the efficacy of RT {+-} indomethacin in preventing HO in patients with different BMI. Results: Analysis of BMI showed an increasing incidence of HO with increasing BMI: <18.5, (0%) 0/6 patients; 18.5-24.9 (6%), 6 of 105 patients developed HO; 25-29.9 (19%), 22 of 117; >30 (31%), 51 of 167. Chi-square and multivariate logistic regression analysis showed that the correlation between odds of HO and BMI is significant, p < 0.0001. As the BMI increased, the risk of HO and Brooker Classes 3, 4 HO increased. The risk of developing HO is 1.0 Multiplication-Sign (10%) more likely among those with higher BMI compared with those with lower BMI. For a one-unit increase in BMI the log odds of HO increases by 1.0, 95% CI (1.06-1.14). Chi-square test shows no significant difference among all other factors and HO (e.g., indomethacin, race, gender). Conclusions: Despite similar surgical treatment and prophylactic measures (RT {+-} indomethacin), the risk of HO appears to significantly increase in patients with higher BMI after DAF. Higher single-fraction doses or multiple fractions and/or combination therapy with nonsteroidal inflammatory drugs may be of greater benefit to these patients.

Limitations of using aggrecan and type X collagen as markers of chondrogenesis in mesenchymal stem cell differentiation.

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Mwale, Fackson; Stachura, Dorothy; Roughley, Peter; Antoniou, John

2006-08-01

The study was initially designed to differentiate human bone marrow-derived mesenchymal stem cells (MSC) into chondrocyte-like cells, for use in tissue engineering. We cultured MSCs in defined chondrogenic medium as pellet cultures supplemented with transforming growth factor (TGF)-beta1 or -beta3 and dexamethazone, as they are commonly used to promote in vitro chondrogenesis. Markers of chondrogenesis used were type II collagen and aggrecan, with type X collagen being used as a marker of late-stage chondrocyte hypertrophy (associated with endochondral ossification). Our results show that aggrecan is constitutively expressed by MSCs and that type X collagen is expressed as an early event. Furthermore, we found that type X collagen was expressed before type II collagen in some cases. This is surprising because it is understood that stem cells have to be differentiated into chondrocytes before they can become hypertrophic. Thus, caution must be exercised when using aggrecan and type X collagen as markers for chondrogenesis and chondrocyte hypertrophy, respectively, in association with stem cell differentiation from this source.

Beef carcasses with larger eye muscle areas, lower ossification scores and improved nutrition have a lower incidence of dark cutting.

Science.gov (United States)

McGilchrist, P; Alston, C L; Gardner, G E; Thomson, K L; Pethick, D W

2012-12-01

This study evaluated the effect of eye muscle area (EMA), ossification, carcass weight, marbling and rib fat depth on the incidence of dark cutting (pH(u)>5.7) using routinely collected Meat Standards Australia (MSA) data. Data was obtained from 204,072 carcasses at a Western Australian processor between 2002 and 2008. Binomial data of pH(u) compliance was analysed using a logit model in a Bayesian framework. Increasing eye muscle area from 40 to 80 cm², increased pH(u) compliance by around 14% (Pcutting. Increasing musculature and growth combined with good nutrition will minimise dark cutting beef in Australia. Copyright © 2012 Elsevier Ltd. All rights reserved.

Centralized mouse repositories.

Science.gov (United States)

Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

2012-10-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

Generation and Development of Paravertebral Ossification in Cervical Artificial Disk Replacement: A Detailed Analytic Report Using Coronal Reconstruction CT.

Science.gov (United States)

Tian, Wei; Han, Xiao; Liu, Bo; He, Da; Lv, Yanwei; Yue, James

2017-04-01

A retrospective follow-up study and review of images in published papers. To determine whether true heterotopic ossification (HO) occurs in artificial disk replacement (ADR); to evaluate the incidence of paravertebral ossification (PO) and its influence on ADR. HO is typically defined as the abnormal formation of true bone within extraskeletal soft tissues. However, HO in ADR does not fit this definition precisely, as it originates from vertebral body, making it hard to distinguish radiologically from preexisting osteophytes. In this study, the term used for bone formation around ADR is PO. First, all images in the published papers were evaluated as to whether the presented PO in ADR fit the classic definition of HO or osteophytes. Second, we studied 37 consecutive patients who underwent ADR and follow-up for minimum 24 months. The preoperative and follow-up incidence of PO and its influence on range of motion were evaluated using x-ray and computed tomography. All 52 images of PO were found adjacent to the disk in 1 segment rather than entire cervical spine. Fifty (96.2%) of the POs were found to originate from the vertebral body rather than in the soft tissue. A total of 31 patients were included in the follow-up study. No significant difference was found in the incidence of PO between the follow-up and preoperation (61.29% vs. 48.39%, P>0.05). The range of motion of the ADR segment in patients with progressed PO (7.44±4.64 degrees) was significantly lower than that of patients with stable PO grade (12.13±4.42 degrees, P<0.01) at last follow-up. A proportion of HO might in fact be the natural development of preoperative osteophytes, which is unrelated to ADR; the remaining HO might be due to changes in biomechanical environment after surgery, which promotes the grade of osteophytes and affects the segment motion.

Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

Directory of Open Access Journals (Sweden)

Rebecca E McIntyre

Full Text Available Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4, which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.

Radiation prophylaxis for heterotopic ossification about the hip joint - a multicenter study

International Nuclear Information System (INIS)

Seegenschmiedt, Michael Heinrich; Makoski, Hans-Bruno; Micke, Oliver

2001-01-01

Purpose: Prophylactic radiotherapy (RT) can prevent ectopic bone formation about the hip after total hip arthroplasty. The German Cooperative Group on Radiotherapy for Benign Diseases conducted a patterns of care study about this indication addressing the involved institutions, RT dose concepts, clinical handling, and treatment outcome of prophylactic RT about the hip joint. Methods and Materials: In 1999, a patterns of care study was conducted in all German institutions to analyze the accrual pattern, number of patients, and different indications for the use and performance of prophylactic RT about the hip. The applied RT concepts of prophylactic RT were evaluated with regard to the RT technique, timing of RT (pre- or postoperative), RT dose prescription (median, range of single and total doses), and treatment outcome. All institutions were asked about the radiologic and functional failure rates at least 1 year after the completion of RT using the established radiologic (Brooker) and functional (Harris) scores with objective and subjective evaluation components. Results: One hundred fourteen institutions reported their clinical experience with prophylactic RT for the prevention of heterotopic ossification about the hip joint: 70 community hospitals, 23 university hospitals, and 21 private RT practices. In 1999, 5677 patients (5989 hips) had received prophylactic RT. The median number per institution was 36 patients (range 8-240). The interdisciplinary referral included orthopedic surgery (89 institutions; 3763 patients), trauma surgery (82 institutions; 1611 patients), or other disciplines (8 institutions; 298 patients). Preoperative RT was applied in 53 institutions 0.5-24 h before surgery, and postoperative RT was applied in 54 institutions 1-120 h after surgery. Most patients received 1 x 7 Gy either pre- or postoperatively. The total dose range was 5-10 Gy (preoperative RT) or 5-16 Gy (postoperative RT); the median total RT dose of both RT concepts was 7 Gy

Skeletal development of mice lacking bone sialoprotein (BSP--impairment of long bone growth and progressive establishment of high trabecular bone mass.

Directory of Open Access Journals (Sweden)

Wafa Bouleftour

Full Text Available Adult Ibsp-knockout mice (BSP-/- display shorter stature, lower bone turnover and higher trabecular bone mass than wild type, the latter resulting from impaired bone resorption. Unexpectedly, BSP knockout also affects reproductive behavior, as female mice do not construct a proper "nest" for their offsprings. Multiple crossing experiments nonetheless indicated that the shorter stature and lower weight of BSP-/- mice, since birth and throughout life, as well as their shorter femur and tibia bones are independent of the genotype of the mothers, and thus reflect genetic inheritance. In BSP-/- newborns, µCT analysis revealed a delay in membranous primary ossification, with wider cranial sutures, as well as thinner femoral cortical bone and lower tissue mineral density, reflected in lower expression of bone formation markers. However, trabecular bone volume and osteoclast parameters of long bones do not differ between genotypes. Three weeks after birth, osteoclast number and surface drop in the mutants, concomitant with trabecular bone accumulation. The growth plates present a thinner hypertrophic zone in newborns with lower whole bone expression of IGF-1 and higher IHH in 6 days old BSP-/- mice. At 3 weeks the proliferating zone is thinner and the hypertrophic zone thicker in BSP-/- than in BSP+/+ mice of either sex, maybe reflecting a combination of lower chondrocyte proliferation and impaired cartilage resorption. Six days old BSP-/- mice display lower osteoblast marker expression but higher MEPE and higher osteopontin(Opn/Runx2 ratio. Serum Opn is higher in mutants at day 6 and in adults. Thus, lack of BSP alters long bone growth and membranous/cortical primary bone formation and mineralization. Endochondral development is however normal in mutant mice and the accumulation of trabecular bone observed in adults develops progressively in the weeks following birth. Compensatory high Opn may allow normal endochondral development in BSP-/- mice

[A case of pycnodysostosis--observation of the skull by CT scan].

Science.gov (United States)

Anegawa, S; Bekki, Y; Furukawa, Y; Yokota, S; Torigoe, R

1987-07-01

A 13-year-old boy was presented to the Department of Neurosurgery, Saiseikai Fukuoka General Hospital for further examinations concerning abnormal findings in the skull radiogram taken when he struck his head. His physical features showed some characteristics the same as those of pycnodysostosis as follows--proportionate dwarfism, prominent forehead, short spoon-shaped fingers, bilateral exophthalmos. A skull radiogram revealed widely open cranial sutures with no healing of the fracture and craniotomy which was performed for an acute epidural hematoma 6 years ago. Furthermore, the mandible was hypoplastic with a virtual loss of mandibular angle. CT of the soft tissues showed somewhat dilated cortical sulci and ventricles without any structural abnormalities in the brain. CT of bone algorithm revealed specific characteristics of this disease. The paranasal sinuses were quite hypoplastic. Especially in the maxillary sinuses, frontal sinuses and mastoid air cells, none of developments of sinuses were noted, even though the middle and internal ear seemed to be normal. Moreover, the ethmoid and sphenoid sinuses were noted, although their developments were poor. The appearance of skull base was normal, including the inlets and outlets of cranial nerves or vessels and synchondroses. However, the density of the skull base, especially in the diploe, was higher than normal in Hansfield number. Furthermore, detailed measurements of skull base demonstrated that the skull base itself was also dwarfism. Pycnodysostosis is a generalized skeletal disease whose cardinal features are moderate generalized osteosclerosis and dwarfism. However, the detailed observation on the cranium by CT has not been reported. In our study, the development of sinuses in bones with intramembranous ossification are worse than that with endochondral ossification.(ABSTRACT TRUNCATED AT 250 WORDS)

Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation.

Science.gov (United States)

Koziel, Lydia; Wuelling, Manuela; Schneider, Sabine; Vortkamp, Andrea

2005-12-01

During endochondral ossification, the secreted growth factor Indian hedgehog (Ihh) regulates several differentiation steps. It interacts with a second secreted factor, parathyroid hormone-related protein (PTHrP), to regulate the onset of hypertrophic differentiation, and it regulates chondrocyte proliferation and ossification of the perichondrium independently of PTHrP. To investigate how the Ihh signal is translated in the different target tissues, we analyzed the role of the zinc-finger transcription factor Gli3, which acts downstream of hedgehog signals in other organs. Loss of Gli3 in Ihh mutants restores chondrocyte proliferation and delays the accelerated onset of hypertrophic differentiation observed in Ihh-/- mutants. Furthermore the expression of the Ihh target genes patched (Ptch) and PTHrP is reactivated in Ihh-/-;Gli3-/- mutants. Gli3 seems thus to act as a strong repressor of Ihh signals in regulating chondrocyte differentiation. In addition, loss of Gli3 in mice that overexpress Ihh in chondrocytes accelerates the onset of hypertrophic differentiation by reducing the domain and possibly the level of PTHrP expression. Careful analysis of chondrocyte differentiation in Gli3-/- mutants revealed that Gli3 negatively regulates the differentiation of distal, low proliferating chondrocytes into columnar, high proliferating cells. Our results suggest a model in which the Ihh/Gli3 system regulates two distinct steps of chondrocyte differentiation: (1) the switch from distal into columnar chondrocytes is repressed by Gli3 in a PTHrP-independent mechanism; (2) the transition from proliferating into hypertrophic chondrocytes is regulated by Gli3-dependent expression of PTHrP. Furthermore, by regulating distal chondrocyte differentiation, Gli3 seems to position the domain of PTHrP expression.

Oxygen tension regulates the osteogenic, chondrogenic and endochondral phenotype of bone marrow derived mesenchymal stem cells

Energy Technology Data Exchange (ETDEWEB)

Sheehy, Eamon J.; Buckley, Conor T. [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin, Dublin 2 (Ireland); Kelly, Daniel J., E-mail: kellyd9@tcd.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin, Dublin 2 (Ireland)

2012-01-06

chondrogenic phenotype for use in cartilage repair therapies or to promote hypertrophy of cartilaginous grafts for endochondral bone repair strategies.

Mouse allergen exposure and immunologic responses: IgE-mediated mouse sensitization and mouse specific IgG and IgG4 levels

NARCIS (Netherlands)

Matsui, Elizabeth C.; Krop, Esmeralda J. M.; Diette, Gregory B.; Aalberse, Rob C.; Smith, Abigail L.; Eggleston, Peyton A.

2004-01-01

Although there is evidence that contact with mice is associated with IgE-mediated mouse sensitization and mouse specific antibody responses, the exposure-response relationships remain unclear. To determine whether IgE-mediated mouse sensitization and mouse specific IgG (mIgG) and mIgG4 levels

Mead acid (20:3n-9) and n-3 polyunsaturated fatty acids are not associated with risk of posterior longitudinal ligament ossification: results of a case-control study.

Science.gov (United States)

Hamazaki, Kei; Kawaguchi, Yoshiharu; Nakano, Masato; Yasuda, Taketoshi; Seki, Shoji; Hori, Takeshi; Hamazaki, Tomohito; Kimura, Tomoatsu

2015-05-01

Ossification of the posterior longitudinal ligament (OPLL) involves the replacement of ligamentous tissue with ectopic bone. Although genetics and heritability appear to be involved in the development of OPLL, its pathogenesis remains to be elucidated. Given previous findings that 5,8,11-eicosatrienoic acid [20:3n-9, Mead acid (MA)] has depressive effects on osteoblastic activity and anti-angiogenic effects, and that n-3 polyunsaturated fatty acids (PUFAs) have a preventive effect on heterotopic ossification, we hypothesized that both fatty acids would be involved in OPLL development. To examine the biological significance of these and other fatty acids in OPLL, we conducted this case-control study involving 106 patients with cervical OPLL and 109 age matched controls. Fatty acid composition was determined from plasma samples by gas chromatography. Associations between fatty acid levels and incident OPLL were evaluated by logistic regression. Contrary to our expectations, we found no significant differences between patients and controls in the levels of MA or n-3 PUFAs (e.g., eicosapentaenoic acid and docosahexaenoic acid). Logistic regression analysis did not reveal any associations with OPLL risk for MA or n-3 PUFAs. In conclusion, no potential role was found for MA or n-3 PUFAs in ectopic bone formation in the spinal canal. Copyright © 2015 Elsevier Ltd. All rights reserved.

A new small-animal model for the study of acquired heterotopic ossification after hip surgery.

Science.gov (United States)

Anthonissen, Joris; Ossendorf, Christian; Hock, Johanna Lisa; Ritz, Ulrike; Hofmann, Alexander; Rommens, Pol Maria

2015-01-01

Heterotopic ossification (HO)--the formation of bone in soft tissues--is a frequent problem after surgery of the hip and pelvis, but little is known about its underlying pathogenic mechanisms. It is vital to study the underlying pathogenesis in animal models to develop and evaluate new prophylactic regimens directed against HO. However, previously developed small-animal models for the study of HO imitate neither surgery nor trauma-mechanisms that potentially cause HO. Hence, the goal of this study was to develop a novel small-animal model imitating hip surgery that can reliably produce HO. Twenty male Wistar rats were subjected to surgery of the right hip during which the femoral canal was reamed in three steps up to 2 mm, and a muscle lesion was made. Twelve weeks after surgery, the amount of heterotopic bone was assessed using micro-computed tomography. Eighteen of 20 animals showed HO around the hip 12 weeks after surgery. The amount of heterotopic bone varied from very small particles up to near ankylosis. A rat model of hip/pelvic surgery that does not use exogenous osteogenic stimulus and can reliably produce HO was developed.

Postoperative Bowel Perforation due to Heterotopic Ossification (Myositis Ossificans Traumatica: A Case Report and Review of the Literature

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Victoria Valinluck Lao

2011-01-01

Full Text Available Heterotopic ossification (HO is the ectopic development of normal bone within soft tissue that can occur after traumatic injury. It is uncommon and may be missed or misdiagnosed, which can lead to complications. We report the case of an 84-year-old male with a previous history of a laparotomy who underwent resection of an intra-abdominal tumor through a midline incision. On postoperative day six, the patient was taken to the operating room, as succus was draining from the incision. Upon re-exploration, sharp bone-like material was found in the wound directly adjacent to an enterotomy. Pathology confirmed mature lamellar bone and the diagnosis of HO. This is the first report of postoperative intestinal perforation secondary to HO in a midline wound. We report this case to encourage accurate reporting of HO and its morbidity and complications for the benefit of appropriate surgical planning and epidemiologic tracking of outcomes.

Mouse adhalin

DEFF Research Database (Denmark)

Liu, L; Vachon, P H; Kuang, W

1997-01-01

. To analyze the biological roles of adhalin, we cloned the mouse adhalin cDNA, raised peptide-specific antibodies to its cytoplasmic domain, and examined its expression and localization in vivo and in vitro. The mouse adhalin sequence was 80% identical to that of human, rabbit, and hamster. Adhalin...... was specifically expressed in striated muscle cells and their immediate precursors, and absent in many other cell types. Adhalin expression in embryonic mouse muscle was coincident with primary myogenesis. Its expression was found to be up-regulated at mRNA and protein levels during myogenic differentiation...

RB1CC1 Protein Suppresses Type II Collagen Synthesis in Chondrocytes and Causes Dwarfism*

Science.gov (United States)

Nishimura, Ichiro; Chano, Tokuhiro; Kita, Hiroko; Matsusue, Yoshitaka; Okabe, Hidetoshi

2011-01-01

RB1-inducible coiled-coil 1 (RB1CC1) functions in various processes, such as cell growth, differentiation, senescence, apoptosis, and autophagy. The conditional transgenic mice with cartilage-specific RB1CC1 excess that were used in the present study were made for the first time by the Cre-loxP system. Cartilage-specific RB1CC1 excess caused dwarfism in mice without causing obvious abnormalities in endochondral ossification and subsequent skeletal development from embryo to adult. In vitro and in vivo analysis revealed that the dwarf phenotype in cartilaginous RB1CC1 excess was induced by reductions in the total amount of cartilage and the number of cartilaginous cells, following suppressions of type II collagen synthesis and Erk1/2 signals. In addition, we have demonstrated that two kinds of SNPs (T-547C and C-468T) in the human RB1CC1 promoter have significant influence on the self-transcriptional level. Accordingly, human genotypic variants of RB1CC1 that either stimulate or inhibit RB1CC1 transcription in vivo may cause body size variations. PMID:22049074

Characterization of progenitor cells derived from torn human rotator cuff tendons by gene expression patterns of chondrogenesis, osteogenesis, and adipogenesis.

Science.gov (United States)

Nagura, Issei; Kokubu, Takeshi; Mifune, Yutaka; Inui, Atsuyuki; Takase, Fumiaki; Ueda, Yasuhiro; Kataoka, Takeshi; Kurosaka, Masahiro

2016-03-31

It is important to regenerate the tendon-to-bone interface after rotator cuff repair to prevent re-tears. The cells from torn human rotator cuff were targeted, and their capacity for multilineage differentiation was investigated. The edges of the rotator cuff were harvested during arthroscopic rotator cuff repair from nine patients, minced into pieces, and cultured on dishes. Adherent cells were cultured, phenotypically characterized. Then expandability, differentiation potential and gene expression were analyzed. Flow cytometry revealed that the mesenchymal stem cells (MSC)-related markers CD29, CD44, CD105, and CD166 were positive. However, CD14, CD34, and CD45 were negative. On RT-PCR analyses, the cells showed osteogenic, adipogenic, and chondrogenic potential after 3 weeks of culture under the respective differentiation conditions. In addition, SOX9, type II collagen, and type X collagen expression patterns during chondrogenesis were similar to those of endochondral ossification at the enthesis. The cells derived from torn human rotator cuff are multipotent mesenchymal stem cells with the ability to undergo multilineage differentiation, suggesting that MSCs form this tissue could be regenerative capacity for potential self-repair.

Radiation-induced osteochondroma-like lesion in young rat radius

International Nuclear Information System (INIS)

Delgado, E.; Rodriguez, J.I.; Serrada, A.; Tellez, M.; Paniagua, R.

1985-01-01

To investigate the effects of radiation on the perichondrial groove of Ranvier in osteochondroma development, the external surface of the distal growth plate of the radius in both forelimbs of 30 ten-day-old rats was exposed to a single low dose of radiation (150 r), which was focused on the perichondrial groove. This induced the formation of a chondrocyte nest at the proximal external edge of the growth plate (five to nine days after irradiation). With advancing longitudinal growth of the bone, the chondrocyte nest occupied a diaphyseal position. At nine to 11 days the chondrocyte nest underwent endochondral ossification. At 13-15 days, this osteochondroma-like lesion began to regress with the disappearance of the chondrocyte nest. After 19-21 days, only an irregularly thickened cortical bone remains at the osteochondroma site. Although the possible role of the growth plate subjacent to the irradiated perichondrial groove must be taken into account, the continuity between the perichondrial groove and the osteochondroma, which is separated from the growth plate by the periosteal ring (bone bark), suggests that the perichondrial groove was involved in osteochondroma-like lesion development

Calvarial Suture-Derived Stem Cells and Their Contribution to Cranial Bone Repair

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Daniel H. Doro

2017-11-01

Full Text Available In addition to the natural turnover during life, the bones in the skeleton possess the ability to self-repair in response to injury or disease-related bone loss. Based on studies of bone defect models, both processes are largely supported by resident stem cells. In the long bones, the source of skeletal stem cells has been widely investigated over the years, where the major stem cell population is thought to reside in the perivascular niche of the bone marrow. In contrast, we have very limited knowledge about the stem cells contributing to the repair of calvarial bones. In fact, until recently, the presence of specific stem cells in adult craniofacial bones was uncertain. These flat bones are mainly formed via intramembranous rather than endochondral ossification and thus contain minimal bone marrow space. It has been previously proposed that the overlying periosteum and underlying dura mater provide osteoprogenitors for calvarial bone repair. Nonetheless, recent studies have identified a major stem cell population within the suture mesenchyme with multiple differentiation abilities and intrinsic reparative potential. Here we provide an updated review of calvarial stem cells and potential mechanisms of regulation in the context of skull injury repair.

Visualization of living terminal hypertrophic chondrocytes of growth plate cartilage in situ by differential interference contrast microscopy and time-lapse cinematography.

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Farnum, C E; Turgai, J; Wilsman, N J

1990-09-01

The functional unit within the growth plate consists of a column of chondrocytes that passes through a sequence of phases including proliferation, hypertrophy, and death. It is important to our understanding of the biology of the growth plate to determine if distal hypertrophic cells are viable, highly differentiated cells with the potential of actively controlling terminal events of endochondral ossification prior to their death at the chondro-osseous junction. This study for the first time reports on the visualization of living hypertrophic chondrocytes in situ, including the terminal hypertrophic chondrocyte. Chondrocytes in growth plate explants are visualized using rectified differential interference contrast microscopy. We record and measure, using time-lapse cinematography, the rate of movement of subcellular organelles at the limit of resolution of this light microscopy system. Control experiments to assess viability of hypertrophic chondrocytes include coincubating organ cultures with the intravital dye fluorescein diacetate to assess the integrity of the plasma membrane and cytoplasmic esterases. In this system, all hypertrophic chondrocytes, including the very terminal chondrocyte, exist as rounded, fully hydrated cells. By the criteria of intravital dye staining and organelle movement, distal hypertrophic chondrocytes are identical to chondrocytes in the proliferative and early hypertrophic cell zones.

Mutations in fam20b and xylt1 reveal that cartilage matrix controls timing of endochondral ossification by inhibiting chondrocyte maturation.

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B Frank Eames

2011-08-01

Full Text Available Differentiating cells interact with their extracellular environment over time. Chondrocytes embed themselves in a proteoglycan (PG-rich matrix, then undergo a developmental transition, termed "maturation," when they express ihh to induce bone in the overlying tissue, the perichondrium. Here, we ask whether PGs regulate interactions between chondrocytes and perichondrium, using zebrafish mutants to reveal that cartilage PGs inhibit chondrocyte maturation, which ultimately dictates the timing of perichondral bone development. In a mutagenesis screen, we isolated a class of mutants with decreased cartilage matrix and increased perichondral bone. Positional cloning identified lesions in two genes, fam20b and xylosyltransferase1 (xylt1, both of which encode PG synthesis enzymes. Mutants failed to produce wild-type levels of chondroitin sulfate PGs, which are normally abundant in cartilage matrix, and initiated perichondral bone formation earlier than their wild-type siblings. Primary chondrocyte defects might induce the bone phenotype secondarily, because mutant chondrocytes precociously initiated maturation, showing increased and early expression of such markers as runx2b, collagen type 10a1, and ihh co-orthologs, and ihha mutation suppressed early perichondral bone in PG mutants. Ultrastructural analyses demonstrated aberrant matrix organization and also early cellular features of chondrocyte hypertrophy in mutants. Refining previous in vitro reports, which demonstrated that fam20b and xylt1 were involved in PG synthesis, our in vivo analyses reveal that these genes function in cartilage matrix production and ultimately regulate the timing of skeletal development.

A case of pycnodysostosis

International Nuclear Information System (INIS)

Anegawa, Shigetaka; Bekki, Yoshiaki; Furukawa, Yasuhiro; Yokota, Seishi; Torigoe, Ryuichiro.

1987-01-01

A 13-year-old boy was presented to the Department of Neurosurgery, Saiseikai Fukuoka General Hospital for further examinations concerning abnormal findings in the skull radiogram taken when he struck his head. His physical features showed some characteristics the same as those of pycnodysostosis as follows - proportionate dwarfism, prominent forehead, short spoon-shaped fingers, bilateral exophthalmos. A skull radiogram revealed widely open cranial sutures with no healing of the fracture and craniotomy which was performed for an acute epidural hematoma 6 years ago. Furthermore, the mandible was hypoplastic with a virtural loss of mandibular angle. CT of the soft tissues showed somewhat dilated cortical sulci and ventricles without any structural abnormalities in the brain. CT of bone algorythum revealed specific characteristics of this disease. The paranasal sinuses were quite hypoplastic. Especially in the maxillary sinuses, frontal sinussus and mastoid air cells, none of developments of sinuses were noted, even though the middle and internal ear seemed to be normal. Moreover, the ethomoid and sphenoid sinuses were noted, although their developments were poor. The appearance of skull base was normal, including the inlets and outlets of cranial nerves or vessels and synchondroses. However, the density of the skull base, especially in the diploe, was higher than normal in Hansfield number. Furthermore, detailed measurements of skull base demonstrated that the skull base itself was also dwarfish. In our study, the development of sinuses in bones with intramembranous ossification are worse than that with endochondral ossification. Furthermore, sutures or synchondroses in the skull base were well-developed than those of the convex. So, it is considered that pycnodysostosis must be the neighboring entity of diseases such as achondroplastic dwarfism or cleidocranial dysplasia. (J.P.N.)

Case of pycnodysostosis. Observation of skull by CT scan

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Anegawa, Shigetaka; Bekki, Yoshiaki; Furukawa, Yasuhiro; Yokota, Seishi; Torigoe, Ryuichiro

1987-07-01

A 13-year-old boy was presented to the Department of Neurosurgery, Saiseikai Fukuoka General Hospital for further examinations concerning abnormal findings in the skull radiogram taken when he struck his head. His physical features showed some characteristics the same as those of pycnodysostosis as follows - proportionate dwarfism, prominent forehead, short spoon-shaped fingers, bilateral exophthalmos. A skull radiogram revealed widely open cranial sutures with no healing of the fracture and craniotomy which was performed for an acute epidural hematoma 6 years ago. Furthermore, the mandible was hypoplastic with a virtural loss of mandibular angle. CT of the soft tissues showed somewhat dilated cortical sulci and ventricles without any structural abnormalities in the brain. CT of bone algorythum revealed specific characteristics of this disease. The paranasal sinuses were quite hypoplastic. Especially in the maxillary sinuses, frontal sinussus and mastoid air cells, none of developments of sinuses were noted, even though the middle and internal ear seemed to be normal. Moreover, the ethomoid and sphenoid sinuses were noted, although their developments were poor. The appearance of skull base was normal, including the inlets and outlets of cranial nerves or vessels and synchondroses. However, the density of the skull base, especially in the diploe, was higher than normal in Hansfield number. Furthermore, detailed measurements of skull base demonstrated that the skull base itself was also dwarfish. In our study, the development of sinuses in bones with intramembranous ossification are worse than that with endochondral ossification. Furthermore, sutures or synchondroses in the skull base were well-developed than those of the convex. So, it is considered that pycnodysostosis must be the neighboring entity of diseases such as achondroplastic dwarfism or cleidocranial dysplasia. (J.P.N.).

Postoperative Single-Fraction Radiation for Prevention of Heterotopic Ossification of the Elbow

International Nuclear Information System (INIS)

Robinson, Clifford G.; Polster, Joshua M.; Reddy, Chandana A.; Lyons, Janice A.; Evans, Peter J.; Lawton, Jeffrey N.; Graham, Thomas J.; Suh, John H.

2010-01-01

Purpose: Heterotopic ossification (HO) about the elbow has been described after surgery, trauma, and burns. Even limited deposits can lead to significant functional deficits. Little data exist regarding outcomes of patients treated with radiation therapy (RT) after elbow surgery. We report here the Cleveland Clinic experience with single-fraction radiation following surgery to the elbow. The primary endpoint was the rate of new HO after RT. Secondary endpoints were range of motion, functional compromise, and toxicity. Methods and Materials: From May 1993 to July 2006, 36 patients underwent elbow surgery followed by single-fraction RT. Range of motion data were collected before and during surgery and at last follow-up. Radiographs were reviewed for persistent or new HO. Patient and treatment factors were analyzed for correlation with development of HO or functional compromise. Results: Median follow-up was 8.7 months, median age was 42 years, and 75% of patients were male. Twenty-six (72%) patients had HO prior to surgery. All patients had significant limitations in flexion/extension or pronation/supination at baseline. Thirty-one (86%) patients had prior elbow trauma, and 26 (72%) patients had prior surgery. RT was administered a median of 1 day postoperatively (range, 1-4 days). Thirty-four patients received 700 cGy, and 2 patients received 600 cGy. Three (8%) patients developed new HO after RT. All patients had improvement in range of motion from baseline. No patient or treatment factors were significantly associated with the development of HO or functional compromise. Conclusions: Single-fraction RT after surgery to the elbow is associated with favorable functional and radiographic outcomes.

Constitutive activation of Gli2 impairs bone formation in postnatal growing mice.

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Kyu Sang Joeng

Full Text Available Indian hedgehog (Ihh signaling is indispensable for osteoblast differentiation during endochondral bone development in the mouse embryo. We have previously shown that the Gli2 transcription activator critically mediates Ihh function in osteoblastogenesis. To explore the possibility that activation of Hedgehog (Hh signaling may enhance bone formation, we generated mice that expressed a constitutively active form of Gli2 in the Osx-lineage cells. Unexpectedly, these mice exhibited severe osteopenia due to a marked decrease in osteoblast number and function, although bone resorption was not affected. Quantitative analyses of the molecular markers indicated that osteoblast differentiation was impaired in the mutant mouse. However, the osteoblast-lineage cells isolated from these mice exhibited more robust osteoblast differentiation than normal in vitro. Similarly, pharmacological stimulation of Hh signaling enhanced osteoblast differentiation from Osx-expressing cells isolated from the wild-type mouse. Thus, even though Hh signaling directly promotes osteoblast differentiation in vitro, constitutive activation of this pathway impairs bone formation in vivo, perhaps through an indirect mechanism.

Insulin antagonises pigment epithelium-derived factor (PEDF)-induced modulation of lineage commitment of myocytes and heterotrophic ossification.

Science.gov (United States)

Carnagarin, Revathy; Elahy, Mina; Dharmarajan, Arun M; Dass, Crispin R

2017-12-16

Extensive bone defects arising as a result of trauma, infection and tumour resection and other bone pathologies necessitates the identification of effective strategies in the form of tissue engineering, gene therapy and osteoinductive agents to enhance the bone repair process. PEDF is a multifunctional glycoprotein which plays an important role in regulating osteoblastic differentiation and bone formation. PEDF treatment of mice and human skeletal myocytes at physiological concentration inhibited myogenic differentiation and activated Erk1/2 MAPK- dependent osteogenic transdifferentiation of myocytes. In mice, insulin, a promoter of bone regeneration, attenuated PEDF-induced expression of osteogenic markers such as osteocalcin, alkaline phosphatase and mineralisation for bone formation in the muscle and surrounding adipose tissue. These results provide new insights into the molecular aspects of the antagonising effect of insulin on PEDF-dependent modulation of the differentiation commitment of musculoskeletal environment into osteogenesis, and suggest that PEDF may be developed as an effective clinical therapy for bone regeneration as its heterotopic ossification can be controlled via co-administration of insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones.

Science.gov (United States)

Amano, Katsuhiko; Densmore, Michael; Fan, Yi; Lanske, Beate

2016-02-01

Digit formation is a process, which requires the proper segmentation, formation and growth of phalangeal bones and is precisely regulated by several important factors. One such factor is Ihh, a gene linked to BDA1 and distal symphalangism in humans. In existing mouse models, mutations in Ihh have been shown to cause multiple synostosis in the digits but lead to perinatal lethality. To better study the exact biological and pathological events which occur in these fused digits, we used a more viable Prx1-Cre;Ihh(fl/fl) model in which Cre recombinase is expressed during mesenchymal condensation in the earliest limb buds at E9.5 dpc and found that mutant digits continuously fuse postnatally until phalanges are finally replaced by an unsegmented "one-stick bone". Mutant mice displayed osteocalcin-positive mature osteoblasts, but had reduced proliferation and abnormal osteogenesis. Because of the close interaction between Ihh and PTHrP during endochondral ossification, we also examined the digits of Prx1-Cre;PTH1R(fl/fl) mice, where the receptor for PTHrP was conditionally deleted. Surprisingly, we found PTH1R deletion caused symphalangism, demonstrating another novel function of PTH1R signaling in digit formation. We characterized the symphalangism process whereby initial cartilaginous fusion prevented epiphyseal growth plate formation, resulting in resorption and replacement of the remaining cartilage by bony tissue. Chondrocyte differentiation displayed abnormal directionality in both mutants. Lastly, Prx1-Cre;Ihh(fl/fl);Jansen Tg mice, in which a constitutively active PTH1R allele was introduced into Ihh mutants, were established to address the possible involvement of PTH1R signaling in Ihh mutant digits. These rescue mice failed to show significantly improved phenotype, suggesting that PTH1R signaling in chondrocytes is not sufficient to restore digit formation. Our results demonstrate that Ihh and PTH1R signaling in limb mesenchyme are both essential to regulate

A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.

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Xiaoquan Zhu

2014-10-01

Full Text Available Distal arthrogryposis type 2B (DA2B is an important genetic disorder in humans. However, the mechanisms governing this disease are not clearly understood. In this study, we generated knock-in mice carrying a DA2B mutation (K175del in troponin I type 2 (skeletal, fast (TNNI2, which encodes a fast-twitch skeletal muscle protein. Tnni2K175del mice (referred to as DA2B mice showed typical DA2B phenotypes, including limb abnormality and small body size. However, the current knowledge concerning TNNI2 could not explain the small body phenotype of DA2B mice. We found that Tnni2 was expressed in the osteoblasts and chondrocytes of long bone growth plates. Expression profile analysis using radii and ulnae demonstrated that Hif3a expression was significantly increased in the Tnni2K175del mice. Chromatin immunoprecipitation assays indicated that both wild-type and mutant tnni2 protein can bind to the Hif3a promoter using mouse primary osteoblasts. Moreover, we showed that the mutant tnni2 protein had a higher capacity to transactivate Hif3a than the wild-type protein. The increased amount of hif3a resulted in impairment of angiogenesis, delay in endochondral ossification, and decrease in chondrocyte differentiation and osteoblast proliferation, suggesting that hif3a counteracted hif1a-induced Vegf expression in DA2B mice. Together, our data indicated that Tnni2K175del mutation led to abnormally increased hif3a and decreased vegf in bone, which explain, at least in part, the small body size of Tnni2K175del mice. Furthermore, our findings revealed a new function of tnni2 in the regulation of bone development, and the study of gain-of-function mutation in Tnni2 in transgenic mice opens a new avenue to understand the pathological mechanism of human DA2B disorder.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

Science.gov (United States)

Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Optimization of the virtual mouse HeadMouse to foster its classroom use by children with physical disabilities

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Merce TEIXIDO

2014-03-01

Full Text Available This paper presents the optimization of a virtual mouse called HeadMouse in order to foster its classroom use by children with physical disabilities. HeadMouse is an absolute virtual mouse that converts head movements in cursor displacement and facial gestures in click actions. The virtual mouse combines different image processing algorithms: face detection, pattern matching and optical flow in order to emulate the behaviour of a conventional computer mouse. The original implementation of HeadMouse requires large computational power and this paper proposes specific optimizations in order to enable its use by children with disabilities in standard low cost classroom computers.

Radiographic analysis of the correlation between ossification of the nuchal ligament and sagittal alignment and segmental stability of the cervical spine in patients with cervical spondylotic myelopathy.

Science.gov (United States)

Ying, Jinwei; Teng, Honglin; Qian, Yunfan; Hu, Yingying; Wen, Tianyong; Ruan, Dike; Zhu, Minyu

2018-01-01

Background Ossification of the nuchal ligament (ONL) caused by chronic injury to the nuchal ligament (NL) is very common in instability-related cervical disorders. Purpose To determine possible correlations between ONL, sagittal alignment, and segmental stability of the cervical spine. Material and Methods Seventy-three patients with cervical spondylotic myelopathy (CSM) and ONL (ONL group) and 118 patients with CSM only (control group) were recruited. Radiographic data included the characteristics of ONL, sagittal alignment and segmental stability, and ossification of the posterior longitudinal ligament (OPLL). We performed comparisons in terms of radiographic parameters between the ONL and control groups. The correlations between ONL size, cervical sagittal alignment, and segmental stability were analyzed. Multivariate logistic regression was used to identify the independent risk factors of the development of ONL. Results C2-C7 sagittal vertical axis (SVA), T1 slope (T1S), T1S minus cervical lordosis (T1S-CL) on the lateral plain, angular displacement (AD), and horizontal displacement (HD) on the dynamic radiograph increased significantly in the ONL group compared with the control group. The size of ONL significantly correlated with C2-C7 SVA, T1S, AD, and HD. The incidence of ONL was higher in patients with OPLL and segmental instability. Cervical instability, sagittal malalignment, and OPLL were independent predictors of the development of ONL through multivariate analysis. Conclusion Patients with ONL are more likely to have abnormal sagittal alignment and instability of the cervical spine. Thus, increased awareness and appreciation of this often-overlooked radiographic finding is warranted during diagnosis and treatment of instability-related cervical pathologies and injuries.

Comparative Analysis of Osteogenic/Chondrogenic Differentiation Potential in Primary Limb Bud-Derived and C3H10T1/2 Cell Line-Based Mouse Micromass Cultures

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Róza Zákány

2013-08-01

Full Text Available Murine micromass models have been extensively applied to study chondrogenesis and osteogenesis to elucidate pathways of endochondral bone formation. Here we provide a detailed comparative analysis of the differentiation potential of micromass cultures established from either BMP-2 overexpressing C3H10T1/2 cells or mouse embryonic limb bud-derived chondroprogenitor cells, using micromass cultures from untransfected C3H10T1/2 cells as controls. Although the BMP-2 overexpressing C3H10T1/2 cells failed to form chondrogenic nodules, cells of both models expressed mRNA transcripts for major cartilage-specific marker genes including Sox9, Acan, Col2a1, Snorc, and Hapln1 at similar temporal sequence, while notable lubricin expression was only detected in primary cultures. Furthermore, mRNA transcripts for markers of osteogenic differentiation including Runx2, Osterix, alkaline phosphatase, osteopontin and osteocalcin were detected in both models, along with matrix calcification. Although the adipogenic lineage-specific marker gene FABP4 was also expressed in micromass cultures, Oil Red O-positive cells along with PPARγ2 transcripts were only detected in C3H10T1/2-derived micromass cultures. Apart from lineage-specific marker genes, pluripotency factors (Nanog and Sox2 were also expressed in these models, reflecting on the presence of various mesenchymal lineages as well as undifferentiated cells. This cellular heterogeneity has to be taken into consideration for the interpretation of data obtained by using these models.

Rac1 Dosage Is Crucial for Normal Endochondral Bone Growth.

Science.gov (United States)

Suzuki, Dai; Bush, Jason R; Bryce, Dawn-Marie; Kamijo, Ryutaro; Beier, Frank

2017-10-01

Rac1, a member of the small Rho GTPase family, plays multiple cellular roles. Studies of mice conditionally lacking Rac1 have revealed essential roles for Rac1 in various tissues, including cartilage and limb mesenchyme, where Rac1 loss produces dwarfism and long bone shortening. To gain further insight into the role of Rac1 in skeletal development, we have used transgenic mouse lines to express a constitutively active (ca) Rac1 mutant protein in a Cre recombinase-dependent manner. Overexpression of caRac1 in limb bud mesenchyme or chondrocytes leads to reduced body weight and shorter bones compared with control mice. Histological analysis of growth plates showed that caRac1;Col2-Cre mice displayed ectopic hypertrophic chondrocytes in the proliferative zone and enlarged hypertrophic zones. These mice also displayed a reduced proportion of proliferating cell nuclear antigen-positive cells in the proliferative zone and nuclear β-catenin localization in the ectopic hypertrophic chondrocytes. Importantly, overexpression of caRac1 partially rescued the phenotypes of Rac1fl/fl;Col2-Cre and Rac1fl/fl;Prx1-Cre conditional knockout mice, including body weight, bone length, and growth plate disorganization. These results suggest that tight regulation of Rac1 activity is necessary for normal cartilage development. Copyright © 2017 Endocrine Society.

Ossification of the stylohyoid chain on computed tomograms - Eagle syndrome; Die Ossifikation der stylohyoidalen Kette im Computertomogramm - Eagle-Syndrom

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Lugmayr, H; Krennmair, G [Krankenhaus St. Franziskus, Grieskirchen (Austria). Inst. fuer Radiologie; Lenglinger, F [Allgemeines Krankenhaus, Wels (Austria). Inst. fuer Radiologie

1997-11-01

The computed tomographic morphology of a typical Eagle syndrome is presented on the basis of a case history. In a 40-year-old female patient presenting with bilateral tinnitus, globus hystericus, and increasing hoarseness computed tomography revealed bilateral ossification of the stylohyoid ligament. The incidence of stylalgia is very low in comparison to the occurrence of a elongated styloid process or an ossified stylohyoid ligament. However, in cases of unexplained complaints in the head and neck region it should be considered in the differential diagnosis as it has therapeutic consequences. (orig.) [Deutsch] Anhand einer Kasuistik wird die computertomographische Morphologie eines typischen Eagle-Syndroms vorgestellt: Bei einem 40jaehrigen Patienten, der an beidseitigem Tinnitus, Globusgefuehl und zunehmender Heiserkeit litt, wurde computertomographisch eine beidseitige Ossifikation des Ligamentum stylohoideum nachgewiesen. Die Inzidenz einer Stylalgie ist verglichen mit der Praevalenz eines elongierten Processus styloideus oder einem verknoecherten Ligamentum stylochyoideum sehr selten. Sie sollte jedoch bei ungeklaerten Beschwerden im Kopf-Halsbereich differentialdiagnostisch in Erwaegung gezogen werden, da sie therapeutische Konsequenzen nach sich zieht. (orig.)

Development of mPMab-1, a Mouse-Rat Chimeric Antibody Against Mouse Podoplanin.

Science.gov (United States)

Yamada, Shinji; Kaneko, Mika K; Nakamura, Takuro; Ichii, Osamu; Konnai, Satoru; Kato, Yukinari

2017-04-01

Podoplanin (PDPN), the ligand of C-type lectin-like receptor-2, is used as a lymphatic endothelial marker. We previously established clone PMab-1 of rat IgG 2a as a specific monoclonal antibody (mAb) against mouse PDPN. PMab-1 is also very sensitive in immunohistochemical analysis; however, rat mAbs seem to be unfavorable for pathologists because anti-mouse IgG and anti-rabbit IgG are usually used as secondary antibodies in commercially available kits for immunohistochemical analysis. In this study, we develop a mouse-rat chimeric antibody, mPMab-1 of mouse IgG 2a , which was derived from rat PMab-1 mAb. Immunohistochemical analysis shows that mPMab-1 detects podocytes of the kidney, lymphatic endothelial cells of the colon, and type I alveolar cells of the lung. Importantly, mPMab-1 is more sensitive than PMab-1. This conversion strategy from rat mAb to mouse mAb could be applicable to other mAbs.

Gaze beats mouse

DEFF Research Database (Denmark)

Mateo, Julio C.; San Agustin, Javier; Hansen, John Paulin

2008-01-01

Facial EMG for selection is fast, easy and, combined with gaze pointing, it can provide completely hands-free interaction. In this pilot study, 5 participants performed a simple point-and-select task using mouse or gaze for pointing and a mouse button or a facial-EMG switch for selection. Gaze...

Sciatic nerve compression by neurogenic heterotopic ossification: use of CT to determine surgical indications

International Nuclear Information System (INIS)

Salga, Marjorie; Jourdan, Claire; Durand, Marie-Christine; Hangard, Chloe; Carlier, Robert-Yves; Denormandie, Philippe; Genet, Francois

2015-01-01

To describe the characteristics of neurogenic heterotopic ossification (NHO) based on clinical tests, electroneuromyography (ENMG) and CT in a database of patients with lesions of the central nervous system who required sciatic nerve neurolysis along with posterior hip NHO resection, and to determine the respective roles of ENMG and CT in the management of posterior hip NHOs in patients who are unable to communicate or express pain. The consistency of the ENMG results with clinical findings, CT results and macroscopic signs of lesions was retrospectively assessed after sciatic nerve neurolysis and ablation of 55 posterior hip NHOs. Sciatic nerve neurolysis was necessary in 55 cases (47.4 %; 55 out of 116). CT showed contact of the NHO with the nerve in all cases: 5 in contact with no deflection, 3 in contact with deflection, 21 moulded into a gutter and 26 entrapped in the NHO. There were clinical signs of sciatic nerve lesion in 21.8 % of cases (12 out of 55). ENMG showed signs of sciatic nerve lesions in only 55.6 % (10 out of 18), only 4 of whom presented with clinical signs of a nerve lesion. No significant relationship was found between clinical symptoms and ENMG findings of sciatic nerve compression (n = 13, p = 0.77). Nerve compression by NHO is likely an underdiagnosed condition, particularly in patients who are unable to communicate. Diagnosis of sciatic compression by NHO should be based on regular clinical examinations and CT. ENMG is not sufficiently sensitive to be used alone for surgical decision-making. (orig.)

Sciatic nerve compression by neurogenic heterotopic ossification: use of CT to determine surgical indications

Energy Technology Data Exchange (ETDEWEB)

Salga, Marjorie [Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Physical Medicine and Rehabilitation, Garches (France); Jourdan, Claire [Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Physical Medicine and Rehabilitation, Garches (France); Universite de Versailles Saint Quentin en Yvelines, Handi-Resp, (EA4047), Versailles (France); Durand, Marie-Christine [Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Neurophysiology, Garches (France); Universite de Versailles Saint Quentin en Yvelines, Groupement de Recherche Clinique et Technologique sur le Handicap (GRCTH, EA 4497), Versailles (France); Hangard, Chloe; Carlier, Robert-Yves [Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Medical Imaging, Garches (France); Denormandie, Philippe [Universite de Versailles Saint Quentin en Yvelines, Groupement de Recherche Clinique et Technologique sur le Handicap (GRCTH, EA 4497), Versailles (France); Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Orthopaedic Surgery, Garches (France); Genet, Francois [Hopital Raymond Poincare, APHP, CIC-IT 805, Department of Physical Medicine and Rehabilitation, Garches (France); Universite de Versailles Saint Quentin en Yvelines, Groupement de Recherche Clinique et Technologique sur le Handicap (GRCTH, EA 4497), Versailles (France); Military Medical Service, Hopital d' Instruction des Armees Percy, Department of Physical Medicine and Rehabilitation, Clamart (France)

2014-09-14

To describe the characteristics of neurogenic heterotopic ossification (NHO) based on clinical tests, electroneuromyography (ENMG) and CT in a database of patients with lesions of the central nervous system who required sciatic nerve neurolysis along with posterior hip NHO resection, and to determine the respective roles of ENMG and CT in the management of posterior hip NHOs in patients who are unable to communicate or express pain. The consistency of the ENMG results with clinical findings, CT results and macroscopic signs of lesions was retrospectively assessed after sciatic nerve neurolysis and ablation of 55 posterior hip NHOs. Sciatic nerve neurolysis was necessary in 55 cases (47.4 %; 55 out of 116). CT showed contact of the NHO with the nerve in all cases: 5 in contact with no deflection, 3 in contact with deflection, 21 moulded into a gutter and 26 entrapped in the NHO. There were clinical signs of sciatic nerve lesion in 21.8 % of cases (12 out of 55). ENMG showed signs of sciatic nerve lesions in only 55.6 % (10 out of 18), only 4 of whom presented with clinical signs of a nerve lesion. No significant relationship was found between clinical symptoms and ENMG findings of sciatic nerve compression (n = 13, p = 0.77). Nerve compression by NHO is likely an underdiagnosed condition, particularly in patients who are unable to communicate. Diagnosis of sciatic compression by NHO should be based on regular clinical examinations and CT. ENMG is not sufficiently sensitive to be used alone for surgical decision-making. (orig.)

Assessment of plasminogen synthesis in vitro by mouse tumor cells using a competition radioimmunoassay for mouse plasminogen

International Nuclear Information System (INIS)

Roblin, R.O.; Bell, T.E.; Young, P.L.

1978-01-01

A sensitive, specific competition radioimmunoassay for mouse plasmin(ogen) has been developed in order to determine whether mouse tumor cells can synthesize plasminogen in vitro. The rabbit anti-BALB/c mouse plasminogen antibodies used in the assay react with the plasminogen present in serum from BALB/c, C3H, AKR and C57BL/6 mice, and also recognized mouse plasmin. The competition radiommunoassay can detect as little as 50 ng of mouse plasminogen. No competition was observed with preparations of fetal calf, human and rabbit plasminogens. A variety of virus-transformed and mouse tumor cell lines were all found to contain less than 100 ng mouse plasminogen/mg of cell extract protein. Thus, if the plasminogen activator/plasmin system is important in the growth or movement of this group of tumor cells, the cells will be dependent upon the circulatory system of the host for their plasminogen supply. (Auth.)

Utility of radiation in the prevention of heterotopic ossification following repair of traumatic acetabular fracture

International Nuclear Information System (INIS)

Haas, Michael L.; Kennedy, Andrew S.; Copeland, Carol C.; Ames, John W.; Scarboro, Mark; Slawson, Robert G.

1999-01-01

Purpose: Heterotopic ossification (HO) is a common problem following surgical repair of traumatic acetabular fracture (TAF), potentially causing severe pain and decreased range of motion. This report analyzes the role of radiation therapy for prevention of HO in TAF. Methods and Materials: The charts of all patients who received RT to the hip following TAF repair between July 1988 and January 1998 were reviewed. Sixty-six patients were identified. RT was given in 5 fractions of 2 Gy in 45 patients, 1 fraction of 8 Gy in 17 patients, and other doses in 4 patients. Treatment fields encompassed peri acetabular tissues at highest risk for HO. Time to RT was ≤ 24 hours for 46 patients. Results: Radiographic follow-up at least 6 months following RT was available in 47/66 (71%) patients to permit Brooker classification, revealing 6 cases (13%) of Grade III HO, compared to historical incidence in this population of 50%. No Grade IV HO was found. Mean follow-up was 18 months. Four of the Grade III patients had received 10 Gy/5 fractions, and 2 received 8 Gy/1 fraction. Postoperative wound infection occurred in 6 patients, and osteonecrosis of the femoral head was found in 13. Conclusions: RT following surgical repair of TAF provides effective prophylaxis against formation of clinically significant HO. We recommend a single fraction of 7-8 Gy within 24 hours of surgery to prevent HO formation and minimize patient discomfort

Peripheral denervation participates in heterotopic ossification in a spinal cord injury model.

Directory of Open Access Journals (Sweden)

Charlotte Debaud

Full Text Available We previously reported the development of a new acquired neurogenic HO (NHO mouse model, combining spinal cord transection (SCI and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7, bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5 compared to contralateral sides (0.56 mm3 +/-0.4, p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6, bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI. Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro

Investigation of aluminum and iron deposition on metaplastic bones in three patients with diffuse pulmonary ossification.

Science.gov (United States)

Ohtsuki, Yuji; Mori, Kousuke; Ohnishi, Hirozo; Enzan, Hideaki; Iguchi, Mitsuko; Lee, Gang-Hong; Furihata, Mutsuo

2015-12-01

Diffuse pulmonary ossification (DPO) is a rare pulmonary lesion. DPO is typically detected at autopsy rather than premortem. Recently, however, several cases were diagnosed antemortem using computed tomography, high-resolution computed tomography, or video-assisted thoracic surgery. In the present study, we evaluated DPO at autopsy from two patients with post-myocardial infarction (cases 1 and 3) and one patient with duodenal cancer (case 2). Multiple metaplastic bones (nodular in case 1 and 3 or dendriform in case 2) were detected in these three cases. In an attempt to detect aluminum and iron deposition in these metaplastic bones, histochemical investigations were performed. The two nodular types of one and three cases were positive for aluminum and iron, but the dendriform type of case 2 was positive only for aluminum. The depositions occurred in a linear pattern along the calcifying front. It is of great interest that these deposition patterns were similar to those of bones from three previously reported DPO cases and from the bones of hemodialysis patients. It is suggested that these abnormal metal depositions in the calcifying front might disturb the normal mineralization processes of the metaplastic bones, although no morphological abnormality was detected, except for dense black color of calcifying front lines. Further investigations are needed in more patients with DPO to obtain more information on this topic.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Science.gov (United States)

Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

2012-01-01

Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420

Not all hypochondroplasia families are linked to chromosome 4p16.3

Energy Technology Data Exchange (ETDEWEB)

Rousseau, F.; Munnich, A.; Merrer, M.Le. [INSERM, Paris (France)] [and others

1994-09-01

Achondroplasia (ACH, MIM 100800) and hypochondroplasia (HCH, MIM 146000) are short limb dwarfism with enlarged head sharing some specific radiological features. Inter- and intrafamilial clinical variability and histolopathological aspects of the growth cartilage suggested that ACH and HCH are allelic disorders. Recently, the gene for achondroplasia was mapped to chromosome 4p and no recombinants were found in 9 families with hypochondroplasia between D4S111 and the telomere (Zmax=1.70, {theta}=0). By using an additional polymorphic DNA marker which detects VNTR-like polymorphism at the D4S227 locus and a new microsatellite at locus D4S? (AFM163yc1), we observed recombinant events with markers of the chromosome 4p16.3 in 3/10 hypochondroplasia families, indicating that not all hypochondroplasia families are linked to chromosome 4p. A fibroblast growth factor receptor (FGFR3) expressed in chondrocytes during endochondral ossification which is located in the 2.5 Mb candidate region for achondroplasia was regarded as a good candidate gene. No major rearrangement of the FGFR3 gene was detected by Southern blot analysis using an FGFR3 cDNA probe. Further investigations will be required to conclude as to the possible involvement of this gene in ACH.

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

Science.gov (United States)

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Reprogramming of Mouse Calvarial Osteoblasts into Induced Pluripotent Stem Cells

Directory of Open Access Journals (Sweden)

Yinxiang Wang

2018-01-01

Full Text Available Previous studies have demonstrated the ability of reprogramming endochondral bone into induced pluripotent stem (iPS cells, but whether similar phenomenon occurs in intramembranous bone remains to be determined. Here we adopted fluorescence-activated cell sorting-based strategy to isolate homogenous population of intramembranous calvarial osteoblasts from newborn transgenic mice carrying both Osx1-GFP::Cre and Oct4-EGFP transgenes. Following retroviral transduction of Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc, enriched population of osteoblasts underwent silencing of Osx1-GFP::Cre expression at early stage of reprogramming followed by late activation of Oct4-EGFP expression in the resulting iPS cells. These osteoblast-derived iPS cells exhibited gene expression profiles akin to embryonic stem cells and were pluripotent as demonstrated by their ability to form teratomas comprising tissues from all germ layers and also contribute to tail tissue in chimera embryos. These data demonstrate that iPS cells can be generated from intramembranous osteoblasts.

MSX2 stimulates chondrocyte maturation by controlling Ihh expression.

Science.gov (United States)

Amano, Katsuhiko; Ichida, Fumitaka; Sugita, Atsushi; Hata, Kenji; Wada, Masahiro; Takigawa, Yoko; Nakanishi, Masako; Kogo, Mikihiko; Nishimura, Riko; Yoneda, Toshiyuki

2008-10-24

Several studies indicated that a homeobox gene, Msx2, is implicated in regulation of skeletal development by controlling enchondral ossification as well as membranous ossification. However, the molecular basis by which Msx2 conducts chondrogenesis is currently unclear. In this study, we examined the role of Msx2 in chondrocyte differentiation using mouse primary chondrocytes and embryonic metatarsal explants. Treatment with BMP2 up-regulated the expression of Msx2 mRNA along with chondrocyte differentiation in murine primary chondrocytes. Overexpression of wild-type Msx2 stimulated calcification of primary chondrocytes in the presence of BMP2. We also found that constitutively active Msx2 (caMsx2) enhanced BMP2-dependent calcification more efficiently than wild-type Msx2. Consistently, caMsx2 overexpression up-regulated the expression of alkaline phosphatase and collagen type X induced by BMP2. Furthermore, organ culture experiments using mouse embryonic metatarsals indicated that caMsx2 clearly stimulated the maturation of chondrocytes into the prehypertrophic and hypertrophic stages in the presence of BMP2. In contrast, knockdown of Msx2 inhibited maturation of primary chondrocytes. The stimulatory effect of Msx2 on chondrocyte maturation was enhanced by overexpression of Smad1 and Smad4 but inhibited by Smad6, an inhibitory Smad for BMP2 signaling. These data suggest that Msx2 requires BMP2/Smad signaling for its chondrogenic action. In addition, caMsx2 overexpression induced Ihh (Indian hedgehog) expression in mouse primary chondrocytes. Importantly, treatment with cyclopamine, a specific inhibitor for hedgehogs, blocked Msx2-induced chondrogenesis. Collectively, our results indicated that Msx2 promotes the maturation of chondrocytes, at least in part, through up-regulating Ihh expression.

The Mouse That Soared

Science.gov (United States)

2004-09-01

Astronomers have used an X-ray image to make the first detailed study of the behavior of high-energy particles around a fast moving pulsar. The image, from NASA's Chandra X-ray Observatory, shows the shock wave created as a pulsar plows supersonically through interstellar space. These results will provide insight into theories for the production of powerful winds of matter and antimatter by pulsars. Chandra's image of the glowing cloud, known as the Mouse, shows a stubby bright column of high-energy particles, about four light years in length, swept back by the pulsar's interaction with interstellar gas. The intense source at the head of the X-ray column is the pulsar, estimated to be moving through space at about 1.3 million miles per hour. VLA Radio Image of the Mouse, Full Field VLA Radio Image of the Mouse, Full Field A cone-shaped cloud of radio-wave-emitting particles envelopes the X-ray column. The Mouse, a.k.a. G359.23-0.82, was discovered in 1987 by radio astronomers using the National Science Foundation's Very Large Array in New Mexico. It gets its name from its appearance in radio images that show a compact snout, a bulbous body, and a remarkable long, narrow, tail that extends for about 55 light years. "A few dozen pulsar wind nebulae are known, including the spectacular Crab Nebula, but none have the Mouse's combination of relatively young age and incredibly rapid motion through interstellar space," said Bryan Gaensler of the Harvard-Smithsonian Center for Astrophysics and lead author of a paper on the Mouse that will appear in an upcoming issue of The Astrophysical Journal. "We effectively are seeing a supersonic cosmic wind tunnel, in which we can study the effects of a pulsar's motion on its pulsar wind nebula, and test current theories." Illustration of the Mouse System Illustration of the Mouse System Pulsars are known to be rapidly spinning, highly magnetized neutron stars -- objects so dense that a mass equal to that of the Sun is packed into a

Burn mouse models

DEFF Research Database (Denmark)

Calum, Henrik; Høiby, Niels; Moser, Claus

2014-01-01

Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third-degree b......Severe thermal injury induces immunosuppression, involving all parts of the immune system, especially when large fractions of the total body surface area are affected. An animal model was established to characterize the burn-induced immunosuppression. In our novel mouse model a 6 % third...... with infected burn wound compared with the burn wound only group. The burn mouse model resembles the clinical situation and provides an opportunity to examine or develop new strategies like new antibiotics and immune therapy, in handling burn wound victims much....

A Transgenic Tri-Modality Reporter Mouse

OpenAIRE

Yan, Xinrui; Ray, Pritha; Paulmurugan, Ramasamy; Tong, Ricky; Gong, Yongquan; Sathirachinda, Ataya; Wu, Joseph C.; Gambhir, Sanjiv S.

2013-01-01

Transgenic mouse with a stably integrated reporter gene(s) can be a valuable resource for obtaining uniformly labeled stem cells, tissues, and organs for various applications. We have generated a transgenic mouse model that ubiquitously expresses a tri-fusion reporter gene (fluc2-tdTomato-ttk) driven by a constitutive chicken β-actin promoter. This "Tri-Modality Reporter Mouse" system allows one to isolate most cells from this donor mouse and image them for bioluminescent (fluc2), fluorescent...

HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia.

Science.gov (United States)

Ota, Sara; Zhou, Zi-Qiang; Romero, Megan P; Yang, Guang; Hurlin, Peter J

2016-10-01

Mutations that cause increased and/or inappropriate activation of FGFR3 are responsible for a collection of short-limbed chondrodysplasias. These mutations can alter receptor trafficking and enhance receptor stability, leading to increased receptor accumulation and activity. Here, we show that wildtype and mutant activated forms of FGFR3 increase expression of the cytoplasmic deacetylase HDAC6 (Histone Deacetylase 6) and that FGFR3 accumulation is compromised in cells lacking HDAC6 or following treatment of fibroblasts or chondrocytes with small molecule inhibitors of HDAC6. The reduced accumulation of FGFR3 was linked to increased FGFR3 degradation that occurred through a lysosome-dependent mechanism. Using a mouse model of Thanatophoric Dysplasia Type II (TDII) we show that both HDAC6 deletion and treatment with the small molecule HDAC6 inhibitor tubacin reduced FGFR3 accumulation in the growth plate and improved endochondral bone growth. Defective endochondral growth in TDII is associated with reduced proliferation and poor hypertrophic differentiation and the improved bone growth was associated with increased chondrocyte proliferation and expansion of the differentiation compartment within the growth plate. These findings further define the mechanisms that control FGFR3 accumulation and contribute to skeletal pathology caused by mutations in FGFR3. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Choice of surgical approach for ossification of the posterior longitudinal ligament in combination with cervical disc hernia.

Science.gov (United States)

Yang, Hai-song; Chen, De-yu; Lu, Xu-hua; Yang, Li-li; Yan, Wang-jun; Yuan, Wen; Chen, Yu

2010-03-01

Ossification of the posterior longitudinal ligament (OPLL) is a common spinal disorder that presents with or without cervical myelopathy. Furthermore, there is evidence suggesting that OPLL often coexists with cervical disc hernia (CDH), and that the latter is the more important compression factor. To raise the awareness of CDH in OPLL for spinal surgeons, we performed a retrospective study on 142 patients with radiologically proven OPLL who had received surgery between January 2004 and January 2008 in our hospital. Plain radiograph, three-dimensional computed tomography construction (3D CT), and magnetic resonance imaging (MRI) of the cervical spine were all performed. Twenty-six patients with obvious CDH (15 of segmental-type, nine of mixed-type, two of continuous-type) were selected via clinical and radiographic features, and intraoperative findings. By MRI, the most commonly involved level was C5/6, followed by C3/4, C4/5, and C6/7. The areas of greatest spinal cord compression were at the disc levels because of herniated cervical discs. Eight patients were decompressed via anterior cervical discectomy and fusion (ACDF), 13 patients via anterior cervical corpectomy and fusion (ACCF), and five patients via ACDF combined with posterior laminectomy and fusion. The outcomes were all favorable. In conclusion, surgeons should consider the potential for CDH when performing spinal cord decompression and deciding the surgical approach in patients presenting with OPLL.

The effect of conditional inactivation of beta 1 integrins using twist 2 Cre, Osterix Cre and osteocalcin Cre lines on skeletal phenotype.

Science.gov (United States)

Shekaran, Asha; Shoemaker, James T; Kavanaugh, Taylor E; Lin, Angela S; LaPlaca, Michelle C; Fan, Yuhong; Guldberg, Robert E; García, Andrés J

2014-11-01

Skeletal development and growth are complex processes regulated by multiple microenvironmental cues, including integrin-ECM interactions. The β1 sub-family of integrins is the largest integrin sub-family and constitutes the main integrin binding partners of collagen I, the major ECM component of bone. As complete β1 integrin knockout results in embryonic lethality, studies of β1 integrin function in vivo rely on tissue-specific gene deletions. While multiple in vitro studies indicate that β1 integrins are crucial regulators of osteogenesis and mineralization, in vivo osteoblast-specific perturbations of β1 integrins have resulted in mild and sometimes contradictory skeletal phenotypes. To further investigate the role of β1 integrins on skeletal phenotype, we used the Twist2-Cre, Osterix-Cre and osteocalcin-Cre lines to generate conditional β1 integrin deletions, where Cre is expressed primarily in mesenchymal condensation, pre-osteoblast, and mature osteoblast lineage cells respectively within these lines. Mice with Twist2-specific β1 integrin disruption were smaller, had impaired skeletal development, especially in the craniofacial and vertebral tissues at E19.5, and did not survive beyond birth. Osterix-specific β1 integrin deficiency resulted in viable mice which were normal at birth but displayed early defects in calvarial ossification, incisor eruption and growth as well as femoral bone mineral density, structure, and mechanical properties. Although these defects persisted into adulthood, they became milder with age. Finally, a lack of β1 integrins in mature osteoblasts and osteocytes resulted in minor alterations to femur structure but had no effect on mineral density, biomechanics or fracture healing. Taken together, our data indicate that β1 integrin expression in early mesenchymal condensations play an important role in skeletal ossification, while β1 integrin-ECM interactions in pre-osteoblast, odontoblast- and hypertrophic chondryocyte

Mouse SNP Miner: an annotated database of mouse functional single nucleotide polymorphisms

Directory of Open Access Journals (Sweden)

Ramensky Vasily E

2007-01-01

Full Text Available Abstract Background The mapping of quantitative trait loci in rat and mouse has been extremely successful in identifying chromosomal regions associated with human disease-related phenotypes. However, identifying the specific phenotype-causing DNA sequence variations within a quantitative trait locus has been much more difficult. The recent availability of genomic sequence from several mouse inbred strains (including C57BL/6J, 129X1/SvJ, 129S1/SvImJ, A/J, and DBA/2J has made it possible to catalog DNA sequence differences within a quantitative trait locus derived from crosses between these strains. However, even for well-defined quantitative trait loci ( Description To help identify functional DNA sequence variations within quantitative trait loci we have used the Ensembl annotated genome sequence to compile a database of mouse single nucleotide polymorphisms (SNPs that are predicted to cause missense, nonsense, frameshift, or splice site mutations (available at http://bioinfo.embl.it/SnpApplet/. For missense mutations we have used the PolyPhen and PANTHER algorithms to predict whether amino acid changes are likely to disrupt protein function. Conclusion We have developed a database of mouse SNPs predicted to cause missense, nonsense, frameshift, and splice-site mutations. Our analysis revealed that 20% and 14% of missense SNPs are likely to be deleterious according to PolyPhen and PANTHER, respectively, and 6% are considered deleterious by both algorithms. The database also provides gene expression and functional annotations from the Symatlas, Gene Ontology, and OMIM databases to further assess candidate phenotype-causing mutations. To demonstrate its utility, we show that Mouse SNP Miner successfully finds a previously identified candidate SNP in the taste receptor, Tas1r3, that underlies sucrose preference in the C57BL/6J strain. We also use Mouse SNP Miner to derive a list of candidate phenotype-causing mutations within a previously

Inhalant abuse of 1,1-difluoroethane (DFE) leading to heterotopic ossification: a case report.

Science.gov (United States)

Little, Jill; Hileman, Barbara; Ziran, Bruce H

2008-10-30

Heterotopic ossification (HO) is the formation of mature, lamellar bone within soft tissues other than the periosteum. There are three recognized etiologies of HO: traumatic, neurogenic, and genetic. Presently, there are no definitively documented causal factors of HO. The following factors are presumed to place a patient at higher risk: 60 years of age or older, male, previous HO, hypertrophic osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, prior hip surgery, and surgical risk factors. A 33-year-old male, involved in a motor vehicle crash, sustained an irreducible acetabulum fracture/dislocation, displaced proximal humerus fracture, and an impacted pilon fracture. During the time of injury, he was intoxicated from inhaling the aerosol propellant used in "dust spray" cans (1,1-difluoroethane, C2H4F2). Radiographs identified rapid pathologic bone formation about the proximal humeral metaphysis, proximal femur, elbow, and soft tissue several months following the initial injury. The patient did not have any genetic disorders that could have attributed to the bone formation but had some risk factors (male, fracture with dislocation). Surgically, the recommended precautions were followed to decrease the chance of HO. Although the patient did not have neurogenic injuries, the difluoroethane in dusting spray can cause damage to the central nervous system. Signals may have been mixed causing the patient's body to produce bone instead of tissue to strengthen the injured area. What is unusual in this case is the rate at which the pathological bone formation appeared, which was long outside the 4-6 week window in which HO starts to appear. The authors are not certain as to the cause of this rapid formation but suspect that the patient's continued abuse of inhaled aerosol propellants may be the culprit.

Inhalant abuse of 1,1-difluoroethane (DFE leading to heterotopic ossification: a case report

Directory of Open Access Journals (Sweden)

Hileman Barbara

2008-10-01

Full Text Available Abstract Background Heterotopic ossification (HO is the formation of mature, lamellar bone within soft tissues other than the periosteum. There are three recognized etiologies of HO: traumatic, neurogenic, and genetic. Presently, there are no definitively documented causal factors of HO. The following factors are presumed to place a patient at higher risk: 60 years of age or older, male, previous HO, hypertrophic osteoarthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, prior hip surgery, and surgical risk factors. Case presentation A 33-year-old male, involved in a motor vehicle crash, sustained an irreducible acetabulum fracture/dislocation, displaced proximal humerus fracture, and an impacted pilon fracture. During the time of injury, he was intoxicated from inhaling the aerosol propellant used in "dust spray" cans (1,1-difluoroethane, C2H4F2. Radiographs identified rapid pathologic bone formation about the proximal humeral metaphysis, proximal femur, elbow, and soft tissue several months following the initial injury. Discussion The patient did not have any genetic disorders that could have attributed to the bone formation but had some risk factors (male, fracture with dislocation. Surgically, the recommended precautions were followed to decrease the chance of HO. Although the patient did not have neurogenic injuries, the difluoroethane in dusting spray can cause damage to the central nervous system. Signals may have been mixed causing the patient's body to produce bone instead of tissue to strengthen the injured area. Conclusion What is unusual in this case is the rate at which the pathological bone formation appeared, which was long outside the 4–6 week window in which HO starts to appear. The authors are not certain as to the cause of this rapid formation but suspect that the patient's continued abuse of inhaled aerosol propellants may be the culprit.

Heterotopic ossification of the long head of the triceps after reverse total shoulder arthroplasty.

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Ko, Jia-Wei Kevin; Tompson, Jeffrey D; Sholder, Daniel S; Black, Eric M; Abboud, Joseph A

2016-11-01

Heterotopic ossification (HO) around shoulder arthroplasty is a frequent finding with unclear clinical relevance. This study evaluated the incidence, relevance, and predisposing factors of HO in the long head of the triceps tendon after reverse shoulder arthroplasty. Retrospective chart review was conducted to identify patients who had a reverse shoulder arthroplasty performed between 2008 and 2012. Patient demographics, implant types, and diagnoses were noted. Three fellowship-trained shoulder/elbow surgeons independently evaluated postoperative Grashey radiographs using a novel classification system. Within a 164-patient cohort, the overall HO rate in the long head of the triceps tendon was 61.6%; 23.2% of osteophytes were considered impinging, 14.6% had notching, 14.0% were free-floating, and 3.0% appeared ankylosed. Although not statistically significant, revision surgery had a higher rate of HO (68.3%) compared with primary surgery (59.4%). There was no difference in HO rates between diagnoses or implant types. Male and female HO rates were 74.0% and 56.1%, respectively (P = .0304). Between patients with and without HO, forward elevation was 121° compared with 133° (P = .0087) and external rotation was 19° compared with 25° (P = .0266); however, HO size did not significantly affect motion. Using our novel classification scheme, HO was a common finding in this series. Men had a higher rate of HO formation, and HO formation was associated with worse postoperative motion. Further study is needed to fully characterize the clinical implications of HO involving the long head of the triceps tendon and to explore potential preventive measures. Copyright © 2016 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.

Steroid metabolism in the mouse placenta

International Nuclear Information System (INIS)

Okker-Reitsma, G.H.

1976-01-01

The purpose of the study described in this thesis was to investigate the capacity for steroid synthesis of the mouse placenta - especially the production of progesterone, androgens and estrogens - and to determine, if possible, the relation of steroid synthesis to special cell types. In an introductory chapter the androgen production in the mouse placenta is surveyed by means of a histochemical and bioindicator study of different stages of development of the placenta. The metabolism of [ 3 H]-dehydroepiandrosterone and [ 3 H]-progesterone by mouse placental tissue in vitro is studied. The metabolism of [ 3 H]-progesterone by the mouse fetal adrenal in vitro is also studied

Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse.

Science.gov (United States)

Law, MeiYee; Shaw, David R

2018-01-01

Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration.

Thumb Ossification Composite Index (TOCI) for Predicting Peripubertal Skeletal Maturity and Peak Height Velocity in Idiopathic Scoliosis: A Validation Study of Premenarchal Girls with Adolescent Idiopathic Scoliosis Followed Longitudinally Until Skeletal Maturity.

Science.gov (United States)

Hung, Alec L H; Chau, W W; Shi, B; Chow, Simon K; Yu, Fiona Y P; Lam, T P; Ng, Bobby K W; Qiu, Y; Cheng, Jack C Y

2017-09-06

Accurate skeletal maturity assessment is important to guide clinical evaluation of idiopathic scoliosis, but commonly used methods are inadequate or too complex for rapid clinical use. The objective of the study was to propose a new simplified staging method, called the thumb ossification composite index (TOCI), based on the ossification pattern of the 2 thumb epiphyses and the adductor sesamoid bone; to determine its accuracy in predicting skeletal maturation when compared with the Sanders simplified skeletal maturity system (SSMS); and to validate its interrater and intrarater reliability. Hand radiographs of 125 girls, acquired when they were newly diagnosed with idiopathic scoliosis prior to menarche and during longitudinal follow-up until skeletal maturity (a minimum of 4 years), were scored with the TOCI and SSMS. These scores were compared with digital skeletal age (DSA) and radius, ulna, and small hand bones (RUS) scores; anthropometric data; peak height velocity; and growth-remaining profiles. Correlations were analyzed with the chi-square test, Spearman and Cramer V correlation methods, and receiver operating characteristic curve analysis. Reliability analysis using the intraclass correlation (ICC) was conducted. Six hundred and forty-five hand radiographs (average, 5 of each girl) were scored. The TOCI staging system was highly correlated with the DSA and RUS scores (r = 0.93 and 0.92, p systems predicted peak height velocity with comparable accuracy, with a strong Cramer V association (0.526 and 0.466, respectively; p 0.97. The new proposed TOCI could provide a simplified staging system for the assessment of skeletal maturity of subjects with idiopathic scoliosis. The index needs to be subjected to further multicenter validation in different ethnic groups.

Cost of Radiotherapy Versus NSAID Administration for Prevention of Heterotopic Ossification After Total Hip Arthroplasty

International Nuclear Information System (INIS)

Strauss, Jonathan B.; Chen, Sea S.; Shah, Anand P.; Coon, Alan B.; Dickler, Adam

2008-01-01

Purpose: Heterotopic ossification (HO), or abnormal bone formation, is a common sequela of total hip arthroplasty. This abnormal bone can impair joint function and must be surgically removed to restore mobility. HO can be prevented by postoperative nonsteroidal anti-inflammatory drug (NSAID) use or radiotherapy (RT). NSAIDs are associated with multiple toxicities, including gastrointestinal bleeding. Although RT has been shown to be more efficacious than NSAIDs at preventing HO, its cost-effectiveness has been questioned. Methods and Materials: We performed an analysis of the cost of postoperative RT to the hip compared with NSAID administration, taking into account the costs of surgery for HO formation, treatment-induced morbidity, and productivity loss from missed work. The costs of RT, surgical revision, and treatment of gastrointestinal bleeding were estimated using the 2007 Medicare Fee Schedule and inpatient diagnosis-related group codes. The cost of lost wages was estimated using the 2006 median salary data from the U.S. Census Bureau. Results: The cost of administering RT was estimated at $899 vs. $20 for NSAID use. After accounting for the additional costs associated with revision total hip arthroplasty and gastrointestinal bleeding, the corresponding estimated costs were $1,208 vs. $930. Conclusion: If the costs associated with treatment failure and treatment-induced morbidity are considered, the cost of NSAIDs approaches that of RT. Other NSAID morbidities and quality-of-life differences that are difficult to quantify add to the cost of NSAIDs. These considerations have led us to recommend RT as the preferred modality for use in prophylaxis against HO after total hip arthroplasty, even when the cost is considered

MouseMine: a new data warehouse for MGI.

Science.gov (United States)

Motenko, H; Neuhauser, S B; O'Keefe, M; Richardson, J E

2015-08-01

MouseMine (www.mousemine.org) is a new data warehouse for accessing mouse data from Mouse Genome Informatics (MGI). Based on the InterMine software framework, MouseMine supports powerful query, reporting, and analysis capabilities, the ability to save and combine results from different queries, easy integration into larger workflows, and a comprehensive Web Services layer. Through MouseMine, users can access a significant portion of MGI data in new and useful ways. Importantly, MouseMine is also a member of a growing community of online data resources based on InterMine, including those established by other model organism databases. Adopting common interfaces and collaborating on data representation standards are critical to fostering cross-species data analysis. This paper presents a general introduction to MouseMine, presents examples of its use, and discusses the potential for further integration into the MGI interface.

Mesenteric ossification in CT indicates sclerosing peritonitis in chronic bacterial infection and pancreatitis; Mesenteriale Verknoecherungen als computertomographische Zeichen einer sklerosierenden Peritonitis bei chronischer Bauchfellentzuendung und Pankreatitis

Energy Technology Data Exchange (ETDEWEB)

Kirchner, J.; Kirchner, E.M. [Abt. fuer Diagnostische und Interventionelle Radiologie, Klinikum Niederberg Velbert (Germany); Kickuth, R. [Klinik fuer Radiologie und Nuklearmedizin, Katholisches Marienhospital Herne, Universitaetsklinik der Ruhr Univ. Bochum (Germany); Stein, A. [Klinik fuer Strahlentherapie und Onkologie, Universitaetsklinikum Frankfurt/Main (Germany)

2004-07-01

Sclerosing peritonitis already has been described as a serious complication of the continuous ambulatory peritoneal dialysis. But different other affections of the pertioneum such as chronic bacterial peritonitis and pancreatitis may result in sclerosing peritonitis, too. The symptom is characterised by thickened small bowel walls and periotoneal membranes as well as peritoneal calcifications which can be shown in computed tomography. We demonstrate two cases of peritoneal ossifications due to peritonitis and pancreatitis. (orig.) [German] Die sklerosierende Peritonitis wurde wiederholt als ernste Komplikation der Bauchfelldialyse beschrieben. Aber auch verschiedene andere Reizzustaende wie chronische bakterielle Peritonitis und Pankreatitis koennen eine sklerosierende Peritonitis nach sich ziehen. Hierbei zeigen sich neben einer Verdickung des Peritoneums und der Waende des Duenndarms auch computertomographisch nachweisbare Kalkeinlagerungen. Wir stellen zwei Patienten mit chronischer Peritonitis nach Sigmaperforation und Pankreatitis mit Verknoecherungen des Peritoneums vor. (orig.)

Risk of radiation-induced malignancy with heterotopic ossification prophylaxis: a case-control analysis.

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Sheybani, Arshin; TenNapel, Mindi J; Lack, William D; Clerkin, Patrick; Hyer, Daniel E; Sun, Wenqing; Jacobson, Geraldine M

2014-07-01

To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). A matched case-control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not. Copyright © 2014 Elsevier Inc. All rights reserved.

Risk of Radiation-Induced Malignancy With Heterotopic Ossification Prophylaxis: A Case–Control Analysis

International Nuclear Information System (INIS)

Sheybani, Arshin; TenNapel, Mindi J.; Lack, William D.; Clerkin, Patrick; Hyer, Daniel E.; Sun, Wenqing; Jacobson, Geraldine M.

2014-01-01

Purpose: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). Methods and Materials: A matched case–control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. Results: A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. Conclusion: We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not

Risk of Radiation-Induced Malignancy With Heterotopic Ossification Prophylaxis: A Case–Control Analysis

Energy Technology Data Exchange (ETDEWEB)

Sheybani, Arshin, E-mail: arshin-sheybani@uiowa.edu [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); TenNapel, Mindi J. [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); Lack, William D. [Department of Orthopaedic Surgery and Rehabilitation, Loyola University Medical Center, Chicago, Illinois (United States); Clerkin, Patrick; Hyer, Daniel E.; Sun, Wenqing [Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa (United States); Jacobson, Geraldine M. [Department of Radiation Oncology, West Virginia University, Morgantown, West Virginia (United States)

2014-07-01

Purpose: To determine the risk of radiation-induced malignancy after prophylactic treatment for heterotopic ossification (HO). Methods and Materials: A matched case–control study was conducted within a population-based cohort of 3489 patients treated either for acetabular fractures with acetabular open reduction internal fixation or who underwent total hip arthroplasty from 1990 to 2009. Record-linkage techniques identified patients who were diagnosed with a malignancy from our state health registry. Patients with a prior history of malignancy were excluded from the cohort. For each documented case of cancer, 2 controls were selected by stratified random sampling from the cohort that did not develop a malignancy. Matching factors were sex, age at time of hip treatment, and duration of follow-up. Results: A total of 243 patients were diagnosed with a malignancy after hip treatment. Five patients were excluded owing to inadequate follow-up time in the corresponding control cohort. A cohort of 238 cases (control, 476 patients) was included. Mean follow-up was 10 years, 12 years in the control group. In the cancer cohort, 4% of patients had radiation therapy (RT), compared with 7% in the control group. Of the 9 patients diagnosed with cancer after RT, none occurred within the field. The mean latency period was 5.9 years in the patients who received RT and 6.6 years in the patients who did not. Median (range) age at time of cancer diagnosis in patients who received RT was 62 (43-75) years, compared with 70 (32-92) years in the non-RT patients. An ad hoc analysis was subsequently performed in all 2749 patients who were not matched and found neither an increased incidence of malignancy nor a difference in distribution of type of malignancy. Conclusion: We were unable to demonstrate an increased risk of malignancy in patients who were treated with RT for HO prophylaxis compared with those who were not.

9 CFR 113.33 - Mouse safety tests.

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Mouse safety tests. 113.33 Section 113.33 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Procedures § 113.33 Mouse safety tests. One of the mouse safety tests provided in this section shall be...

Cartilaginous Metabolomic Study Reveals Potential Mechanisms of Osteophyte Formation in Osteoarthritis.

Science.gov (United States)

Xu, Zhongwei; Chen, Tingmei; Luo, Jiao; Ding, Shijia; Gao, Sichuan; Zhang, Jian

2017-04-07

Osteophyte is one of the inevitable consequences of progressive osteoarthritis with the main characteristics of cartilage degeneration and endochondral ossification. The pathogenesis of osteophyte formation is not fully understood to date. In this work, metabolomic approaches were employed to explore potential mechanisms of osteophyte formation by detecting metabolic variations between extracts of osteophyte cartilage tissues (n = 32) and uninvolved control cartilage tissues (n = 34), based on the platform of ultraperformance liquid chromatography tandem quadrupole time-of-flight mass spectrometry, as well as the use of multivariate statistic analysis and univariate statistic analysis. The osteophyte group was significantly separated from the control group by the orthogonal partial least-squares discriminant analysis models, indicating that metabolic state of osteophyte cartilage had been changed. In total, 28 metabolic variations further validated by mass spectrum (MS) match, tandom mass spectrum (MS/MS) match, and standards match mainly included amino acids, sulfonic acids, glycerophospholipids, and fatty acyls. These metabolites were related to some specific physiological or pathological processes (collagen dissolution, boundary layers destroyed, self-restoration triggered, etc.) which might be associated with the procedure of osteophyte formation. Pathway analysis showed phenylalanine metabolism (PI = 0.168, p = 0.004) was highly correlative to this degenerative process. Our findings provided a direction for targeted metabolomic study and an insight into further reveal the molecular mechanisms of ostophyte formation.

Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing.

Science.gov (United States)

Cunniffe, Gráinne M; Vinardell, Tatiana; Murphy, J Mary; Thompson, Emmet M; Matsiko, Amos; O'Brien, Fergal J; Kelly, Daniel J

2015-09-01

Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as 'off-the-shelf' implants to promote tissue regeneration. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Rickets: case series and diagnostic review of hypovitaminosis D in swine.

Science.gov (United States)

Madson, Darin M; Ensley, Steve M; Gauger, Phil C; Schwartz, Kent J; Stevenson, Greg W; Cooper, Vickie L; Janke, Bruce H; Burrough, Eric R; Goff, Jesse P; Horst, Ronald L

2012-11-01

Rickets can be attributed to nutritional, genetic, hormonal, or toxic disturbances and is classified as a metabolic bone disease. Rickets is most often associated with inappropriate dietary levels of calcium, phosphorus, and/or vitamin D. During a 27-month period (January 2010 through March 2012), the Iowa State University Veterinary Diagnostic Laboratory investigated causes of sudden, unexpected death and lameness in growing pigs throughout the Midwestern United States. Clinical observations from 17 growing pig cases included weakness, lameness, reluctance to move, muscle fasciculations and/or tremors, tetany, and death. Ribs were weak, soft, and bent prior to breaking; rachitic lesions were apparent at costochondral junctions in multiple cases. Acute and/or chronic bone fractures were also noted in multiple bones. Failure of endochondral ossification, expanded physes, infractions, thin trabeculae, and increased osteoclasts were noted microscopically. Decreased bone ash and serum 25(OH)D(3), combined with clinical and microscopic evaluation, confirmed a diagnosis of vitamin D-dependent rickets in all cases. In 3 cases, disease was linked to a specific nutrient supplier that ultimately resulted in a voluntary feed recall; however, most cases in the current investigation were not associated with a particular feed company. The present report describes vitamin D-associated rickets and its importance as a potential cause of weakness, lameness, muscle fasciculations, recumbency or sudden unexpected death in swine, and describes appropriate samples and tests for disease diagnosis.

Discoid Meniscus Associated With Achondroplasia.

Science.gov (United States)

Hoernschemeyer, Daniel G; Atanda, Alfred; Dean-Davis, Ellen; Gupta, Sumit K

2016-05-01

Achondroplasia is the most common skeletal dysplasia. This form of dwarfism is caused by a point mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, leading to inhibition of endochondral ossification for these patients. This results in a normal trunk height but shortened limbs. The discoid meniscus may be an important associated finding to better understand the common complaints of leg pain for these patients. Although the incidence for a discoid meniscus is between 3% and 5% for the general population, it is unknown with achondroplasia. This case series includes 4 patients, with ages ranging from adolescence to early adulthood, with symptoms of knee pain that were not attributable to some of the more common findings seen in this patient population. Typically, patients with achondroplasia who experience knee pain are evaluated for more common and well-known etiologies such as genu varum, ligamentous instability, and neurogenic claudication. However, the authors propose that symptomatic discoid lateral meniscus should be added to the differential diagnosis for lower-extremity pain in the achondroplasia population. A thorough history and physical examination, in combination with magnetic resonance imaging, can aid in making the diagnosis. Treatment with arthroscopic debridement, saucerization of the meniscus, and repair for unstable injuries has yielded good outcomes for this patient population. [Orthopedics. 2016; 39(3):e498-e503.]. Copyright 2016, SLACK Incorporated.

Radiologic anthropometry of the hand in patients with familial short stature

International Nuclear Information System (INIS)

Cervantes, C.D.; Lifshitz, F.; Levenbrown, J.; North Shore Univ. Hospital, Manhasset, NY; Cornell Univ., New York

1988-01-01

Fifth metacarpal bone shortening (brachymetacarpia V) was recently described to be highly prevalent in children with familial short stature (FSS). To characterize the hand bones of FSS patients with and without brachymetacarpia V, the left hand bone age radiographs of 26 FSS children were reviewed. In 16/19 patients with clinical brachymetacarpia V radiographs revealed fifth metacarpal bone shortening with a gap of 2 mm or more between the distal end of the fifth metacarpal bone and a tangential line connecting the distal ends of the third and fourth metacarpal bones. Only one of 7 patients without clinical brachymetacarpia V had a gap of 2 mm. Radiologic anthropometry revealed that FSS patients with clinically shortened fifth metacarpal bone frequently had shortened first metacarpal bones, second and third proximal phalanges, and fifth distal phalanx as well. FSS patients without clinical fifth metacarpal bone shortening had shortened 3rd and 4th metacarpal bones, fifth proximal phalanx, and fifth distal phalanx. Fifth metacarpal bone shortening was only detected clinically if the fourth metacarpal bone was not short as well. Reduction in height correlated more with reduction in metacarpal bone length than with that of the other hand bones. These peculiar tubular bone alterations commonly seen in FSS suggest a disturbance in endochondral ossification, the process primarily involved in tubular bone elongation. (orig.)

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

Science.gov (United States)

Matthes, Michaela; Preusse, Martin; Zhang, Jingzhong; Schechter, Julia; Mayer, Daniela; Lentes, Bernd; Theis, Fabian; Prakash, Nilima; Wurst, Wolfgang; Trümbach, Dietrich

2014-01-01

The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input. http://mouseidgenes.helmholtz-muenchen.de. © The Author(s) 2014. Published by Oxford University Press.

Compartmentalised expression of Delta-like 1 in epithelial somites is required for the formation of intervertebral joints

Directory of Open Access Journals (Sweden)

Gossler Achim

2007-06-01

Full Text Available Abstract Background Expression of the mouse Delta-like 1 (Dll1 gene in the presomitic mesoderm and in the caudal halves of somites of the developing embryo is required for the formation of epithelial somites and for the maintenance of caudal somite identity, respectively. The rostro-caudal polarity of somites is initiated early on within the presomitic mesoderm in nascent somites. Here we have investigated the requirement of restricted Dll1 expression in caudal somite compartments for the maintenance of rostro-caudal somite polarity and the morphogenesis of the axial skeleton. We did this by overexpressing a functional copy of the Dll1 gene throughout the paraxial mesoderm, in particular in anterior somite compartments, during somitogenesis in transgenic mice. Results Epithelial somites were generated normally and appeared histologically normal in embryos of two independent Dll1 over-expressing transgenic lines. Gene expression analyses of rostro-caudal marker genes suggested that over-expression of Dll1 without restriction to caudal compartments was not sufficient to confer caudal identity to rostral somite halves in transgenic embryos. Nevertheless, Dll1 over-expression caused dysmorphologies of the axial skeleton, in particular, in morphological structures that derive from the articular joint forming compartment of vertebrae. Accordingly, transgenic animals exhibited missing or reduced intervertebral discs, rostral and caudal articular processes as well as costal heads of ribs. In addition, the midline of the vertebral column did not develop normally. Transgenic mice had open neural arches and split vertebral bodies with ectopic pseudo-growth plates. Endochondral bone formation and ossification in the developing vertebrae were delayed. Conclusion The mice overexpressing Dll1 exhibit skeletal dysmorphologies that are also evident in several mutant mice with defects in somite compartmentalisation. The Dll1 transgenic mice demonstrate that

Effect of heat treatment on the properties of SiO2-CaO-MgO-P 2O 5 bioactive glasses.

Science.gov (United States)

Zhou, Yue; Li, Hongying; Lin, Kaili; Zhai, Wanying; Gu, Weiming; Chang, Jiang

2012-09-01

Since the invention of 45S5 Bioglass, researchers never stopped exploring new generation bioactive glass (BG) materials for wider applications in regenerative medicine, among which a novel SiO(2)-CaO-MgO-P(2)O(5) bioactive glass (BG20) is an excellent candidate. However, apart from their biocompatibility and bioactivity, a porous structure is also a must for a tissue engineering scaffold in successfully fixing bone defect. The porosity is the outcome of the high temperature (500-1,000 °C) treatment in the fabricating process of the bioglass scaffold. Under the high temperature, the amorphous glass material will become crystallized at certain percentage in the glass matrix, and possibly leading to consequent changes in the mechanical strength, biodegradability and bioactivity. To elucidate the effect of phase transition on the change of the properties of BG20, the experiments in this report were designed to fine-tuning the heat treating temperatures to fabricate a series of BG20 powders with different crystallization structures. X-ray diffraction revealed a positive correlation between the heating temperature and the crystallization, as well as the compressive strength of the materials. In vitro degradation and ion analysis by ICP-AES demonstrated a similar releasing behavior of different ions including Mg(2+), Ca(2+) and Si(4+), which in common is the tendency of decreasing of the ion concentration along with the increasing of the treating temperature. Cell proliferation assay using both mouse fibroblasts (NIH3T3) and bone marrow stromal cells (BMSCs) showed little toxicity of the ionic extract of the BG20 powders at all the treating temperatures, while fibroblasts demonstrated a significant promoting in the percentage of proliferation. Furthermore, reverse-transcription and polymerase chain reaction analysis on two representative marker genes for early osteogenesis and endochondral ossification, respectively, type I collagen alpha 1 and Indian Hedge-hog, showed

The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics.

Science.gov (United States)

Melozzi, Francesca; Woodman, Marmaduke M; Jirsa, Viktor K; Bernard, Christophe

2017-01-01

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brain's structure-function relationship, necessitating the close integration of diverse neuroinformatics fields. Here we extend the open-source simulation software The Virtual Brain (TVB) to whole mouse brain network modeling based on individual diffusion magnetic resonance imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain (TVMB) to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease. TVMB enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

Immunostimulatory mouse granuloma protein.

Science.gov (United States)

Fontan, E; Fauve, R M; Hevin, B; Jusforgues, H

1983-10-01

Earlier studies have shown that from subcutaneous talc-induced granuloma in mice, a fraction could be extracted that fully protected mice against Listeria monocytogenes. Using standard biochemical procedures--i.e., ammonium sulfate fractionation, preparative electrophoresis, gel filtration chromatography, isoelectric focusing, and preparative polyacrylamide gel electrophoresis--we have now purified an active factor to homogeneity. A single band was obtained in NaDodSO4/polyacrylamide gel with an apparent Mr of 55,000. It migrated with alpha 1-globulins and the isoelectric point was 5 +/- 0.1. The biological activity was destroyed with Pronase but not with trypsin and a monospecific polyclonal rabbit antiserum was obtained. The intravenous injection of 5 micrograms of this "mouse granuloma protein" fully protects mice against a lethal inoculum of L. monocytogenes. Moreover, after their incubation with 10 nM mouse granuloma protein, mouse peritoneal cells became cytostatic against Lewis carcinoma cells.

Mouse Resource Browser-a database of mouse databases

NARCIS (Netherlands)

Zouberakis, Michael; Chandras, Christina; Swertz, Morris; Smedley, Damian; Gruenberger, Michael; Bard, Jonathan; Schughart, Klaus; Rosenthal, Nadia; Hancock, John M.; Schofield, Paul N.; Kollias, George; Aidinis, Vassilis

2010-01-01

The laboratory mouse has become the organism of choice for discovering gene function and unravelling pathogenetic mechanisms of human diseases through the application of various functional genomic approaches. The resulting deluge of data has led to the deployment of numerous online resources and the

EuroPhenome and EMPReSS: online mouse phenotyping resource.

Science.gov (United States)

Mallon, Ann-Marie; Blake, Andrew; Hancock, John M

2008-01-01

EuroPhenome (http://www.europhenome.org) and EMPReSS (http://empress.har.mrc.ac.uk/) form an integrated resource to provide access to data and procedures for mouse phenotyping. EMPReSS describes 96 Standard Operating Procedures for mouse phenotyping. EuroPhenome contains data resulting from carrying out EMPReSS protocols on four inbred laboratory mouse strains. As well as web interfaces, both resources support web services to enable integration with other mouse phenotyping and functional genetics resources, and are committed to initiatives to improve integration of mouse phenotype databases. EuroPhenome will be the repository for a recently initiated effort to carry out large-scale phenotyping on a large number of knockout mouse lines (EUMODIC).

Determining early markers of disease using Raman spectroscopy in a rat combat-trauma model of heterotopic ossification

Science.gov (United States)

Cilwa, Katherine E.; Qureshi, Ammar T.; Forsberg, Jonathan A.; Davis, Thomas A.; Crane, Nicole J.

2016-02-01

Traumatic heterotopic ossification (HO) is the pathological formation of bone in soft tissue and is a debilitating sequela following acute trauma involving blast-related extremity musculoskeletal injuries, severe burns, spinal cord injury, and traumatic brain injury. Over 60% of combat related injuries and severe burns develop HO; often resulting in reduced mobility, chronic pain, ulceration, tissue entrapment, and reduced ambulation. Detection and prognosis is limited by current clinical imaging modalities (computed tomography, radiography, and ultrasound). This study identifies Raman spectral signatures corresponding to histological changes in a combat-trauma induced rat HO model at early time points prior to radiographic evidence of HO. HO was induced in Sprague-Dawley rats via blast over pressure injury, mid-femoral fracture, soft tissue crush injury, and limb amputation through the zone of injury. Rats were euthanized, and amputated limbs were formalin fixed and embedded in paraffin; 10 μm sections were placed on gold slides, and paraffin was chemically removed. Tissues from sham-treated animals served as controls. Tissue maps consisting of Raman spectra were generated using a Raman microprobe system with an 80-90 μm spot size and 785 nm excitation in regions exhibiting histological evidence of early HO development according to adjacent HE sections. Factors were extracted from mapping data using Band-Target Entropy Minimization algorithms. Areas of early HO were highlighted by a Raman factor indicative of the presence of collagen. Identification of collagen as an early marker of HO prior to radiographic detection in a clinically relevant animal model serves to inform future clinical work.

Shielding of the Hip Prosthesis During Radiation Therapy for Heterotopic Ossification is Associated with Increased Failure of Prophylaxis

International Nuclear Information System (INIS)

Balboni, Tracy A.; Gaccione, Peter; Gobezie, Reuben; Mamon, Harvey J.

2007-01-01

Purpose: Radiation therapy (RT) is frequently administered to prevent heterotopic ossification (HO) after total hip arthroplasty (THA). The purpose of this study was to determine if there is an increased risk of HO after RT prophylaxis with shielding of the THA components. Methods and Materials: This is a retrospective analysis of THA patients undergoing RT prophylaxis of HO at Brigham and Women's Hospital between June 1994 and February 2004. Univariate and multivariate logistic regressions were used to assess the relationships of all variables to failure of RT prophylaxis. Results: A total of 137 patients were identified and 84 were eligible for analysis (61%). The median RT dose was 750 cGy in one fraction, and the median follow-up was 24 months. Eight of 40 unshielded patients (20%) developed any progression of HO compared with 21 of 44 shielded patients (48%) (p = 0.009). Brooker Grade III-IV HO developed in 5% of unshielded and 18% of shielded patients (p 0.08). Multivariate analysis revealed shielding (p = 0.02) and THA for prosthesis infection (p = 0.03) to be significant predictors of RT failure, with a trend toward an increasing risk of HO progression with age (p = 0.07). There was no significant difference in the prosthesis failure rates between shielded and unshielded patients. Conclusions: A significantly increased risk of failure of RT prophylaxis for HO was noted in those receiving shielding of the hip prosthesis. Shielding did not appear to reduce the risk of prosthesis failure

Teratology studies in the mouse.

Science.gov (United States)

Marsden, Edward; Leroy, Mariline

2013-01-01

The rat is the routine species of choice as the rodent model for regulatory safety testing of xenobiotics such as medicinal products, food additives, and other chemicals. However, the rat is not always suitable for pharmacological, toxicological, immunogenic, pharmacokinetic, or even practical reasons. Under such circumstances, the mouse offers an alternative for finding a suitable rodent model acceptable to the regulatory authorities. Since all essential routes of administration are possible, the short reproductive cycle and large litter size of the mouse make it a species well adapted for use in teratology studies. Given that good quality animals, including virgin mated females, can be acquired relatively easily and inexpensively, the mouse has been used in reproductive toxicity studies for decades and study protocols are well established.

Circadian oscillators in the mouse brain

DEFF Research Database (Denmark)

Rath, Martin F; Rovsing, Louise; Møller, Morten

2014-01-01

with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje...... and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes...... are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum...

Number and location of mouse mammary tumor virus proviral DNA in mouse DNA of normal tissue and of mammary tumors.

Science.gov (United States)

Groner, B; Hynes, N E

1980-01-01

The Southern DNA filter transfer technique was used to characterize the genomic location of the mouse mammary tumor proviral DNA in different inbred strains of mice. Two of the strains (C3H and CBA) arose from a cross of a Bagg albino (BALB/c) mouse and a DBA mouse. The mouse mammary tumor virus-containing restriction enzyme DNA fragments of these strains had similar patterns, suggesting that the proviruses of these mice are in similar genomic locations. Conversely, the pattern arising from the DNA of the GR mouse, a strain genetically unrelated to the others, appeared different, suggesting that its mouse mammary tumor proviruses are located in different genomic sites. The structure of another gene, that coding for beta-globin, was also compared. The mice strains which we studied can be categorized into two classes, expressing either one or two beta-globin proteins. The macroenvironment of the beta-globin gene appeared similar among the mice strains belonging to one genetic class. Female mice of the C3H strain exogenously transmit mouse mammary tumor virus via the milk, and their offspring have a high incidence of mammary tumor occurrence. DNA isolated from individual mammary tumors taken from C3H mice or from BALB/c mice foster nursed on C3H mothers was analyzed by the DNA filter transfer technique. Additional mouse mammary tumor virus-containing fragments were found in the DNA isolated from each mammary tumor. These proviral sequences were integrated into different genomic sites in each tumor. Images PMID:6245257

The mouse-human anatomy ontology mapping project.

Science.gov (United States)

Hayamizu, Terry F; de Coronado, Sherri; Fragoso, Gilberto; Sioutos, Nicholas; Kadin, James A; Ringwald, Martin

2012-01-01

The overall objective of the Mouse-Human Anatomy Project (MHAP) was to facilitate the mapping and harmonization of anatomical terms used for mouse and human models by Mouse Genome Informatics (MGI) and the National Cancer Institute (NCI). The anatomy resources designated for this study were the Adult Mouse Anatomy (MA) ontology and the set of anatomy concepts contained in the NCI Thesaurus (NCIt). Several methods and software tools were identified and evaluated, then used to conduct an in-depth comparative analysis of the anatomy ontologies. Matches between mouse and human anatomy terms were determined and validated, resulting in a highly curated set of mappings between the two ontologies that has been used by other resources. These mappings will enable linking of data from mouse and human. As the anatomy ontologies have been expanded and refined, the mappings have been updated accordingly. Insights are presented into the overall process of comparing and mapping between ontologies, which may prove useful for further comparative analyses and ontology mapping efforts, especially those involving anatomy ontologies. Finally, issues concerning further development of the ontologies, updates to the mapping files, and possible additional applications and significance were considered. DATABASE URL: http://obofoundry.org/cgi-bin/detail.cgi?id=ma2ncit.

mouseTube – a database to collaboratively unravel mouse ultrasonic communication [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Nicolas Torquet

2016-09-01

Full Text Available Ultrasonic vocalisation is a broadly used proxy to evaluate social communication in mouse models of neuropsychiatric disorders. The efficacy and robustness of testing these models suffer from limited knowledge of the structure and functions of these vocalisations as well as of the way to analyse the data. We created mouseTube, an open database with a web interface, to facilitate sharing and comparison of ultrasonic vocalisations data and metadata attached to a recording file. Metadata describe 1 the acquisition procedure, e.g., hardware, software, sampling frequency, bit depth; 2 the biological protocol used to elicit ultrasonic vocalisations; 3 the characteristics of the individual emitting ultrasonic vocalisations (e.g., strain, sex, age. To promote open science and enable reproducibility, data are made freely available. The website provides searching functions to facilitate the retrieval of recording files of interest. It is designed to enable comparisons of ultrasonic vocalisation emission between strains, protocols or laboratories, as well as to test different analysis algorithms and to search for protocols established to elicit mouse ultrasonic vocalisations. Over the long term, users will be able to download and compare different analysis results for each data file. Such application will boost the knowledge on mouse ultrasonic communication and stimulate sharing and comparison of automatic analysis methods to refine phenotyping techniques in mouse models of neuropsychiatric disorders.

Utrophin Compensates dystrophin Loss during Mouse Spermatogenesis

OpenAIRE

Chen, Hung-Chih; Chin, Yu-Feng; Lundy, David J.; Liang, Chung-Tiang; Chi, Ya-Hui; Kuo, Paolin; Hsieh, Patrick C. H.

2017-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder resulting from mutations in the dystrophin gene. The mdx/utrn ?/? mouse, lacking in both dystrophin and its autosomal homologue utrophin, is commonly used to model the clinical symptoms of DMD. Interestingly, these mice are infertile but the mechanisms underlying this phenomenon remain unclear. Using dystrophin deficient mdx mouse and utrophin haplodeficient mdx/utrn +/? mouse models, we demonstrate the contribution of Dp427 (f...

Mousetrap: An integrated, open-source mouse-tracking package.

Science.gov (United States)

Kieslich, Pascal J; Henninger, Felix

2017-10-01

Mouse-tracking - the analysis of mouse movements in computerized experiments - is becoming increasingly popular in the cognitive sciences. Mouse movements are taken as an indicator of commitment to or conflict between choice options during the decision process. Using mouse-tracking, researchers have gained insight into the temporal development of cognitive processes across a growing number of psychological domains. In the current article, we present software that offers easy and convenient means of recording and analyzing mouse movements in computerized laboratory experiments. In particular, we introduce and demonstrate the mousetrap plugin that adds mouse-tracking to OpenSesame, a popular general-purpose graphical experiment builder. By integrating with this existing experimental software, mousetrap allows for the creation of mouse-tracking studies through a graphical interface, without requiring programming skills. Thus, researchers can benefit from the core features of a validated software package and the many extensions available for it (e.g., the integration with auxiliary hardware such as eye-tracking, or the support of interactive experiments). In addition, the recorded data can be imported directly into the statistical programming language R using the mousetrap package, which greatly facilitates analysis. Mousetrap is cross-platform, open-source and available free of charge from https://github.com/pascalkieslich/mousetrap-os .

Melatonin receptors: latest insights from mouse models

Science.gov (United States)

Tosini, Gianluca; Owino, Sharon; Guillame, Jean-Luc; Jockers, Ralf

2014-01-01

Summary Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications towards type 2 diabetes development, visual functions, sleep disturbances and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2, which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1/MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models. PMID:24903552

Radioprotection by dipyridamole in the aging mouse. Effects on lipid peroxidation in mouse liver, spleen and brain after whole-body X-ray irradiation

International Nuclear Information System (INIS)

Seino, Noritaka

1995-01-01

To investigate the radioprotective effect of dipyridamole in the aging mouse, the lipid peroxide content in aging mouse liver, spleen and brain irradiated by X-ray were measured both before and after injection of dipyridamole. The lipid peroxide content increased with aging from 2 months old to 16 months old in the mouse liver, spleen and brain. The content of lipid peroxide in the liver and spleen of the aging mouse was significantly increased in 7 days after whole-body irradiation with 8 Gy, but was unchanged in the brain. Dipyridamole, given before irradiation, significantly inhibited the increase of lipid peroxide after irradiation. These results suggest that dipyridamole may have radioprotective effects on aging mouse liver and spleen as well as on young mouse, and that inhibition of lipid peroxidation is a possible factor in the radioprotective effect of dipyridamole. (author)

Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

Science.gov (United States)

He, Xuzhi; Cruz, Jazmina L; Joseph, Shannon; Pett, Nicola; Chew, Hui Yi; Tuong, Zewen K; Okano, Satomi; Kelly, Gabrielle; Veitch, Margaret; Simpson, Fiona; Wells, James W

2018-02-23

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

Difference in occurrence of heterotopic ossification according to prosthesis type in the cervical artificial disc replacement.

Science.gov (United States)

Yi, Seong; Kim, Keung Nyun; Yang, Moon Sul; Yang, Joong Won; Kim, Hoon; Ha, Yoon; Yoon, Do Heum; Shin, Hyun Chul

2010-07-15

Retrospective study of the difference of heterotopic ossification (HO) occurrence according to 3 different types of prosthesis. This study was designed to investigate the difference of HO occurrence according to different type of prosthesis. HO is defined as formation of the bone outside the skeletal system. Reported HO occurrence rate in cervical artificial disc replacement (ADR) was unexpectedly high and varied. But the influencing factors of HO in cervical ADR have not been elucidated well. The prosthesis-related factors for making difference of HO occurrence were investigated in this study. A total of 170 patients undergoing cervical arthroplasty with the Bryan cervical disc prosthesis (Medtroic Sofamor Danek, Memphis, TN), Mobi-C disc prosthesis (LDR Medical, Troyes, France), and ProDisc-C (Synthes, Inc., West Chester, PA) were included. Cervical lateral radiographs obtained before and after surgery were used to identify HO. Occurrence rate, occurrence-free period, location, and grade of HOs were investigated according to the different prosthesis. Each prosthesis group included patients as follows: Bryan disc, 81 patients; Mobi-C, 61 patients; and ProDisc-C, 28 patients. Overall HO rate was 40.6% (69 of 170 patients). Each HO occurrence rate by prosthesis was as follows: the Bryan disc group, 21.0%; Mobi-C group, 52.5%; and the ProDisc-C group, 71.4%. In the survival analysis, all patients showed 27.1 +/- 3.7 months as the median survival. The Bryan disc group showed statistically longer survival (48.4 +/- 7.4 months) than the other groups. Occurrence of HO is an inevitable postoperative complication after cervical ADR. The occurrence rate of HO was higher than our expectation. Moreover, definite differences in occurrence rate according to the prosthesis type were identified by this study.

A report from the Sixth International Mouse Genome Conference

Energy Technology Data Exchange (ETDEWEB)

Brown, S. [Saint Mary`s Hospital Medical School, London (United Kingdom). Dept. of Biochemistry and Molecular Genetics

1992-12-31

The Sixth Annual Mouse Genome Conference was held in October, 1992 at Buffalo, USA. The mouse is one of the primary model organisms in the Human Genome Project. Through the use of gene targeting studies the mouse has become a powerful biological model for the study of gene function and, in addition, the comparison of the many homologous mutations identified in human and mouse have widened our understanding of the biology of these two organisms. A primary goal in the mouse genome program has been to create a genetic map of STSs of high resolution (<1cM) that would form the basis for the physical mapping of the whole mouse genome. Buffalo saw substantial new progress towards the goal of a very high density genetic map and the beginnings of substantive efforts towards physical mapping in chromosome regions with a high density of genetic markers.

Enhanced casein kinase II activity during mouse embryogenesis. Identification of a 110-kDa phosphoprotein as the major phosphorylation product in mouse embryos and Krebs II mouse ascites tumor cells

DEFF Research Database (Denmark)

Schneider, H R; Reichert, G H; Issinger, O G

1986-01-01

Mouse embryos at various stages of development were used to study the relationship of protein kinase activities with normal embryogenesis. Casein kinase II (CKII) activity in developing mouse embryos shows a 3-4-fold activity increase at day 12 of gestation. Together with the CKII activity...... mouse tumour cells also show an enhanced CKII activity. Here too, a 110-kDa phosphoprotein was the major phosphoryl acceptor. Partial proteolytic digestion shows that both proteins are identical. Other protein kinases tested (cAMP- and cGMP-dependent protein kinases) only show a basal level of enzyme...

The MAGIC Touch: Combining MAGIC-Pointing with a Touch-Sensitive Mouse

Science.gov (United States)

Drewes, Heiko; Schmidt, Albrecht

In this paper, we show how to use the combination of eye-gaze and a touch-sensitive mouse to ease pointing tasks in graphical user interfaces. A touch of the mouse positions the mouse pointer at the current gaze position of the user. Thus, the pointer is always at the position where the user expects it on the screen. This approach changes the user experience in tasks that include frequent switching between keyboard and mouse input (e.g. working with spreadsheets). In a user study, we compared the touch-sensitive mouse with a traditional mouse and observed speed improvements for pointing tasks on complex backgrounds. For pointing task on plain backgrounds, performances with both devices were similar, but users perceived the gaze-sensitive interaction of the touch-sensitive mouse as being faster and more convenient. Our results show that using a touch-sensitive mouse that positions the pointer on the user’s gaze position reduces the need for mouse movements in pointing tasks enormously.

Relationship between radiobiological hypoxia in a C3H mouse mammary carcinoma and osteopontin levels in mouse serum

DEFF Research Database (Denmark)

Lukácová, Slávka; Khalil, Azza Ahmed; Overgaard, Jens

2005-01-01

To investigate the possible relationship between radiobiological hypoxia in a C3H mouse mammary carcinoma and osteopontin (OPN) levels measured in mouse serum. MATERIAL AND METHODS: Experiments were performed in CDF1 mice that were either non-tumour bearing or with different sized tumours implanted...... in the right rear foot. Osteopontin levels in extracted mouse blood serum and tissue from the transplanted tumours were measured using an ELISA assay. The tumour oxygenation status was estimated using the Eppendorf Histograph and the fraction of oxygen partial pressure (pO2) values =5 mm Hg (HF5...

Doublecortin May Play a Role in Defining Chondrocyte Phenotype

Directory of Open Access Journals (Sweden)

Dongxia Ge

2014-04-01

Full Text Available Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.

Sequence and chromosomal localization of the mouse brevican gene

DEFF Research Database (Denmark)

Rauch, U; Meyer, H; Brakebusch, C

1997-01-01

Brevican is a brain-specific proteoglycan belonging to the aggrecan family. Phage clones containing the complete mouse brevican open reading frame of 2649 bp and the complete 3'-untranslated region of 341 bp were isolated from a mouse brain cDNA library, and cosmid clones containing the mouse...

Minimally invasive surgery for resection of ossification of the ligamentum flavum in the thoracic spine.

Science.gov (United States)

Zhao, Wei; Shen, Chaoxiong; Cai, Ranze; Wu, Jianfeng; Zhuang, Yuandong; Cai, Zhaowen; Wang, Rui; Chen, Chunmei

2017-01-01

Thoracic ossification of the ligamentum flavum (TOLF) is a common cause of progressive thoracic myelopathy. Surgical decompression is commonly used to treat TOLF. To evaluate the clinical outcomes of microsurgical decompression of TOLF via a paraspinal approach, using a percutaneous tubular retractor system. First, three-dimensional (3D) image reconstruction and printed models were made from thin computed tomography scans for each patient. Then, 3D computer-assisted virtual surgery was performed using the 3D reconstruction to calculate the precise location and sizes of the bone window and the angle of insertion of the percutaneous tubular retractor system. In total, 13 patients underwent the surgery through the percutaneous micro channel unilateral vertebral approach under electrophysiological monitoring. Five days after the surgery, increased creatine phosphokinase levels returned to preoperative levels. The Japanese Orthopedic Association (JOA) score was improved and computed tomography reconstruction and magnetic resonance imaging of the thoracic spine showed that decompression was achieved without injuries to the spinal cord or nerve root. The stability of the spine was not affected, nor were any deformities of the spine detected. Finally, nerve functional recovery was achieved with minimal injury to the paraspinal muscle, articulum, spinous process and ligament. The mean operative time was 98.23 ±19.10 min, and mean blood loss was 19.77 ±5.97 ml. At a mean follow-up of 13.3 months (median: 12 months), the mean JOA score was 7.54 ±1.13 at the final follow-up, yielding a mean RR of 49.10 ±15.71%. Using The recovery rate, 7 (53.85%) patients had good outcomes, 5 (38.46%) patients had a fair outcome, and 1 (7.69%) patient had poor outcomes, indicating significant improvement by the final follow-up examination (p < 0.05). The 3D printed patient model-based microsurgical resection of TOLF via the paraspinal approach can achieve decompression of the spinal canal

The wobbler mouse, an ALS animal model

DEFF Research Database (Denmark)

Moser, Jakob Maximilian; Bigini, Paolo; Schmitt-John, Thomas

2013-01-01

This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking...

Chemical Aspects of Lesser Mouse Deer Meat

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Djalal Rosyidi

2012-02-01

Full Text Available An experiment aiming for studying chemical aspects of lesser mouse deer meat (Tragulus javanicus. This research explored the chemical aspects of lesser mouse deer meat (Tragulus javanicus. Eight lesser mouse deer (four female and four male were used in chemical aspects of lesser mouse deer meat. The parameters observed included proximate analysis, amino acid, fatty acid, cholesterol and EPA-DHA of the meat. The results showed that average meat chemical composition were content of water, protein, fat, ash and cholesterol were 76.33 %, 21.42 %, 0.51 %, 1.20% and 50.00 mg/100 g, respectively. Fatty acid consist of lauric acid, miristate, palmitate, stearic, oleic, linoleic, and linolenic were 1.04 % 3.09%, 30.97, 0.77%., 59.41%, 3.22% and 1.12%, respectively. The total EPA and DHA was 0.13% and 0.05%,   Keywords: amino acid, fatty acid, cholesterol and EPA-DHA

A catalog of the mouse gut metagenome

DEFF Research Database (Denmark)

Xiao, Liang; Feng, Qiang; Liang, Suisha

2015-01-01

laboratories and fed either a low-fat or high-fat diet. Similar to the human gut microbiome, >99% of the cataloged genes are bacterial. We identified 541 metagenomic species and defined a core set of 26 metagenomic species found in 95% of the mice. The mouse gut microbiome is functionally similar to its human......We established a catalog of the mouse gut metagenome comprising ∼2.6 million nonredundant genes by sequencing DNA from fecal samples of 184 mice. To secure high microbiome diversity, we used mouse strains of diverse genetic backgrounds, from different providers, kept in different housing...... counterpart, with 95.2% of its Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologous groups in common. However, only 4.0% of the mouse gut microbial genes were shared (95% identity, 90% coverage) with those of the human gut microbiome. This catalog provides a useful reference for future studies....

10. international mouse genome conference

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Meisler, M.H.

1996-12-31

Ten years after hosting the First International Mammalian Genome Conference in Paris in 1986, Dr. Jean-Louis Guenet presided over the Tenth Conference at the Pasteur Institute, October 7--10, 1996. The 1986 conference was a satellite to the Human Gene Mapping Workshop and had approximately 50 attendees. The 1996 meeting was attended by 300 scientists from around the world. In the interim, the number of mapped loci in the mouse increased from 1,000 to over 20,000. This report contains a listing of the program and its participants, and two articles that review the meeting and the role of the laboratory mouse in the Human Genome project. More than 200 papers were presented at the conference covering the following topics: International mouse chromosome committee meetings; Mutant generation and identification; Physical and genetic maps; New technology and resources; Chromatin structure and gene regulation; Rate and hamster genetic maps; Informatics and databases; and Quantitative trait analysis.

Mouse Models of Gastric Cancer

Science.gov (United States)

Hayakawa, Yoku; Fox, James G.; Gonda, Tamas; Worthley, Daniel L.; Muthupalani, Sureshkumar; Wang, Timothy C.

2013-01-01

Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field. PMID:24216700

Mouse models of Fanconi anemia

International Nuclear Information System (INIS)

Parmar, Kalindi; D'Andrea, Alan; Niedernhofer, Laura J.

2009-01-01

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Mouse models of Fanconi anemia

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Parmar, Kalindi; D' Andrea, Alan [Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115 (United States); Niedernhofer, Laura J., E-mail: niedernhoferl@upmc.edu [Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine and Cancer Institute, 5117 Centre Avenue, Hillman Cancer Center, Research Pavilion 2.6, Pittsburgh, PA 15213-1863 (United States)

2009-07-31

Fanconi anemia is a rare inherited disease characterized by congenital anomalies, growth retardation, aplastic anemia and an increased risk of acute myeloid leukemia and squamous cell carcinomas. The disease is caused by mutation in genes encoding proteins required for the Fanconi anemia pathway, a response mechanism to replicative stress, including that caused by genotoxins that cause DNA interstrand crosslinks. Defects in the Fanconi anemia pathway lead to genomic instability and apoptosis of proliferating cells. To date, 13 complementation groups of Fanconi anemia were identified. Five of these genes have been deleted or mutated in the mouse, as well as a sixth key regulatory gene, to create mouse models of Fanconi anemia. This review summarizes the phenotype of each of the Fanconi anemia mouse models and highlights how genetic and interventional studies using the strains have yielded novel insight into therapeutic strategies for Fanconi anemia and into how the Fanconi anemia pathway protects against genomic instability.

Cancer risk estimates from radiation therapy for heterotopic ossification prophylaxis after total hip arthroplasty

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Mazonakis, Michalis; Berris, Theoharris; Damilakis, John [Department of Medical Physics, Faculty of Medicine, University of Crete, P.O. Box 2208, 71003 Iraklion, Crete (Greece); Lyraraki, Efrossyni [Department of Radiotherapy and Oncology, University Hospital of Iraklion, 71110 Iraklion, Crete (Greece)

2013-10-15

Purpose: Heterotopic ossification (HO) is a frequent complication following total hip arthroplasty. This study was conducted to calculate the radiation dose to organs-at-risk and estimate the probability of cancer induction from radiotherapy for HO prophylaxis.Methods: Hip irradiation for HO with a 6 MV photon beam was simulated with the aid of a Monte Carlo model. A realistic humanoid phantom representing an average adult patient was implemented in Monte Carlo environment for dosimetric calculations. The average out-of-field radiation dose to stomach, liver, lung, prostate, bladder, thyroid, breast, uterus, and ovary was calculated. The organ-equivalent-dose to colon, that was partly included within the treatment field, was also determined. Organ dose calculations were carried out using three different field sizes. The dependence of organ doses upon the block insertion into primary beam for shielding colon and prosthesis was investigated. The lifetime attributable risk for cancer development was estimated using organ, age, and gender-specific risk coefficients.Results: For a typical target dose of 7 Gy, organ doses varied from 1.0 to 741.1 mGy by the field dimensions and organ location relative to the field edge. Blocked field irradiations resulted in a dose range of 1.4–146.3 mGy. The most probable detriment from open field treatment of male patients was colon cancer with a high risk of 564.3 × 10{sup −5} to 837.4 × 10{sup −5} depending upon the organ dose magnitude and the patient's age. The corresponding colon cancer risk for female patients was (372.2–541.0) × 10{sup −5}. The probability of bladder cancer development was more than 113.7 × 10{sup −5} and 110.3 × 10{sup −5} for males and females, respectively. The cancer risk range to other individual organs was reduced to (0.003–68.5) × 10{sup −5}.Conclusions: The risk for cancer induction from radiation therapy for HO prophylaxis after total hip arthroplasty varies considerably by

Cancer risk estimates from radiation therapy for heterotopic ossification prophylaxis after total hip arthroplasty

International Nuclear Information System (INIS)

Mazonakis, Michalis; Berris, Theoharris; Damilakis, John; Lyraraki, Efrossyni

2013-01-01

Purpose: Heterotopic ossification (HO) is a frequent complication following total hip arthroplasty. This study was conducted to calculate the radiation dose to organs-at-risk and estimate the probability of cancer induction from radiotherapy for HO prophylaxis.Methods: Hip irradiation for HO with a 6 MV photon beam was simulated with the aid of a Monte Carlo model. A realistic humanoid phantom representing an average adult patient was implemented in Monte Carlo environment for dosimetric calculations. The average out-of-field radiation dose to stomach, liver, lung, prostate, bladder, thyroid, breast, uterus, and ovary was calculated. The organ-equivalent-dose to colon, that was partly included within the treatment field, was also determined. Organ dose calculations were carried out using three different field sizes. The dependence of organ doses upon the block insertion into primary beam for shielding colon and prosthesis was investigated. The lifetime attributable risk for cancer development was estimated using organ, age, and gender-specific risk coefficients.Results: For a typical target dose of 7 Gy, organ doses varied from 1.0 to 741.1 mGy by the field dimensions and organ location relative to the field edge. Blocked field irradiations resulted in a dose range of 1.4–146.3 mGy. The most probable detriment from open field treatment of male patients was colon cancer with a high risk of 564.3 × 10 −5 to 837.4 × 10 −5 depending upon the organ dose magnitude and the patient's age. The corresponding colon cancer risk for female patients was (372.2–541.0) × 10 −5 . The probability of bladder cancer development was more than 113.7 × 10 −5 and 110.3 × 10 −5 for males and females, respectively. The cancer risk range to other individual organs was reduced to (0.003–68.5) × 10 −5 .Conclusions: The risk for cancer induction from radiation therapy for HO prophylaxis after total hip arthroplasty varies considerably by the treatment parameters, organ

PEDF Is Associated with the Termination of Chondrocyte Phenotype and Catabolism of Cartilage Tissue.

Science.gov (United States)

Klinger, P; Lukassen, S; Ferrazzi, F; Ekici, A B; Hotfiel, T; Swoboda, B; Aigner, T; Gelse, K

2017-01-01

Objective. To investigate the expression and target genes of pigment epithelium-derived factor (PEDF) in cartilage and chondrocytes, respectively. Methods. We analyzed the expression pattern of PEDF in different human cartilaginous tissues including articular cartilage, osteophytic cartilage, and fetal epiphyseal and growth plate cartilage, by immunohistochemistry and quantitative real-time (qRT) PCR. Transcriptome analysis after stimulation of human articular chondrocytes with rhPEDF was performed by RNA sequencing (RNA-Seq) and confirmed by qRT-PCR. Results. Immunohistochemically, PEDF could be detected in transient cartilaginous tissue that is prone to undergo endochondral ossification, including epiphyseal cartilage, growth plate cartilage, and osteophytic cartilage. In contrast, PEDF was hardly detected in healthy articular cartilage and in the superficial zone of epiphyses, regions that are characterized by a permanent stable chondrocyte phenotype. RNA-Seq analysis and qRT-PCR demonstrated that rhPEDF significantly induced the expression of a number of matrix-degrading factors including SAA1, MMP1, MMP3, and MMP13. Simultaneously, a number of cartilage-specific genes including COL2A1, COL9A2, COMP, and LECT were among the most significantly downregulated genes. Conclusions. PEDF represents a marker for transient cartilage during all neonatal and postnatal developmental stages and promotes the termination of cartilage tissue by upregulation of matrix-degrading factors and downregulation of cartilage-specific genes. These data provide the basis for novel strategies to stabilize the phenotype of articular cartilage and prevent its degradation.

Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism.

Science.gov (United States)

Xing, Lianping; Chen, Di; Boyce, Brendan F

2013-12-01

NF-κBp50/p52 double knockout (dKO) and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism. In contrast, Op/Op mice, which form few osteoclasts, and Src KO mice, which have osteoclasts with defective resorptive function, are osteopetrotic, but they are not dwarfed. Here, we compared the morphologic features of long bones from p50/p52 dKO, RANK KO, Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths. We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2-3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone. This growth plate abnormality disappears when animals become older, but their dwarfism persists. Op/Op or Src KO mice have relatively normal growth plate morphology. In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes. Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9, markers for proliferative chondrocytes, but RANKL reduced the number of type 10 collagen-expressing hypertrophic chondrocytes. Thus, RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.

Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats.

Science.gov (United States)

Tanaka, Masami; Watanabe, Minoru; Yokomi, Izuru; Matsumoto, Naoki; Sudo, Katsuko; Satoh, Hitoshi; Igarashi, Tsuneo; Seki, Azusa; Amano, Hitoshi; Ohura, Kiyoshi; Ryu, Kakei; Shibata, Shunichi; Nagayama, Motohiko; Tanuma, Jun-ichi

2015-01-01

Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats.

Spontaneous rickets in the wild arctic fox Alopex lagopus

International Nuclear Information System (INIS)

Ogden, J.A.; Conlogue, G.J.

1981-01-01

Normal and rachitic, skeletally immature arctic foxes (Alopex lagopus) were subjected to physical examination, roentgenographic studies, and in some cases histologic studies. The involved animals had active rickets coupled with antecedent normal diaphyseal bone formation. Evaluation of all the long bones showed highly variable manifestations of the disease, which undoubtedly reflect different rates of physeal endochondral transformation and metaphyseal remodeling. Histologic examination showed distinct patterns of widening of the physes and variable osteodystrophy in the trabecular and cortical bone of the metaphyses and epiphyseal ossification centers. These aforementioned factors certainly would necessitate different regional calcium needs and, therefore, different regional responses to an overall calcium deficiency. The physes involved in the most rapid growth rates in this period showed the most widening of the growth plate, and the most dystrophic changes in the metaphysis. Skeletal injuries, including metaphyseal fractures and slow-down of longitudinal growth (particularly in the ulna) were also evident. Because of apparent dietary differences in the affected and normal fox kits, this juvenile-onset disease was presumed due to calcium-deficient intake following weaning. To the best of our knowledge this is the first report of spontaneously occurring rickets in a wild animal in its natural habitat. There are several possible mechanisms for the variable widening of the physis and the loss of bone mineralization in these fox kits: calcium-deficient diet, binding of calcium in the bowel by high phosphorus intake, secondary hyperparathyroidism, and vitamin A toxicity. (orig.)

8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage.

Science.gov (United States)

Hoshino, Marie; Kaneko, Kotaro; Miyamoto, Yoichi; Yoshimura, Kentaro; Suzuki, Dai; Akaike, Takaaki; Sawa, Tomohiro; Ida, Tomoaki; Fujii, Shigemoto; Ihara, Hideshi; Tanaka, Junichi; Tsukuura, Risa; Chikazu, Daichi; Mishima, Kenji; Baba, Kazuyoshi; Kamijo, Ryutaro

2017-09-01

In endochondral ossification, growth of bones occurs at their growth plate cartilage. While it is known that nitric oxide (NO) synthases are required for proliferation of chondrocytes in growth plate cartilage and growth of bones, the precise mechanism by which NO facilitates these process has not been clarified yet. C-type natriuretic peptide (CNP) also positively regulate elongation of bones through expansion of the growth plate cartilage. Both NO and CNP are known to use cGMP as the second messenger. Recently, 8-nitro-cGMP was identified as a signaling molecule produced in the presence of NO in various types of cells. Here, we found that 8-nitro-cGMP is produced in proliferating chondrocytes in the growth plates, which was enhanced by CNP, in bones cultured ex vivo. In addition, 8-nitro-cGMP promoted bone growth with expansion of the proliferating zone as well as increase in the number of proliferating cells in the growth plates. 8-Nitro-cGMP also promoted the proliferation of chondrocytes in vitro. On the other hand, 8-bromo-cGMP enhanced the growth of bones with expansion of hypertrophic zone of the growth plates without affecting either the width of proliferating zone or proliferation of chondrocytes. These results indicate that 8-nitro-cGMP formed in growth plate cartilage accelerates chondrocyte proliferation and bone growth as a downstream molecule of NO. Copyright © 2017. Published by Elsevier Inc.

Establishment of a novel dwarf rat strain: cartilage calcification insufficient (CCI) rats

Science.gov (United States)

TANAKA, Masami; WATANABE, Minoru; YOKOMI, Izuru; MATSUMOTO, Naoki; SUDO, Katsuko; SATOH, Hitoshi; IGARASHI, Tsuneo; SEKI, Azusa; AMANO, Hitoshi; OHURA, Kiyoshi; RYU, Kakei; SHIBATA, Shunichi; NAGAYAMA, Motohiko; TANUMA, Jun-ichi

2014-01-01

Rats with dwarfism accompanied by skeletal abnormalities, such as shortness of the limbs, tail, and body (dwarf rats), emerged in a Jcl-derived Sprague-Dawley rat colony maintained at the Institute for Animal Experimentation, St. Marianna University Graduate School of Medicine. Since the dwarfism was assumed to be due to a genetic mutation based on its frequency, we bred the dwarf rats and investigated their characteristics in order to identify the causative factors of their phenotypes and whether they could be used as a human disease model. One male and female that produced dwarf progeny were selected, and reproduction was initiated by mating the pair. The incidence of dwarfism was 25.8% among the resultant litter, and dwarfism occurred in both genders, suggesting that it was inherited in an autosomal recessive manner. At 12 weeks of age, the body weights of the male and female dwarf rats were 40% and 57% of those of the normal rats, respectively. In soft X-ray radiographic and histological examinations, shortening and hypoplasia of the long bones, such as the tibia and femur, were observed, which were suggestive of endochondral ossification abnormalities. An immunohistochemical examination detected an aggrecan synthesis disorder, which might have led to delayed calcification and increased growth plate thickening in the dwarf rats. We hypothesized that the principal characteristics of the dwarf rats were systemically induced by insufficient cartilage calcification in their long bones; thus, we named them cartilage calcification insufficient (CCI) rats. PMID:25736479

Mouse myocardial first-pass perfusion MR imaging

NARCIS (Netherlands)

Coolen, Bram F.; Moonen, Rik P. M.; Paulis, Leonie E. M.; Geelen, Tessa; Nicolay, Klaas; Strijkers, Gustav J.

2010-01-01

A first-pass myocardial perfusion sequence for mouse cardiac MRI is presented. A segmented ECG-triggered acquisition combined with parallel imaging acceleration was used to capture the first pass of a Gd-DTPA bolus through the mouse heart with a temporal resolution of 300-400 msec. The method was

Mouse adenovirus type 1 infection of macrophages

NARCIS (Netherlands)

Ashley, S.L.; Welton, A.R.; Harwood, K.M.; Rooijen, van N.; Spindler, K.R.

2009-01-01

Mouse adenovirus type 1 (MAV-1) causes acute and persistent infections in mice, with high levels of virus found in the brain, spinal cord and spleen in acute infections. MAV-1 infects endothelial cells throughout the mouse, and monocytes/macrophages have also been implicated as targets of the virus.

A Prolonged Time Interval Between Trauma and Prophylactic Radiation Therapy Significantly Increases the Risk of Heterotopic Ossification

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Mourad, Waleed F., E-mail: Waleed246@gmail.com [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Department of Radiation Oncology, Beth Israel Medical Center, New York, NY (Israel); Packianathan, Satyaseelan [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Shourbaji, Rania A. [Department of Epidemiology and Biostatistics, Jackson State University, Jackson, MS (United States); Zhang Zhen; Graves, Mathew [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Khan, Majid A. [Department of Radiology, University of Mississippi Medical Center, Jackson, MS (United States); Baird, Michael C. [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States); Russell, George [Department of Orthopedic Surgery, University of Mississippi Medical Center, Jackson, MS (United States); Vijayakumar, Srinivasan [Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS (United States)

2012-03-01

Purpose: To ascertain whether the time from injury to prophylactic radiation therapy (RT) influences the rate of heterotopic ossification (HO) after operative treatment of displaced acetabular fractures. Methods and Materials: This is a single-institution, retrospective analysis of patients referred for RT for the prevention of HO. Between January 2000 and January 2009, 585 patients with displaced acetabular fractures were treated surgically followed by RT for HO prevention. We analyzed the effect of time from injury on prevention of HO by RT. In all patients, 700 cGy was prescribed in a single fraction and delivered within 72 hours postsurgery. The patients were stratified into five groups according to time interval (in days) from the date of their accident to the date of RT: Groups A {<=}3, B {<=}7, C {<=}14, D {<=}21, and E >21days. Results: Of the 585 patients with displaced acetabular fractures treated with RT, (18%) 106 patients developed HO within the irradiated field. The risk of HO after RT increased from 10% for RT delivered {<=}3 days to 92% for treatment delivered >21 days after the initial injury. Wilcoxon test showed a significant correlation between the risk of HO and the length of time from injury to RT (p < 0.0001). Chi-square test and multiple logistic regression analysis showed no significant association between all other factors and the risk of HO (race, gender, cause and type of fracture, surgical approach, or the use of indomethacin). Conclusions: Our data suggest that there is higher incidence and risk of HO if prophylactic RT is significantly delayed after a displaced acetabular fracture. Thus, RT should be administered as early as clinically possible after the trauma. Patients undergoing RT >3 weeks from their displaced acetabular fracture should be informed of the higher risk (>90%) of developing HO despite prophylaxis.

Pulse low-intensity electromagnetic field as prophylaxis of heterotopic ossification in patients with traumatic spinal cord injury

Directory of Open Access Journals (Sweden)

Đurović Aleksandar

2009-01-01

Full Text Available Background/Aim. Heterotopic ossification (HO is an important complication of head and spinal cord injuries (SCI. Pulse low-intensity electromagnetic field (PLIMF therapy increases blood flow to an area of pain or inflammation, bringing more oxygen to that area and helps to remove toxic substances. The aim of this study was to determine the effect of PLIMF as prophylaxis of HO in patients with SCI. Methods. This prospective random control clinical study included 29 patients with traumatic SCI. The patients were randomly divided into experimental (n = 14 and control group (n = 15. The patients in the experimental group, besides exercise and range of motion therapy, were treated by PLIMF of the following characteristics: induction of 10 mT, frequency of 25 Hz and duration of 30 min. Pulse low-intensity electromagnetic field therapy started in the 7th week after the injury and lasted 4 weeks. The presence or absence of HO around the patients hips we checked by a plane radiography and Brookers classification. Functional capabilities and motor impairment were checked by Functional Independent Measure (FIM, Barthel index and American Spinal Injury Association (ASIA impairment class. Statistic analysis included Kolmogorov-Smirnov test, Shapiro-Wilk test, Mann Whitney Exact test, Exact Wilcoxon signed rank test and Fischer Exact test. Statistical significance was set up to p < 0.05. Results. At the end of the treatment no patient from the experimental group had HO. In the control group, five patients (33.3% had HO. At the end of the treatment the majority of the patients from the experimental group (57.14% moved from ASIA-A to ASIA-B class. Conclusion. Pulse low-intensity electromagnetic field therapy could help as prophylaxis of HO in patients with traumatic SCI.

Mouse myocardial first-pass perfusion MR imaging

NARCIS (Netherlands)

Coolen, B.F.; Moonen, R.P.M.; Paulis, L.E.M.; Geelen, T.; Nicolay, K.; Strijkers, G.J.

2010-01-01

A first-pass myocardial perfusion sequence for mouse cardiac MRI is presented. A segmented ECG-triggered acquisition combined with parallel imaging acceleration was used to capture the first pass of a Gd-DTPA bolus through the mouse heart with a temporal resolution of 300–400 msec. The method was

Immunologic analyses of mouse cystathionase in normal and leukemic cells

International Nuclear Information System (INIS)

Bikel, I.; Faibes, D.; Uren, J.R.; Livingston, D.M.

1978-01-01

Rabbit antisera have been raised against mouse liver cystathionase and shown to possess enzyme neutralizing activity. Agar gel double immunodiffusion analyses demonstrated that both mouse liver cystathionase and rat liver cystathionase react with the antisera, the latter enzyme being completely cross-reactive with the former. Following radioiodination of the purified rat liver enzyme, a double antibody radioimmunoassay was developed in which greater than 90% of the labeled protein could be specifically precipitated with the anti-mouse cystathionase antibodies. In this test the purified rat liver and mouse liver enzymes were virtually indistinguishable, generating superimposable competition displacement curves on a protein mass basis. These results indicate that both enzymes are immunologically identical, thus validating the use of the rat in lieu of the murine liver enzyme as radiolabeled tracer in an assay for mouse cystathionase. In addition, competition radioimmunoassays demonstrated that the immunological reactivities of both the purified rat liver and mouse liver enzymes were equally heat sensitive. The sensitivity of the assay was determined to be 1 ng of enzyme protein/0.22 mL of assay mixture, and the assay could be used to detect the presence of enzyme protein in tissue homogenates of single mouse organs. Mouse or rat cross-reactivity with human liver cystathionase was incomplete; but, with the exception of heart and spleen, parallel radioimmunoassay competition displacement curves were obtained for cystathionase from different mouse organs including thymus. Extracts of 7-, 9-, and 10-month-old spontaneous AKR mouse thymomas were tested in the radioimmunoassay along with extracts of age-matched thymuses which were grossly tumor free. A reaction of nonidentity was observed for all of the tumor extracts while a reaction identical with that of the pure liver enzyme was found with all of the normal thymus extracts

CYP1A1 and CYP1A2 expression: Comparing 'humanized' mouse lines and wild-type mice; comparing human and mouse hepatoma-derived cell lines

International Nuclear Information System (INIS)

Uno, Shigeyuki; Endo, Kaori; Ishida, Yuji; Tateno, Chise; Makishima, Makoto; Yoshizato, Katsutoshi; Nebert, Daniel W.

2009-01-01

Human and rodent cytochrome P450 (CYP) enzymes sometimes exhibit striking species-specific differences in substrate preference and rate of metabolism. Human risk assessment of CYP substrates might therefore best be evaluated in the intact mouse by replacing mouse Cyp genes with human CYP orthologs; however, how 'human-like' can human gene expression be expected in mouse tissues? Previously a bacterial-artificial-chromosome-transgenic mouse, carrying the human CYP1A1 C YP1A2 locus and lacking the mouse Cyp1a1 and Cyp1a2 orthologs, was shown to express robustly human dioxin-inducible CYP1A1 and basal versus inducible CYP1A2 (mRNAs, proteins, enzyme activities) in each of nine mouse tissues examined. Chimeric mice carrying humanized liver have also been generated, by transplanting human hepatocytes into a urokinase-type plasminogen activator(+/+) s evere-combined-immunodeficiency (uPA/SCID) line with most of its mouse hepatocytes ablated. Herein we compare basal and dioxin-induced CYP1A mRNA copy numbers, protein levels, and four enzymes (benzo[a]pyrene hydroxylase, ethoxyresorufin O-deethylase, acetanilide 4-hydroxylase, methoxyresorufin O-demethylase) in liver of these two humanized mouse lines versus wild-type mice; we also compare these same parameters in mouse Hepa-1c1c7 and human HepG2 hepatoma-derived established cell lines. Most strikingly, mouse liver CYP1A1-specific enzyme activities are between 38- and 170-fold higher than human CYP1A1-specific enzyme activities (per unit of mRNA), whereas mouse versus human CYP1A2 enzyme activities (per unit of mRNA) are within 2.5-fold of one another. Moreover, both the mouse and human hepatoma cell lines exhibit striking differences in CYP1A mRNA levels and enzyme activities. These findings are relevant to risk assessment involving human CYP1A1 and CYP1A2 substrates, when administered to mice as environmental toxicants or drugs.

Effect of Duplicate Genes on Mouse Genetic Robustness: An Update

Directory of Open Access Journals (Sweden)

Zhixi Su

2014-01-01

Full Text Available In contrast to S. cerevisiae and C. elegans, analyses based on the current knockout (KO mouse phenotypes led to the conclusion that duplicate genes had almost no role in mouse genetic robustness. It has been suggested that the bias of mouse KO database toward ancient duplicates may possibly cause this knockout duplicate puzzle, that is, a very similar proportion of essential genes (PE between duplicate genes and singletons. In this paper, we conducted an extensive and careful analysis for the mouse KO phenotype data and corroborated a strong effect of duplicate genes on mouse genetics robustness. Moreover, the effect of duplicate genes on mouse genetic robustness is duplication-age dependent, which holds after ruling out the potential confounding effect from coding-sequence conservation, protein-protein connectivity, functional bias, or the bias of duplicates generated by whole genome duplication (WGD. Our findings suggest that two factors, the sampling bias toward ancient duplicates and very ancient duplicates with a proportion of essential genes higher than that of singletons, have caused the mouse knockout duplicate puzzle; meanwhile, the effect of genetic buffering may be correlated with sequence conservation as well as protein-protein interactivity.

Cultures of preimplantation mouse embryos

International Nuclear Information System (INIS)

Streffer, C.; Molls, M.

1987-01-01

In the preimplantation mouse embryos the chromosomal damage develops through several postradiation cell cycles and mitoses. New chromosome aberrations are seen during the second and third postradiation mitoses. Also, more micronuclei appear during later postradiation interphases. This is in agreement with the assumption that unrepaired chromosomal radiation damage develops during the cell generation cycle to such a form (i.e. double-strand breaks in DNA) that chromosomal breaks occur. This proposition is strengthened by the observation that radiation-induced damage is more rapidly expressed after neutron exposure (first or second postradiation mitosis) than after exposure to X rays at the one- or two-cell stage. The preimplantation mouse embryo culture is an inviting system for additional studies at the molecular level, especially now that within the last few years more sensitive methods have been developed for study of DNA and protein structure, regulation, and synthesis. The results from these studies of cultures of preimplantation mouse embryos present a favorable case for the study of complex biological systems under very defined conditions in vitro for extrapolation to effects in vivo

Localization and regulation of mouse pantothenate kinase 2 [The PanK2 Genes of Mouse and Human Specify Proteins with Distinct Subcellular Locations

Energy Technology Data Exchange (ETDEWEB)

Leonardi, Roberta [St. Jude Children' s Research Hospital, Memphis, TN (United States); Zhang, Yong-Mei [St. Jude Children' s Research Hospital, Memphis, TN (United States); Lykidis, Athanasios [DOE Joint Genome Inst., Walnut Creek, CA (United States); Rock, Charles O. [St. Jude Children' s Research Hospital, Memphis, TN (United States); Jackowski, Suzanne [St. Jude Children' s Research Hospital, Memphis, TN (United States)

2007-09-07

Coenzyme A (CoA) biosynthesis is initiated by pantothenatekinase (PanK) and CoA levels are controlled through differentialexpression and feedback regulation of PanK isoforms. PanK2 is amitochondrial protein in humans, but comparative genomics revealed thatacquisition of a mitochondrial targeting signal was limited to primates.Human and mouse PanK2 possessed similar biochemical properties, withinhibition by acetylCoA and activation by palmitoylcarnitine. Mouse PanK2localized in the cytosol, and the expression of PanK2 was higher in humanbrain compared to mouse brain. Differences in expression and subcellularlocalization should be considered in developing a mouse model for humanPanK2 deficiency.

Interactions of mouse pinworms and trichomonads

OpenAIRE

Choutková, Jana

2012-01-01

Oxyurid nematodes Aspiculuris tetraptera and Syphacia obvelata are both common mouse intestinal parasites; in the same location several species of trichomonads occur. Tritrichomonas muris is the most often found, but there are also some others: Tritrichomonas minuta, Pentatrichomonas hominis or Hexamastix muris. It is known that, under some circumstances, trichomonads can be found in the intestine of mouse pinworms, as reported by Theiler and Farber (1936) for T. muris in A. tetraptera and S....

Accesion number Protein name ENOA_MOUSE Alpha-enolase ...

Indian Academy of Sciences (India)

Sandra Feijoo Bandin

Mitochondrial inner membrane protein. CMC1_MOUSE. Calcium-binding mitochondrial carrier protein Aralar1. CMC2_MOUSE. Calcium-binding mitochondrial carrier protein Aralar2. Biological process. Metabolic process. Glycolysis. Lipid metabolism. Respiratory electron transport chain. Others. Calcium ion homeostasis.

Characterization and mapping of the mouse NDP (Norrie disease) locus (Ndp).

Science.gov (United States)

Battinelli, E M; Boyd, Y; Craig, I W; Breakefield, X O; Chen, Z Y

1996-02-01

Norrie disease is a severe X-linked recessive neurological disorder characterized by congenital blindness with progressive loss of hearing. Over half of Norrie patients also manifest different degrees of mental retardation. The gene for Norrie disease (NDP) has recently been cloned and characterized. With the human NDP cDNA, mouse genomic phage libraries were screened for the homolog of the gene. Comparison between mouse and human genomic DNA blots hybridized with the NDP cDNA, as well as analysis of phage clones, shows that the mouse NDP gene is 29 kb in size (28 kb for the human gene). The organization in the two species is very similar. Both have three exons with similar-sized introns and identical exon-intron boundaries between exon 2 and 3. The mouse open reading frame is 393 bp and, like the human coding sequence, is encoded in exons 2 and 3. The absence of six nucleotides in the second mouse exon results in the encoded protein being two amino acids smaller than its human counterpart. The overall homology between the human and mouse NDP protein is 95% and is particularly high (99%) in exon 3, consistent with the apparent functional importance of this region. Analysis of transcription initiation sites suggests the presence of multiple start sites associated with expression of the mouse NDP gene. Pedigree analysis of an interspecific mouse backcross localizes the mouse NDP gene close to Maoa in the conserved segment, which runs from CYBB to PFC in both human and mouse.

Rats and mice immunised with chimeric human/mouse proteinase 3 produce autoantibodies to mouse Pr3 and rat granulocytes

NARCIS (Netherlands)

van der Geld, Ymke M.; Hellmark, Thomas; Selga, Daina; Heeringa, Peter; Huitema, Minke G.; Limburg, Pieter C.; Kallenberg, Cees G. M.

2007-01-01

Aim: In this study, we employed chimeric human/ mouse Proteinase 3 ( PR3) proteins as tools to induce an autoantibody response to PR3 in rats and mice. Method: Rats and mice were immunised with recombinant human PR3 ( HPR3), recombinant murine PR3 ( mPR3), single chimeric human/ mouse PR3 ( HHm,

Mouse Genome Informatics (MGI)

Data.gov (United States)

U.S. Department of Health & Human Services — MGI is the international database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human...

Mouse Phenome Database (MPD)

Data.gov (United States)

U.S. Department of Health & Human Services — The Mouse Phenome Database (MPD) has characterizations of hundreds of strains of laboratory mice to facilitate translational discoveries and to assist in selection...

Efficacy of Nonsteroidal Anti-inflammatory Drug Prophylaxis for Heterotrophic Ossification in Hip Arthroscopy: A Systematic Review.

Science.gov (United States)

Yeung, Marco; Jamshidi, Sahab; Horner, Nolan; Simunovic, Nicole; Karlsson, Jon; Ayeni, Olufemi R

2016-03-01

The purpose of this systematic review was to investigate the efficacy of nonsteroidal anti-inflammatory drug (NSAID) prophylaxis for preventing heterotopic ossification (HO) in the setting of hip arthroscopy. A systematic search was performed in duplicate for studies comparing the use of NSAID prophylaxis for HO in the setting of hip arthroscopy until March 2015. Study parameters--including sample size, incidence of HO, adverse effects, and level of symptoms--were obtained. Furthermore, the level of evidence of studies was collected and quality assessment was performed. The difference in incidence as well as pooled odds ratios were calculated and analyzed to compare no prophylaxis versus NSAID prophylaxis. This systematic review identified 5 studies, consisting of 1,662 patients, investigating NSAID prophylaxis in hip arthroscopy. HO was diagnosed with the use of postoperative hip radiographs at follow-up, with 95% of cases classified using the Brooker classification. The incidence of HO was 13.4% without NSAID prophylaxis and 3.3% with NSAID prophylaxis. Pooled odds ratios from the prospective studies were 0.07 (95% confidence interval [CI], 0.02 to 0.28; P = .0002; I(2) = 0%), showing with statistical significance that NSAID prophylaxis decreased the incidence of HO. The retrospective data similarly showed pooled odds ratios of 0.03 (95% CI, 0.00 to 1.43); P = .08; I(2) = 84%), although it was not statistically significant. Most of the patients who experienced HO in both groups were not reported to be symptomatic. Adverse effects and compliance were not consistently reported. The available orthopaedic literature suggests that the incidence of postoperative HO may be decreased with the use of NSAID prophylaxis in hip arthroscopy. However, the evidence is unclear regarding NSAID drug regimen choice, drug compliance, and adverse effects. Level III, systematic review of Level I, Level II, and Level III studies. Copyright © 2016 Arthroscopy Association of North

Clinical analysis of spinal cord injury with or without cervical ossification of the posterior longitudinal ligament, spondylosis, and canal stenosis in elderly head injury patients

International Nuclear Information System (INIS)

Nakae, Ryuta; Onda, Hidetaka; Yokobori, Shoji; Araki, Takashi; Fuse, Akira; Toda, Shigeki; Kushimoto, Shigeki; Yokota, Hiroyuki; Teramoto, Akira

2010-01-01

Patients with degenerative diseases of the cervical spine, such as ossification of the posterior longitudinal ligament, spondylosis, and canal stenosis, sometimes present with acute spinal cord injury caused by minor trauma. However, the relative risk of cervical cord injury with these diseases is unknown. The clinical and radiological features of 94 elderly patients with head injury, 57 men and 37 women aged from 65 to 98 years (mean 76.6 years), were retrospectively analyzed to assess the association of spinal cord injury with degenerative cervical diseases. Degenerative cervical diseases were present in 25 patients, and spinal cord injury was more common in the patients with degenerative diseases (11/25 patients) than in the patients without such diseases (3/69 patients; relative risk=10.2). The incidence of degenerative cervical diseases seems to be increasing in Japan because life expectancy has increased and the elderly are a rapidly growing part of the population. A fall while walking or cycling is a common mechanism of head injury and/or cervical cord injury in the elderly. To decrease the occurrence of cervical myelopathy, prevention by increasing social awareness and avoiding traffic accidents and falls is important. (author)

Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

NARCIS (Netherlands)

Korstanje, Ron; Desai, Jigar; Lazar, Gloria; King, Benjamin; Rollins, Jarod; Spurr, Melissa; Joseph, Jamie; Kadambi, Sindhuja; Li, Yang; Cherry, Allison; Matteson, Paul G.; Paigen, Beverly; Millonig, James H.

Korstanje R, Desai J, Lazar G, King B, Rollins J, Spurr M, Joseph J, Kadambi S, Li Y, Cherry A, Matteson PG, Paigen B, Millonig JH. Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects. Physiol Genomics 35:

Behavioral phenotypes of genetic mouse models of autism.

Science.gov (United States)

Kazdoba, T M; Leach, P T; Crawley, J N

2016-01-01

More than a hundred de novo single gene mutations and copy-number variants have been implicated in autism, each occurring in a small subset of cases. Mutant mouse models with syntenic mutations offer research tools to gain an understanding of the role of each gene in modulating biological and behavioral phenotypes relevant to autism. Knockout, knockin and transgenic mice incorporating risk gene mutations detected in autism spectrum disorder and comorbid neurodevelopmental disorders are now widely available. At present, autism spectrum disorder is diagnosed solely by behavioral criteria. We developed a constellation of mouse behavioral assays designed to maximize face validity to the types of social deficits and repetitive behaviors that are central to an autism diagnosis. Mouse behavioral assays for associated symptoms of autism, which include cognitive inflexibility, anxiety, hyperactivity, and unusual reactivity to sensory stimuli, are frequently included in the phenotypic analyses. Over the past 10 years, we and many other laboratories around the world have employed these and additional behavioral tests to phenotype a large number of mutant mouse models of autism. In this review, we highlight mouse models with mutations in genes that have been identified as risk genes for autism, which work through synaptic mechanisms and through the mTOR signaling pathway. Robust, replicated autism-relevant behavioral outcomes in a genetic mouse model lend credence to a causal role for specific gene contributions and downstream biological mechanisms in the etiology of autism. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Endonucleases : new tools to edit the mouse genome

NARCIS (Netherlands)

Wijshake, Tobias; Baker, Darren J.; van de Sluis, Bart

2014-01-01

Mouse transgenesis has been instrumental in determining the function of genes in the pathophysiology of human diseases and modification of genes by homologous recombination in mouse embryonic stem cells remains a widely used technology. However, this approach harbors a number of disadvantages, as it

Rational Design of Mouse Models for Cancer Research

NARCIS (Netherlands)

Landgraf, M.; McGovern, J.A.; Friedl, P.; Hutmacher, D.W.

2018-01-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models.

Communication Framework For the Mionix Naos QG Mouse

DEFF Research Database (Denmark)

Wulff-Jensen, Andreas

2017-01-01

The Mionix Naos QG mouse has multiple sensors integrated. It can record all the metrics native to mice: being scroll, clicks and mouse movements. Moreover, this mouse has heart rate (HR) and Galvanic Skin Response (GSR) sensors embedded. Through Mionics API [1] WebSocket can be used to access all...... or be recorded. Another Unity implementation have been developed as well. This was directly connected to the WebSocket, and has the same properties as the first Unity development. Since two nearly identical implementations were made, the quality of their recordings and data communication were tested. Based...

A Comprehensive Atlas of the Adult Mouse Penis

Science.gov (United States)

Phillips, Tiffany R.; Wright, David K.; Gradie, Paul E.; Johnston, Leigh A.; Pask, Andrew J.

2016-01-01

Mice are routinely used to study the development of the external genitalia and, in particular, the process of male urethral closure. This is because misplacement of the male penile urethra, or hypospadias, is amongst the most common birth defects reported in humans. While mice present a tractable model to study penile development, several structures differ between mice and humans, and there is a lack of consensus in the literature on their annotation and developmental origins. Defining the ontology of the mouse prepuce is especially important for the relevance and interpretation of mouse models of hypospadias to human conditions. We have developed a detailed annotation of the adult mouse penis that addresses these differences and enables an accurate comparison of murine and human hypospadias phenotypes. Through MRI data, gross morphology and section histology, we define the origin of the mouse external and internal prepuces, their relationship to the single human foreskin as well as provide a comprehensive view of the various structures of the mouse penis and their associated muscle attachments within the body. These data are combined to annotate structures in a novel 3D adult penis atlas that can be downloaded, viewed at any angle, and manipulated to examine the relationship of various structures. PMID:26112156

The Mouse House: a brief history of the ORNL mouse-genetics program, 1947-2009.

Science.gov (United States)

Russell, Liane B

2013-01-01

The large mouse genetics program at the Oak Ridge National Laboratory (ORNL) is often remembered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-chromosome's importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a

Effect of computer mouse gain and visual demand on mouse clicking performance and muscle activation in a young and elderly group of experienced computer users

DEFF Research Database (Denmark)

Sandfeld, Jesper; Jensen, Bente R.

2005-01-01

and three levels of target size were used. All subjects demonstrated a reduced working speed and hit rate at the highest mouse gain (1:8) when the target size was small. The young group had an optimum at mouse gain 1:4. The elderly group was most sensitive to the combination of high mouse gain and small...

Mouse endometrial stromal cells produce basement-membrane components

DEFF Research Database (Denmark)

Wewer, U M; Damjanov, A; Weiss, J

1986-01-01

During mouse pregnancy, uterine stromal cells transform into morphologically distinct decidual cells under the influence of the implanting embryo and a proper hormonal environment. Mechanical stimulation of hormonally primed uterine stromal cells leads to the same morphologic alterations. The dec......During mouse pregnancy, uterine stromal cells transform into morphologically distinct decidual cells under the influence of the implanting embryo and a proper hormonal environment. Mechanical stimulation of hormonally primed uterine stromal cells leads to the same morphologic alterations....... Mouse decidual cells isolated from 6- to 7-day pregnant uteri explanted in vitro continue to synthesize basement-membrane-like extracellular matrix. Using immunohistochemistry and metabolic labeling followed by immunoprecipitation, SDS-PAGE, and fluorography, it was shown that the decidual cells...... to undergo pseudodecidualization. We thus showed that stromal cells from pregnant and nonpregnant mouse uteri synthesize significant amounts of basement-membrane components in vitro, and hence could serve as a good model for the study of normal basement-membrane components....

Preoperative vs. postoperative radiation prophylaxis of heterotopic ossification: A rural community hospital's experience

International Nuclear Information System (INIS)

Kantorowitz, David A.; Muff, Nicholas S.

1998-01-01

preoperative groups was identical (-0.02). Similarly, improvement in Harris scale scores, from preirradiation to last follow-up, were nonsignificantly different among postoperative (+43.3) and preoperative (+44.8) groups. There was one postoperative infection in either group; there was no acute or late toxicity attributable to irradiation. Conclusion: As heterotopic bone formation is complete within 6 months, the data for both treatment groups may be considered mature. Our community generated results parallel those derived from tertiary care centers. Single-fraction radiation prophylaxis of heterotopic ossification may be given with similar efficacy either ≤4 h pre- or ≤24 h postsurgery. For reasons of minimizing patient discomfort, postsurgical movement and radiation staff resource utilization, we prefer and recommend preoperative radiation prophylaxis

Bone Injury and Repair Trigger Central and Peripheral NPY Neuronal Pathways.

Directory of Open Access Journals (Sweden)

Cecília J Alves

Full Text Available Bone repair is a specialized type of wound repair controlled by complex multi-factorial events. The nervous system is recognized as one of the key regulators of bone mass, thereby suggesting a role for neuronal pathways in bone homeostasis. However, in the context of bone injury and repair, little is known on the interplay between the nervous system and bone. Here, we addressed the neuropeptide Y (NPY neuronal arm during the initial stages of bone repair encompassing the inflammatory response and ossification phases in femoral-defect mouse model. Spatial and temporal analysis of transcriptional and protein levels of NPY and its receptors, Y1R and Y2R, reported to be involved in bone homeostasis, was performed in bone, dorsal root ganglia (DRG and hypothalamus after femoral injury. The results showed that NPY system activity is increased in a time- and space-dependent manner during bone repair. Y1R expression was trigged in both bone and DRG throughout the inflammatory phase, while a Y2R response was restricted to the hypothalamus and at a later stage, during the ossification step. Our results provide new insights into the involvement of NPY neuronal pathways in bone repair.

Resistance of human and mouse myeloid leukemia cells to UV radiation

International Nuclear Information System (INIS)

Poljak-Blazi, M.; Osmak, M.; Hadzija, M.

1989-01-01

Sensitivity of mouse bone marrow and myeloid leukemia cells and sensitivity of human myeloid leukemia cells to UV light was tested. Criteria were the in vivo colony-forming ability of UV exposed cells and the inhibition of DNA synthesis during post-irradiation incubation for 24 h in vitro. Mouse bone marrow cells irradiated with a small dose of UV light (5 J/m 2 ) and injected into x-irradiated animals did not form hemopoietic colonies on recipient's spleens, and recipients died. However, mouse leukemia cells, after irradiation with higher doses of UV light, retained the ability to form colonies on the spleens, and all recipient mice died with typical symptoms of leukemia. In vitro, mouse bone marrow cells exhibited high sensitivity to UV light compared to mouse myeloid leukemia cells. Human leukemia cells were also resistant to UV light, but more sensitive than mouse leukemia cells. (author)

Development of a mouse-feline chimeric antibody against feline tumor necrosis factor-alpha

Science.gov (United States)

DOKI, Tomoyoshi; TAKANO, Tomomi; HOHDATSU, Tsutomu

2016-01-01

Feline infectious peritonitis (FIP) is a fatal inflammatory disease caused by FIP virus infection. Feline tumor necrosis factor (fTNF)-alpha is closely involved in the aggravation of FIP pathology. We previously described the preparation of neutralizing mouse anti-fTNF-alpha monoclonal antibody (mAb 2–4) and clarified its role in the clinical condition of cats with FIP using in vitro systems. However, administration of mouse mAb 2–4 to cat may lead to a production of feline anti-mouse antibodies. In the present study, we prepared a mouse-feline chimeric mAb (chimeric mAb 2–4) by fusing the variable region of mouse mAb 2–4 to the constant region of feline antibody. The chimeric mAb 2–4 was confirmed to have fTNF-alpha neutralization activity. Purified mouse mAb 2–4 and chimeric mAb 2–4 were repeatedly administered to cats, and the changes in the ability to induce feline anti-mouse antibody response were investigated. In the serum of cats treated with mouse mAb 2–4, feline anti-mouse antibody production was induced, and the fTNF-alpha neutralization effect of mouse mAb 2–4 was reduced. In contrast, in cats treated with chimeric mAb 2–4, the feline anti-mouse antibody response was decreased compared to that of mouse mAb 2–4-treated cats. PMID:27264736

Single-mass mutations associated with mouse lymphomas

International Nuclear Information System (INIS)

Guerrero, I.; Berman, J.W.; Diamond, L.E.; Newcomb, E.W.; Villasante, A.

1986-01-01

The authors study the induction of mouse lymphomas after treatment with a chemical carcinogen, nitrosomethyl urea (NMU), or with gamma irradiation. The koplan fractionated gamma radiation scheme and an established protocol for NMU tumor formation were chosen as protocols for induction of mouse lymphomas. In both cases, the mice developed thymic lymphomas with up to 90% incidence. In NMU induction, the latency period is shorter than irradiation

Computed Tomography in the Diagnosis of Myositis Ossificans – Case Report

International Nuclear Information System (INIS)

Nitek, Żaneta; Czwojdziński, Adam; Wolf-Kuś, Alicja; Walecki, Jerzy

2014-01-01

The term myositis ossificans refers to the formation of ossifications in the muscles, ligaments and fascias, usually as a result of trauma. Fibrodysplasia ossificans progressiva is a rare genetic disease in which heterotopic ossifications appear in early childhood and are accompanied by feet and spine defects. We present a case of a 31-year-old woman with massive heterotopic ossifications who suffered multiple injuries. We would like to emphasize the role of computed tomography in the exact localization of ossifications. Thanks to the volume rendering techniques and 3D image reconstructions, it is possible to precisely determine the position of ossifications in relation to the internal organs and blood vessels, allowing to schedule the surgery to remove the lesions

Spallanzani's mouse: a model of restoration and regeneration.

Science.gov (United States)

Heber-Katz, E; Leferovich, J M; Bedelbaeva, K; Gourevitch, D

2004-01-01

The ability to regenerate is thought to be a lost phenotype in mammals, though there are certainly sporadic examples of mammalian regeneration. Our laboratory has identified a strain of mouse, the MRL mouse, which has a unique capacity to heal complex tissue in an epimorphic fashion, i.e., to restore a damaged limb or organ to its normal structure and function. Initial studies using through-and-through ear punches showed rapid full closure of the ear holes with cartilage growth, new hair follicles, and normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to the scarring usually seen in mammals. Since the ear hole closure phenotype is a quantitative trait, this has been used to show-through extensive breeding and backcrossing--that the trait is heritable. Such analysis reveals that there is a complex genetic basis for this trait with multiple loci. One of the major phenotypes of the MRL mouse is a potent remodeling response with the absence or a reduced level of scarring. MRL healing is associated with the upregulation of the metalloproteinases MMP-2 and MMP-9 and the downregulation of their inhibitors TIMP-2 and TIMP-3, both present in inflammatory cells such as neutrophils and macrophages. This model has more recently been extended to the heart. In this case, a cryoinjury to the right ventricle leads to near complete scarless healing in the MRL mouse whereas scarring is seen in the control mouse. In the MRL heart, bromodeoxyuridine uptake by cardiomyocytes filling the wound site can be seen 60 days after injury. This does not occur in the control mouse. Function in the MRL heart, as measured by echocardiography, returns to normal.

Meeting Report: The Twelfth International Mouse Genome Conference

Energy Technology Data Exchange (ETDEWEB)

Manolakou, Katerina; Cross, Sally H.; Simpson, Eleanor H.; Jackson, Ian J.

1998-10-01

The annual International Mouse Genome Conference (IMGC) is where, scientifically speaking, classical mouse genetics meets the relative newcomer of genomics. The 12th meeting took place last October in the delightful Bavarian village of Garmisch-Partenkirchen, and we were greeted by the sight on the mountains of the first snowfall of the season. However the discussions left little time for exploration. Minds of participants in Garmisch were focused by a recent document produced by the NIH and by discussions within other funding agencies worldwide. If implemented, the proposals will further enhance the status of the mouse as the principal model for study of the function of the human genome.

Methods of in-vivo mouse lung micro-CT

Science.gov (United States)

Recheis, Wolfgang A.; Nixon, Earl; Thiesse, Jacqueline; McLennan, Geoffrey; Ross, Alan; Hoffman, Eric

2005-04-01

Micro-CT will have a profound influence on the accumulation of anatomical and physiological phenotypic changes in natural and transgenetic mouse models. Longitudinal studies will be greatly facilitated, allowing for a more complete and accurate description of events if in-vivo studies are accomplished. The purpose of the ongoing project is to establish a feasible and reproducible setup for in-vivo mouse lung micro-computed tomography (μCT). We seek to use in-vivo respiratory-gated μCT to follow mouse models of lung disease with subsequent recovery of the mouse. Methodologies for optimizing scanning parameters and gating for the in-vivo mouse lung are presented. A Scireq flexiVent ventilated the gas-anesthetized mice at 60 breaths/minute, 30 cm H20 PEEP, 30 ml/kg tidal volume and provided a respiratory signal to gate a Skyscan 1076 μCT. Physiologic monitoring allowed the control of vital functions and quality of anesthesia, e.g. via ECG monitoring. In contrary to longer exposure times with ex-vivo scans, scan times for in-vivo were reduced using 35μm pixel size, 158ms exposure time and 18μm pixel size, 316ms exposure time to reduce motion artifacts. Gating via spontaneous breathing was also tested. Optimal contrast resolution was achieved at 50kVp, 200μA, applying an aluminum filter (0.5mm). There were minimal non-cardiac related motion artifacts. Both 35μm and 1μm voxel size images were suitable for evaluation of the airway lumen and parenchymal density. Total scan times were 30 and 65 minutes respectively. The mice recovered following scanning protocols. In-vivo lung scanning with recovery of the mouse delivered reasonable image quality for longitudinal studies, e.g. mouse asthma models. After examining 10 mice, we conclude μCT is a feasible tool evaluating mouse models of lung pathology in longitudinal studies with increasing anatomic detail available for evaluation as one moves from in-vivo to ex-vivo studies. Further developments include automated

The Mouse SAGE Site: database of public mouse SAGE libraries

Czech Academy of Sciences Publication Activity Database

Divina, Petr; Forejt, Jiří

2004-01-01

Roč. 32, - (2004), s. D482-D483 ISSN 0305-1048 R&D Projects: GA MŠk LN00A079; GA ČR GV204/98/K015 Grant - others:HHMI(US) 555000306 Institutional research plan: CEZ:AV0Z5052915 Keywords : mouse SAGE libraries * web -based database Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.260, year: 2004

Morphogenesis of the turtle shell: the development of a novel structure in tetrapod evolution.

Science.gov (United States)

Gilbert, S F; Loredo, G A; Brukman, A; Burke, A C

2001-01-01

The turtle shell is an evolutionary novelty that is synapomorphic for chelonians. The carapace is initiated by the entrapment of the ribs by the carapacial ridge (CR), a lateral bulge of the dorsal ectoderm and dermal mesoderm. The mechanisms by which the CR is initiated, the ribs entrapped and the dorsal dermis ossified, remains unknown. Similarly, the formation of the plastron remains unexplained. Here, we present a series of anatomical investigations into plastron and carapace formation in the red-eared slider, Trachemys scripta, and the snapping turtle, Chelydra serpentina. We document the entrapment of the ribs by the CR and the formation of the plastron and carapacial bones by intramembranous ossification. We note the formation of the ossification centers around each rib, which suggest that the rib is organizing dermal ossification by secreting paracrine factors. The nuchal ossification center is complex and appears to involve multiple bone-forming regions. Individual ossification centers at the periphery of the carapace form the peripheral and pygial bones. The intramembranous ossification of the plastron proceeds from nine distinct ossification centers, and there appear to be interactions between the spicules of apposing centers as they draw near each other.

Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development.

Science.gov (United States)

Hilton, Matthew J; Tu, Xiaolin; Cook, Julie; Hu, Hongliang; Long, Fanxin

2005-10-01

Indian hedgehog (Ihh) controls multiple aspects of endochondral skeletal development, including proliferation and maturation of chondrocytes, osteoblast development and cartilage vascularization. Although it is known that Gli transcription factors are key effectors of hedgehog signaling, it has not been established which Gli protein mediates Ihh activity in skeletal development. Here, we show that removal of Gli3 in Ihh-null mouse embryos restored normal proliferation and maturation of chondrocytes, but only partially rescued the defects in osteoblast development and cartilage vascularization. Remarkably, in both Ihh-/- and Ihh-/-; Gli3-/- embryos, vascularization promoted osteoblast development in perichondrial progenitor cells. Our results not only establish Gli3 as a critical effector for Ihh activity in the developing skeleton, but also identify an osteogenic role for a vasculature-derived signal, which integrates with Ihh and Wnt signals to determine the osteoblast versus chondrocyte fate in the mesenchymal progenitors.

Mouse manipulation through single-switch scanning.

Science.gov (United States)

Blackstien-Adler, Susie; Shein, Fraser; Quintal, Janet; Birch, Shae; Weiss, Patrice L Tamar

2004-01-01

Given the current extensive reliance on the graphical user interface, independent access to computer software requires that users be able to manipulate a pointing device of some type (e.g., mouse, trackball) or be able to emulate a mouse by some other means (e.g., scanning). The purpose of the present study was to identify one or more optimal single-switch scanning mouse emulation strategies. Four alternative scanning strategies (continuous Cartesian, discrete Cartesian, rotational, and hybrid quadrant/continuous Cartesian) were selected for testing based on current market availability as well as on theoretical considerations of their potential speed and accuracy. Each strategy was evaluated using a repeated measures study design by means of a test program that permitted mouse emulation via any one of four scanning strategies in a motivating environment; response speed and accuracy could be automatically recorded and considered in view of the motor, cognitive, and perceptual demands of each scanning strategy. Ten individuals whose disabilities required them to operate a computer via single-switch scanning participated in the study. Results indicated that Cartesian scanning was the preferred and most effective scanning strategy. There were no significant differences between results from the Continuous Cartesian and Discrete Cartesian scanning strategies. Rotational scanning was quite slow with respect to the other strategies, although it was equally accurate. Hybrid Quadrant scanning improved access time but at the cost of fewer correct selections. These results demonstrated the importance of testing and comparing alternate single-switch scanning strategies.

Effect of potassium channel modulators in mouse forced swimming test

Science.gov (United States)

Galeotti, Nicoletta; Ghelardini, Carla; Caldari, Bernardetta; Bartolini, Alessandro

1999-01-01

The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. Tetraethylammonium (TEA; 5 μg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 μg per mouse i.c.v.) and gliquidone (6 μg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg−1 s.c.) and imipramine (30 mg kg−1 s.c.). By contrast pinacidil (10–20 μg per mouse i.c.v.), minoxidil (10–20 μg per mouse i.c.v.) and cromakalim (20–30 μg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test. PMID:10323599

Chromosomal localization of the human and mouse hyaluronan synthase genes

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Spicer, A.P.; McDonald, J.A. [Mayo Clinic Scottsdale, AZ (United States); Seldin, M.F. [Univ. of California Davis, CA (United States)] [and others

1997-05-01

We have recently identified a new vertebrate gene family encoding putative hyaluronan (HA) synthases. Three highly conserved related genes have been identified, designated HAS1, HAS2, and HAS3 in humans and Has1, Has2, and Has3 in the mouse. All three genes encode predicted plasma membrane proteins with multiple transmembrane domains and approximately 25% amino acid sequence identity to the Streptococcus pyogenes HA synthase, HasA. Furthermore, expression of any one HAS gene in transfected mammalian cells leads to high levels of HA biosynthesis. We now report the chromosomal localization of the three HAS genes in human and in mouse. The genes localized to three different positions within both the human and the mouse genomes. HAS1 was localized to the human chromosome 19q13.3-q13.4 boundary and Has1 to mouse Chr 17. HAS2 was localized to human chromosome 8q24.12 and Has2 to mouse Chr 15. HAS3 was localized to human chromosome 16q22.1 and Has3 to mouse Chr 8. The map position for HAS1 reinforces the recently reported relationship between a small region of human chromosome 19q and proximal mouse chromosome 17. HAS2 mapped outside the predicted critical region delineated for the Langer-Giedion syndrome and can thus be excluded as a candidate gene for this genetic syndrome. 33 refs., 2 figs.

Comparison of three mouse strains by radiosensitivity of hemato-immune system

International Nuclear Information System (INIS)

Li, Deguan; Wu, Hongying; Wang, Yong; Zhang, Junling; Wang, Yueying; Lu, Lu; Meng, Aimin

2008-01-01

IRM-2, developed in our Lab, is an inbred strain mouse created by cross of a ICR/JCL female and 615 male mouse. Compared to the parent strains, the IRM-2 mouse exhibit increased resistance to radiation. We examine the damage of hemato-immune system induced by radiation in IRM-2, ICR and 615 mice in order to elucidate the radiation resistant mechanism of IRM-2 mouse. The hemato-immune function and radiosensitivities of three mouse strains (IRM-2, ICR/JCL, 615) have been compared using the following parameters: the white blood cells (WBC) in peripheral blood (PB), the bone marrow nucleated cells (BMC) per femur. Percent of phagocytosis of peritoneal macrophage (PM) was checked by chicken red blood cells. Lymphocyte phenotype in PB were analyzed by flow cytometry. Damage induced by radiation were analysed in the bone marrows cells, splenocytes and thymocyte exposed to irradiation in vitro by cell viability assay (ATP Bioluminescence assay) and apoptosis assay (Annexin V/PI). The WBC and BMC of IRM-2 mice were significantly higher than those in ICR mice and 615 mice, respectively (P<0.01). The ratio of CD4/CD8 in PB of IRM-2 mouse was lower than those in ICR and 615, P<0.01. Cell viability showed difference after 18 hs incubation post radiation in three mouse strains. The results of our primary study suggest that the hemato-immune function in IRM-2 mouse is different to its parent strains. The IRM-2 mouse provides an animal model to conducted further investigation to explore the role of hemato-immune system in radiation resistance. (author)

Immunohistochemical visualization of mouse interneuron subtypes

DEFF Research Database (Denmark)

Jensen, Simon Mølgaard; Ulrichsen, Maj; Boggild, Simon

2014-01-01

, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies...... of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, stainings with high signal-to-noise ratios and location...

Conditional Expression of Wnt4 during Chondrogenesis Leads to Dwarfism in Mice

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Lee, Hu-Hui; Behringer, Richard R.

2007-01-01

Wnts are expressed in the forming long bones, suggesting roles in skeletogenesis. To examine the action of Wnts in skeleton formation, we developed a genetic system to conditionally express Wnt4 in chondrogenic tissues of the mouse. A mouse Wnt4 cDNA was introduced into the ubiquitously expressed Rosa26 (R26) locus by gene targeting in embryonic stem (ES) cells. The expression of Wnt4 from the R26 locus was blocked by a neomycin selection cassette flanked by loxP sites (floxneo) that was positioned between the Rosa26 promoter and the Wnt4 cDNA, creating the allele designated R26floxneoWnt4. Wnt4 expression was activated during chondrogenesis using Col2a1-Cre transgenic mice that express Cre recombinase in differentiating chondrocytes. R26floxneoWnt4; Col2a1-Cre double heterozygous mice exhibited a growth deficiency, beginning approximately 7 to 10 days after birth, that resulted in dwarfism. In addition, they also had craniofacial abnormalities, and delayed ossification of the lumbar vertebrae and pelvic bones. Histological analysis revealed a disruption in the organization of the growth plates and a delay in the onset of the primary and secondary ossification centers. Molecular studies showed that Wnt4 overexpression caused decreased proliferation and altered maturation of chondrocytes. In addition, R26floxneoWnt4; Col2a1-Cre mice had decreased expression of vascular endothelial growth factor (VEGF). These studies demonstrate that Wnt4 overexpression leads to dwarfism in mice. The data indicate that Wnt4 levels must be regulated in chondrocytes for normal growth plate development and skeletogenesis. Decreased VEGF expression suggests that defects in vascularization may contribute to the dwarf phenotype. PMID:17505543

Conditional expression of Wnt4 during chondrogenesis leads to dwarfism in mice.

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Hu-Hui Lee

Full Text Available Wnts are expressed in the forming long bones, suggesting roles in skeletogenesis. To examine the action of Wnts in skeleton formation, we developed a genetic system to conditionally express Wnt4 in chondrogenic tissues of the mouse. A mouse Wnt4 cDNA was introduced into the ubiquitously expressed Rosa26 (R26 locus by gene targeting in embryonic stem (ES cells. The expression of Wnt4 from the R26 locus was blocked by a neomycin selection cassette flanked by loxP sites (floxneo that was positioned between the Rosa26 promoter and the Wnt4 cDNA, creating the allele designated R26(floxneoWnt4. Wnt4 expression was activated during chondrogenesis using Col2a1-Cre transgenic mice that express Cre recombinase in differentiating chondrocytes. R26(floxneoWnt4; Col2a1-Cre double heterozygous mice exhibited a growth deficiency, beginning approximately 7 to 10 days after birth, that resulted in dwarfism. In addition, they also had craniofacial abnormalities, and delayed ossification of the lumbar vertebrae and pelvic bones. Histological analysis revealed a disruption in the organization of the growth plates and a delay in the onset of the primary and secondary ossification centers. Molecular studies showed that Wnt4 overexpression caused decreased proliferation and altered maturation of chondrocytes. In addition, R26(floxneoWnt4; Col2a1-Cre mice had decreased expression of vascular endothelial growth factor (VEGF. These studies demonstrate that Wnt4 overexpression leads to dwarfism in mice. The data indicate that Wnt4 levels must be regulated in chondrocytes for normal growth plate development and skeletogenesis. Decreased VEGF expression suggests that defects in vascularization may contribute to the dwarf phenotype.

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

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Matthew E. Brown

2018-04-01

Full Text Available Summary: Here, we describe the NeoThy humanized mouse model created using non-fetal human tissue sources, cryopreserved neonatal thymus and umbilical cord blood hematopoietic stem cells (HSCs. Conventional humanized mouse models are made by engrafting human fetal thymus and HSCs into immunocompromised mice. These mice harbor functional human T cells that have matured in the presence of human self-peptides and human leukocyte antigen molecules. Neonatal thymus tissue is more abundant and developmentally mature and allows for creation of up to ∼50-fold more mice per donor compared with fetal tissue models. The NeoThy has equivalent frequencies of engrafted human immune cells compared with fetal tissue humanized mice and exhibits T cell function in assays of ex vivo cell proliferation, interferon γ secretion, and in vivo graft infiltration. The NeoThy model may provide significant advantages for induced pluripotent stem cell immunogenicity studies, while bypassing the requirement for fetal tissue. : Corresponding author William Burlingham and colleagues created a humanized mouse model called the NeoThy. The NeoThy uses human neonatal, rather than fetal, tissue sources for generating a human immune system within immunocompromised mouse hosts. NeoThy mice are an attractive alternative to conventional humanized mouse models, as they enable robust and reproducible iPSC immunogenicity experiments in vivo. Keywords: NeoThy, humanized mouse, iPSC, PSC, immunogenicity, transplantation, immunology, hematopoietic stem cells, induced pluripotent stem cells, thymus

Astonishing advances in mouse genetic tools for biomedical research.

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Kaczmarczyk, Lech; Jackson, Walker S

2015-01-01

The humble house mouse has long been a workhorse model system in biomedical research. The technology for introducing site-specific genome modifications led to Nobel Prizes for its pioneers and opened a new era of mouse genetics. However, this technology was very time-consuming and technically demanding. As a result, many investigators continued to employ easier genome manipulation methods, though resulting models can suffer from overlooked or underestimated consequences. Another breakthrough, invaluable for the molecular dissection of disease mechanisms, was the invention of high-throughput methods to measure the expression of a plethora of genes in parallel. However, the use of samples containing material from multiple cell types could obfuscate data, and thus interpretations. In this review we highlight some important issues in experimental approaches using mouse models for biomedical research. We then discuss recent technological advances in mouse genetics that are revolutionising human disease research. Mouse genomes are now easily manipulated at precise locations thanks to guided endonucleases, such as transcription activator-like effector nucleases (TALENs) or the CRISPR/Cas9 system, both also having the potential to turn the dream of human gene therapy into reality. Newly developed methods of cell type-specific isolation of transcriptomes from crude tissue homogenates, followed by detection with next generation sequencing (NGS), are vastly improving gene regulation studies. Taken together, these amazing tools simplify the creation of much more accurate mouse models of human disease, and enable the extraction of hitherto unobtainable data.

Growth and production kinetics of human x mouse and mouse hybridoma cells at reduced temperature and serum content.

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Borth, N; Heider, R; Assadian, A; Katinger, H

1992-09-01

The growth and production kinetics of a mouse hybridoma cell line and a human-mouse heterohybridoma were analyzed under conditions of reduced temperature and serum content. The mouse hybridoma P24 had a constant cell specific production rate and RNA content, while the heterohybridoma 3D6-LC4 showed growth associated production kinetics and an increased RNA content at higher growth rates. This behaviour of 3D6-LC4 cells can be explained by the unusual cell cycle kinetics of this line, which can be arrested in any phase under growth limiting conditions, so that a low growth rate does not result in a greater portion of high producing G1-phase cells. Substrate limitation changes the cell cycle distribution of this cell line to a greater extent than low temperature or serum content, which indicates that this stress factor exerts a greater physiological control than assumed.

Simple and efficient expression of codon-optimized mouse leukemia ...

African Journals Online (AJOL)

Purpose: To obtain a higher yield of mouse leukemia inhibitory factor to maintain the proliferation potential of pluripotent ... It induces mouse myeloid leukemic M1 cells of terminal ... induces the production of acute phase proteins by lipocyte ...

An update on the mouse liver proteome

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Borlak Jürgen

2009-09-01

Full Text Available Abstract Background Decoding of the liver proteome is subject of intense research, but hampered by methodological constraints. We recently developed an improved protocol for studying rat liver proteins based on 2-DE-MALDI-TOF-MS peptide mass finger printing. This methodology was now applied to develop a mouse liver protein database. Results Liver proteins were extracted by two different lysis buffers in sequence followed by a liquid-phase IEF pre-fractionation and separation of proteins by 2 DE at two different pH ranges, notably 5-8 and 7-10. Based on 9600 in gel digests a total of 643 mouse liver proteins with high sequence coverage (> 20 peptides per protein could be identified by MALDI-TOF-MS peptide mass finger printing. Notably, 255 proteins are novel and have not been reported so far by conventional two-dimensional electrophoresis proteome mapping. Additionally, the results of the present findings for mouse liver were compared to published data of the rat proteome to compile as many proteins as possible in a rodent liver database. Conclusion Based on 2-DE MALDI-TOF-MS a significantly improved proteome map of mouse liver was obtained. We discuss some prominent members of newly identified proteins for a better understanding of liver biology.

Colonization, mouse-style

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Searle Jeremy B

2010-10-01

Full Text Available Abstract Several recent papers, including one in BMC Evolutionary Biology, examine the colonization history of house mice. As well as background for the analysis of mouse adaptation, such studies offer a perspective on the history of movements of the humans that accidentally transported the mice. See research article: http://www.biomedcentral.com/1471-2148/10/325

Characteristics of the mouse genomic histamine H1 receptor gene

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Inoue, Isao; Taniuchi, Ichiro; Kitamura, Daisuke [Kyushu Univ., Fukuoka (Japan)] [and others

1996-08-15

We report here the molecular cloning of a mouse histamine H1 receptor gene. The protein deduced from the nucleotide sequence is composed of 488 amino acid residues with characteristic properties of GTP binding protein-coupled receptors. Our results suggest that the mouse histamine H1 receptor gene is a single locus, and no related sequences were detected. Interspecific backcross analysis indicated that the mouse histamine H1 receptor gene (Hrh1) is located in the central region of mouse Chromosome 6 linked to microphthalmia (Mitfmi), ras-related fibrosarcoma oncogene 1 (Raf1), and ret proto-oncogene (Ret) in a region of homology with human chromosome 3p. 12 refs., 3 figs.

The Mouse House: A brief history of the ORNL mouse-genetics program, 1947–2009

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Russell, Liane B.

2013-10-01

The large mouse genetics program at the Oak Ridge National Lab is often re-membered chiefly for the germ-cell mutation-rate data it generated and their uses in estimating the risk of heritable radiation damage. In fact, it soon became a multi-faceted research effort that, over a period of almost 60 years, generated a wealth of information in the areas of mammalian mutagenesis, basic genetics (later enriched by molecular techniques), cytogenetics, reproductive biology, biochemistry of germ cells, and teratology. Research in the area of germ-cell mutagenesis explored the important physical and biological factors that affect the frequency and nature of induced mutations and made several unexpected discoveries, such as the major importance of the perigametic interval (the zygote stage) for the origin of spontaneous mutations and for the sensitivity to induced genetic change. Of practical value was the discovery that ethylnitrosourea was a supermutagen for point mutations, making high-efficiency mutagenesis in the mouse feasible worldwide. Teratogenesis findings resulted in recommendations still generally accepted in radiological practice. Studies supporting the mutagenesis research added whole bodies of information about mammalian germ-cell development and about molecular targets in germ cells. The early decision to not merely count but propagate genetic variants of all sorts made possible further discoveries, such as the Y-Chromosome s importance in mammalian sex determination and the identification of rare X-autosome translocations, which, in turn, led to the formulation of the single-active-X hypothesis and provided tools for studies of functional mosaicism for autosomal genes, male sterility, and chromosome-pairing mechanism. Extensive genetic and then molecular analyses of large numbers of induced specific-locus mutants resulted in fine-structure physical and correlated functional mapping of significant portions of the mouse genome and constituted a valuable

Downregulation of mouse CCR3 by lentiviral shRNA inhibits proliferation and induces apoptosis of mouse eosinophils.

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Zhu, Xin-Hua; Liao, Bing; Xu, Yi; Liu, Ke; Huang, Yun; Huang, Quan-Long; Liu, Yue-Hui

2017-02-01

RNA interference has been considered as an effective gene silencing method in basic and preclinical investigations. The aims of the present study were to construct a lentiviral vector expressing a short hairpin RNA (shRNA) targeting the murine CC chemokine receptor 3 (mCCR3), and to investigate its effects on the proliferation and apoptosis of mouse eosinophils. A recombinant lentiviral vector expressing four fragments of mouse CCR3 shRNA (pLVX‑mCCR3‑1+2+3+4‑shRNA) was constructed using subcloning techniques. This novel lentivirus was then packaged into 293T cells by co‑transduction with plasmids, including Baculo p35, pCMV R8.2 and VSV. The interference effects of the vector were verified using polymerase chain reaction (PCR) and western blot analyses. The effects of the interference on the proliferation and apoptosis of mouse eosinophils were investigated using 3‑(4,5‑dimethylthiazol‑2‑yl)‑5‑(3‑carboxymethoxyphenyl)‑2‑(4‑sulfophenyl)‑2H‑tetrazolium and terminal deoxynucleotidyl transferase dUTP nick end labeling methods, respectively. The results of the PCR and western blot analyses confirmed that the novel recombinant vector, pLVX‑mCCR3‑1+2+3+4‑shRNA, had high efficiency in inhibiting the mRNA and protein expression levels of mCCR3 in mouse eosinophils. The downregulation of mCCR3 significantly inhibited proliferation of the eosinophils. Furthermore, the present study found that the downregulation of mCCR3 significantly promoted apoptosis of the eosinophils. Therefore, the downregulation of mCCR3 led to the inhibition of proliferation and induction of apoptosis in mouse eosinophils. The predominant characteristics of allergic rhinitis are eosinophil infiltration and release of inflammatory mediators, which appear in a variety of clinical manifestations. The results of the present study indicate that mCCR3 silencing may serve as a putative approach for the treatment of allergic rhinitis.

Suppression of mouse-killing in rats following irradiation

International Nuclear Information System (INIS)

O'Boyle, M.

1976-01-01

Suppression of mouse-killing was produced following pairings of mouse-presentations (CS) with 96 roentgens of ionizing radiation (US) at 0 (less than 2 min.) and 30 min. US-CS interstimulus intervals. No suppression was found at CS-US intervals of 30 min., 1 hr., and 2 hr., or at US-CS intervals of 1 hr. and 2 hr

Stromal cell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy.

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Murata, Koichi; Kitaori, Toshiyuki; Oishi, Shinya; Watanabe, Naoki; Yoshitomi, Hiroyuki; Tanida, Shimei; Ishikawa, Masahiro; Kasahara, Takashi; Shibuya, Hideyuki; Fujii, Nobutaka; Nagasawa, Takashi; Nakamura, Takashi; Ito, Hiromu

2012-01-01

Stromal cell-derived factor 1 (SDF-1/CXCL12/PBSF) plays important roles in the biological and physiological functions of haematopoietic and mesenchymal stem cells. This chemokine regulates the formation of multiple organ systems during embryogenesis. However, its roles in skeletal development remain unclear. Here we investigated the roles of SDF-1 in chondrocyte differentiation. We demonstrated that SDF-1 protein was expressed at pre-hypertrophic and hypertrophic chondrocytes in the newly formed endochondral callus of rib fracture as well as in the growth plate of normal mouse tibia by immunohistochemical analysis. Using SDF-1(-/-) mouse embryo, we histologically showed that the total length of the whole humeri of SDF-1(-/-) mice was significantly shorter than that of wild-type mice, which was contributed mainly by shorter hypertrophic and calcified zones in SDF-1(-/-) mice. Actin cytoskeleton of hypertrophic chondrocytes in SDF-1(-/-) mouse humeri showed less F-actin and rounder shape than that of wild-type mice. Primary chondrocytes from SDF-1(-/-) mice showed the enhanced formation of philopodia and loss of F-actin. The administration of SDF-1 to primary chondrocytes of wild-type mice and SDF-1(-/-) mice promoted the formation of actin stress fibers. Organ culture of embryonic metatarsals from SDF-1(-/-) mice showed the growth delay, which was recovered by an exogenous administration of SDF-1. mRNA expression of type X collagen in metatarsals and in primary chondrocytes of SDF-1(-/-) mouse embryo was down-regulated while the administration of SDF-1 to metatarsals recovered. These data suggests that SDF-1 regulates the actin organization and stimulates bone growth by mediating chondrocyte hypertrophy.

Stromal cell-derived factor 1 regulates the actin organization of chondrocytes and chondrocyte hypertrophy.

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Koichi Murata

Full Text Available Stromal cell-derived factor 1 (SDF-1/CXCL12/PBSF plays important roles in the biological and physiological functions of haematopoietic and mesenchymal stem cells. This chemokine regulates the formation of multiple organ systems during embryogenesis. However, its roles in skeletal development remain unclear. Here we investigated the roles of SDF-1 in chondrocyte differentiation. We demonstrated that SDF-1 protein was expressed at pre-hypertrophic and hypertrophic chondrocytes in the newly formed endochondral callus of rib fracture as well as in the growth plate of normal mouse tibia by immunohistochemical analysis. Using SDF-1(-/- mouse embryo, we histologically showed that the total length of the whole humeri of SDF-1(-/- mice was significantly shorter than that of wild-type mice, which was contributed mainly by shorter hypertrophic and calcified zones in SDF-1(-/- mice. Actin cytoskeleton of hypertrophic chondrocytes in SDF-1(-/- mouse humeri showed less F-actin and rounder shape than that of wild-type mice. Primary chondrocytes from SDF-1(-/- mice showed the enhanced formation of philopodia and loss of F-actin. The administration of SDF-1 to primary chondrocytes of wild-type mice and SDF-1(-/- mice promoted the formation of actin stress fibers. Organ culture of embryonic metatarsals from SDF-1(-/- mice showed the growth delay, which was recovered by an exogenous administration of SDF-1. mRNA expression of type X collagen in metatarsals and in primary chondrocytes of SDF-1(-/- mouse embryo was down-regulated while the administration of SDF-1 to metatarsals recovered. These data suggests that SDF-1 regulates the actin organization and stimulates bone growth by mediating chondrocyte hypertrophy.

Ontogeny of the cranial bones of the giant amazon river turtle Podocnemis expansa Schweigger, 1812 (Testudines, Podocnemididae - doi: 10.4025/actascibiolsci.v32i2.5777 Ontogeny of the cranial bones of the giant amazon river turtle Podocnemis expansa Schweigger, 1812 (Testudines, Podocnemididae - doi: 10.4025/actascibiolsci.v32i2.5777

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Fabiano Campos Lima

2010-05-01

Full Text Available In order to determine the normal stages of formation in the sequence of ossification of the cranium of Podocnemis expansa in its various stages of development, embryos were collected starting on the 18th day of natural incubation and were subjected to bone diaphanization and staining. In the neurocranium, the basisphenoid and basioccipital bones present ossification centers in stage 19, the supraoccipital and opisthotic in stage 20, the exoccipital in stage 21, and lastly the prooptic in stage 24. Dermatocranium: the squamosal, pterygoid and maxilla are the first elements to begin the ossification process, which occurs in stage 16. However, ossification centers begin to appear in stage 17 in most of these bone elements, i.e., the frontal, jugal, postorbital, parietal, premaxilla and prefrontal, followed by the palatine and quadratojugal in stage 19 and lastly by the vomer in stage 25. The quadrate bone of the splanchnocranium ossifies in stage 23. The mandible and hyoid apparatus, the dentary, coronoid and supra-angular, show ossification centers in stage 16 and the branchial horn I in stage 17. The sequence and synchronization of ossification in P. expansa show similarities as well as differences when compared with other species of Testudines.In order to determine the normal stages of formation in the sequence of ossification of the cranium of Podocnemis expansa in its various stages of development, embryos were collected starting on the 18th day of natural incubation and were subjected to bone diaphanization and staining. In the neurocranium, the basisphenoid and basioccipital bones present ossification centers in stage 19, the supraoccipital and opisthotic in stage 20, the exoccipital in stage 21, and lastly the prooptic in stage 24. Dermatocranium: the squamosal, pterygoid and maxilla are the first elements to begin the ossification process, which occurs in stage 16. However, ossification centers begin to appear in stage 17 in most of these

The role of the adaptive immune system in burn-induced heterotopic ossification and mesenchymal cell osteogenic differentiation.

Science.gov (United States)

Ranganathan, Kavitha; Agarwal, Shailesh; Cholok, David; Loder, Shawn; Li, Jonathan; Sung Hsieh, Hsiao Hsin; Wang, Stewart C; Buchman, Steven R; Levi, Benjamin

2016-11-01

Heterotopic ossification (HO) is the pathologic process of extraskeletal bone formation. Although the exact etiology remains unknown, inflammation appears to catalyze disease progression. The goal of this study is to determine the impact of the adaptive immune system on HO. HO was induced in 8-wk-old control C57BL/6 and immunocompromised Rag1tm1Mom (Rag1 KO) male mice deficient in B- and T-lymphocytes via combined Achilles tenotomy and burn injury. Microcomputed tomography quantified the extent of HO formation at the tenotomy site. Adipose-derived mesenchymal stem cells were harvested to evaluate osteogenic differentiation potential. Areas of developing HO demonstrated substantial enrichment of CD45 + leukocytes at 3 wk after injury. HO from Rag1 KO mice was substantially less mature with foci of cartilage and disorganized trabecular bone present 12 wk after injury. Rag1 KO mice formed 60% less bone compared to immunocompetent controls (4.67 ± 1.5 mm versus 7.76 ± 0.65 mm; P = 0.001). Tartrate-resistant acid phosphatase staining and immunofluorescent analysis of osteoprotegerin and nuclear factor kappa-light-chain-enhancer of activated B cells demonstrated no appreciable difference in osteoclast number or activation. Alizarin red staining in vitro demonstrated a significant decrease in osteogenic potential in immunocompromised mice compared to controls (29.1 ± 0.54 mm versus 12.1 ± 0.14 mm; P role for the adaptive immune system in the development of HO. In the absence of mature B- and T-lymphocytes, HO growth and development are attenuated. Furthermore, we demonstrate that mesenchymal populations from B- and T-cell deficient mice are inherently less osteogenic. This study identifies a potential therapeutic role for modulation of the adaptive immune system in the treatment of HO. Copyright © 2016 Elsevier Inc. All rights reserved.

Gene expression and functional annotation of the human and mouse choroid plexus epithelium.

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Sarah F Janssen

Full Text Available BACKGROUND: The choroid plexus epithelium (CPE is a lobed neuro-epithelial structure that forms the outer blood-brain barrier. The CPE protrudes into the brain ventricles and produces the cerebrospinal fluid (CSF, which is crucial for brain homeostasis. Malfunction of the CPE is possibly implicated in disorders like Alzheimer disease, hydrocephalus or glaucoma. To study human genetic diseases and potential new therapies, mouse models are widely used. This requires a detailed knowledge of similarities and differences in gene expression and functional annotation between the species. The aim of this study is to analyze and compare gene expression and functional annotation of healthy human and mouse CPE. METHODS: We performed 44k Agilent microarray hybridizations with RNA derived from laser dissected healthy human and mouse CPE cells. We functionally annotated and compared the gene expression data of human and mouse CPE using the knowledge database Ingenuity. We searched for common and species specific gene expression patterns and function between human and mouse CPE. We also made a comparison with previously published CPE human and mouse gene expression data. RESULTS: Overall, the human and mouse CPE transcriptomes are very similar. Their major functionalities included epithelial junctions, transport, energy production, neuro-endocrine signaling, as well as immunological, neurological and hematological functions and disorders. The mouse CPE presented two additional functions not found in the human CPE: carbohydrate metabolism and a more extensive list of (neural developmental functions. We found three genes specifically expressed in the mouse CPE compared to human CPE, being ACE, PON1 and TRIM3 and no human specifically expressed CPE genes compared to mouse CPE. CONCLUSION: Human and mouse CPE transcriptomes are very similar, and display many common functionalities. Nonetheless, we also identified a few genes and pathways which suggest that the CPE

The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines.

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Stanley, Joanna L; Lincoln, Rachael J; Brown, Terry A; McDonald, Louise M; Dawson, Gerard R; Reynolds, David S

2005-05-01

The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.

Enhancement of mouse sperm motility by trophinin-binding peptide

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Park Seong

2012-11-01

Full Text Available Abstract Background Trophinin is an intrinsic membrane protein that forms a complex in the cytoplasm with bystin and tastin, linking it microtubule-associated motor dynein (ATPase in some cell types. Previously, we found that human sperm tails contain trophinin, bystin and tastin proteins, and that trophinin-binding GWRQ (glycine, tryptophan, arginine, glutamine peptide enhanced motility of human sperm. Methods Immunohistochemistry was employed to determine trophinin protein in mouse spermatozoa from wild type mouse, by using spermatozoa from trophinin null mutant mice as a negative control. Multivalent 8-branched GWRQ (glycine, tryptophan, arginine, glutamine peptide or GWRQ-MAPS, was chemically synthesized, purified by HPLC and its structure was confirmed by MALDI-TOF mass spectrometry. Effect of GWRQ-MAPS on mouse spermatozoa from wild type and trophinin null mutant was assessed by a computer-assisted semen analyzer (CASA. Results Anti-trophinin antibody stained the principal (central piece of the tail of wild type mouse sperm, whereas the antibody showed no staining on trophinin null sperm. Phage particles displaying GWRQ bound to the principal piece of sperm tail from wild type but not trophinin null mice. GWRQ-MAPS enhanced motility of spermatozoa from wild type but not trophinin null mice. CASA showed that GWRQ-MAPS enhanced both progressive motility and rapid motility in wild type mouse sperm. Conclusions Present study established the expression of trophinin in the mouse sperm tail and trophinin-dependent effect of GWRQ-MAPS on sperm motility. GWRQ causes a significant increase in sperm motility.

Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance

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Shuaizhang, L I; Zhang, Wen; Yin, Xuejiao; Xing, Shilai; Xie, Qunhui; Cao, Zhengyu; Zhao, Bin

2015-04-28

The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells.

The voluntary driven exoskeleton Hybrid Assistive Limb (HAL) for postoperative training of thoracic ossification of the posterior longitudinal ligament: a case report.

Science.gov (United States)

Fujii, Kengo; Abe, Tetsuya; Kubota, Shigeki; Marushima, Aiki; Kawamoto, Hiroaki; Ueno, Tomoyuki; Matsushita, Akira; Nakai, Kei; Saotome, Kosaku; Kadone, Hideki; Endo, Ayumu; Haginoya, Ayumu; Hada, Yasushi; Matsumura, Akira; Sankai, Yoshiyuki; Yamazaki, Masashi

2017-05-01

The hybrid assistive limb (HAL) is a wearable robot suit that assists in voluntary control of knee and hip joint motion by detecting bioelectric signals on the surface of the skin with high sensitivity. HAL has been reported to be effective for functional recovery in motor impairments. However, few reports have revealed the utility of HAL for patients who have undergone surgery for thoracic ossification of the posterior longitudinal ligament (thoracic OPLL). Herein, we present a postoperative thoracic OPLL patient who showed remarkable functional recovery after training with HAL. A 63-year-old woman, who could not walk due to muscle weakness before surgery, underwent posterior decompression and fusion. Paralysis was re-aggravated after the initial postoperative rising. We diagnosed that paralysis was due to residual compression from the anterior lesion and microinstability after posterior fixation, and prescribed bed rest for a further 3 weeks. The incomplete paralysis gradually recovered, and walking training with HAL was started on postoperative day 44 in addition to standard physical therapy. The patient underwent 10 sessions of HAL training until discharge on postoperative day 73. Results of a 10-m walk test were assessed after every session, and the patient's speed and cadence markedly improved. At discharge, the patient could walk with 2 crutches and no assistance. Furthermore, no adverse events associated with HAL training occurred. HAL training for postoperative thoracic OPLL patients may enhance improvement in walking ability, even if severe impairment of ambulation and muscle weakness exist preoperatively.

Infra Red 3D Computer Mouse

DEFF Research Database (Denmark)

Harbo, Anders La-Cour; Stoustrup, Jakob

2000-01-01

The infra red 3D mouse is a three dimensional input device to a computer. It works by determining the position of an arbitrary object (like a hand) by emitting infra red signals from a number of locations and measuring the reflected intensities. To maximize stability, robustness, and use of bandw......The infra red 3D mouse is a three dimensional input device to a computer. It works by determining the position of an arbitrary object (like a hand) by emitting infra red signals from a number of locations and measuring the reflected intensities. To maximize stability, robustness, and use...

High-throughput mouse genotyping using robotics automation.

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Linask, Kaari L; Lo, Cecilia W

2005-02-01

The use of mouse models is rapidly expanding in biomedical research. This has dictated the need for the rapid genotyping of mutant mouse colonies for more efficient utilization of animal holding space. We have established a high-throughput protocol for mouse genotyping using two robotics workstations: a liquid-handling robot to assemble PCR and a microfluidics electrophoresis robot for PCR product analysis. This dual-robotics setup incurs lower start-up costs than a fully automated system while still minimizing human intervention. Essential to this automation scheme is the construction of a database containing customized scripts for programming the robotics workstations. Using these scripts and the robotics systems, multiple combinations of genotyping reactions can be assembled simultaneously, allowing even complex genotyping data to be generated rapidly with consistency and accuracy. A detailed protocol, database, scripts, and additional background information are available at http://dir.nhlbi.nih.gov/labs/ldb-chd/autogene/.

Providing training enhances the biomechanical improvements of an alternative computer mouse design

NARCIS (Netherlands)

Houwink, A.; Oude Hengel, K.M.; Odell, D.; Dennerlein, J.T.

2009-01-01

To determine if an alternative mouse promotes more neutral postures and decreases forearm muscle activity and if training enhances these biomechanical benefits is the purpose of the study. Computer mouse use is a risk factor for developing musculoskeletal disorders; alternative mouse designs can

Postnatal development of the anterior skull base and nasal septum: CT study

International Nuclear Information System (INIS)

Kim, Kwan Soo; Kim, Hyung Jin; Lee, Kyung Hee; Roh, Hong Gee; Lim, Myung Kwan

2002-01-01

To know the normal CT appearance of the anterior skull base and nasal septum after birth. Coronal CT scans with a helical mode were performed from the nasal bone to the sphenoid sinus in 99 children whose ages ranged from 27 days to 14 years. We investigated the CT appearance of the developing anterior skull base and nasal septum with particular attention to the anteroposterior length of the anterior skull base and the ossification patterns of the cribriform plate, perpendicular plate, crista galli, and vomer. The anteroposterior length of the anterior skull base statistically significantly increased with age. The cribriform plate showed partial or complete ossification in at least one segment at more than 3 months of age and in all three segments at more than 6 months of age. Ossification of the cribriform plate occurred earlier in the middle segment than in the anterior and posterior segments. It began exclusively in the region of the lateral mass of the ethmoid and proceeded medially toward the crista galli. Partial ossification of the perpendicular plate was noted as early as 9 months of age, and complete ossification as early as 13 months of age. All children at 18 months and older showed at least partial ossification of the perpendicular plate. Partial ossification of the crista galli was noted as early as 27 days of age, and complete ossification as early as 3 months of age. CT showed complete ossification of the crista galli in all but two children at 6 months and older. The superior aspect of the vomer exhibited a V- or Y-shape on all CT scans in 66%(65/99) of children at any age. It appeared as an undivided single lump anteriorly and a V or Y posteriorly in 34%(34/99). Knowledge of the normal developing patterns of ossification of the anterior skull base and nasal septum could help prevent errors in interpreting CT scans in this region, especially in infants and young children

Mouse Vocal Communication System: Are Ultrasounds Learned or Innate?

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Arriaga, Gustavo; Jarvis, Erich D.

2013-01-01

Mouse ultrasonic vocalizations (USVs) are often used as behavioral readouts of internal states, to measure effects of social and pharmacological manipulations, and for behavioral phenotyping of mouse models for neuropsychiatric and neurodegenerative disorders. However, little is known about the neurobiological mechanisms of rodent USV production.…

Tamoxifen-independent recombination in the RIP-CreER mouse.

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Yanmei Liu

Full Text Available BACKGROUND: The inducible Cre-lox system is a valuable tool to study gene function in a spatial and time restricted fashion in mouse models. This strategy relies on the limited background activity of the modified Cre recombinase (CreER in the absence of its inducer, the competitive estrogen receptor ligand, tamoxifen. The RIP-CreER mouse (Tg (Ins2-cre/Esr1 1Dam is among the few available β-cell specific CreER mouse lines and thus it has been often used to manipulate gene expression in the insulin-producing cells of the endocrine pancreas. PRINCIPAL FINDINGS: Here, we report the detection of tamoxifen-independent Cre activity as early as 2 months of age in RIP-CreER mice crossed with three distinct reporter strains. SIGNIFICANCE: Evidence of Cre-mediated recombination of floxed alleles even in the absence of tamoxifen administration should warrant cautious use of this mouse for the study of pancreatic β-cells.

A Mouse Model of Chronic West Nile Virus Disease.

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Jessica B Graham

2016-11-01

Full Text Available Infection with West Nile virus (WNV leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

The mechanical heterogeneity of the hard callus influences local tissue strains during bone healing: a finite element study based on sheep experiments.

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Vetter, A; Liu, Y; Witt, F; Manjubala, I; Sander, O; Epari, D R; Fratzl, P; Duda, G N; Weinkamer, R

2011-02-03

During secondary fracture healing, various tissue types including new bone are formed. The local mechanical strains play an important role in tissue proliferation and differentiation. To further our mechanobiological understanding of fracture healing, a precise assessment of local strains is mandatory. Until now, static analyses using Finite Elements (FE) have assumed homogenous material properties. With the recent quantification of both the spatial tissue patterns (Vetter et al., 2010) and the development of elastic modulus of newly formed bone during healing (Manjubala et al., 2009), it is now possible to incorporate this heterogeneity. Therefore, the aim of this study is to investigate the effect of this heterogeneity on the strain patterns at six successive healing stages. The input data of the present work stemmed from a comprehensive cross-sectional study of sheep with a tibial osteotomy (Epari et al., 2006). In our FE model, each element containing bone was described by a bulk elastic modulus, which depended on both the local area fraction and the local elastic modulus of the bone material. The obtained strains were compared with the results of hypothetical FE models assuming homogeneous material properties. The differences in the spatial distributions of the strains between the heterogeneous and homogeneous FE models were interpreted using a current mechanobiological theory (Isakson et al., 2006). This interpretation showed that considering the heterogeneity of the hard callus is most important at the intermediate stages of healing, when cartilage transforms to bone via endochondral ossification. Copyright © 2010 Elsevier Ltd. All rights reserved.

Presence of HLA-B27 is associated with changes of serum levels of mediators of the Wnt and hedgehog pathway.

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Aschermann, Sarah; Englbrecht, Matthias; Bergua, Antonio; Spriewald, Bernd M; Said-Nahal, Rhula; Breban, Maxime; Schett, Georg; Rech, Jürgen

2016-01-01

HLA-B27 is present in 5% of the Caucasian population and is strongly associated with the development of spondyloarthritis (SpA), a disease characterized by inflammation and substantial bone changes. We hypothesized that the presence of HLA-B27 in itself is associated with alterations of key regulatory of bone homeostasis. Sera of 241 individuals were assessed for the serum levels of Wnt pathway regulators, sclerostin and dickkopf (Dkk)-1 as well as Indian hedgehog (IHH) and collagen type I cleavage products (CTX1). Of the 151 HLA-B27+ subjects, 31 had SpA, 30 had anterior uveitis, 30 were healthy individuals and 60 healthy siblings of patients with SpA. Sclerostin levels were significantly (P<0.001) lower in HLA-B27+ subjects (314±21pg/mL) compared to HLA-B27 negative controls (mean±SEM: 492±30pg/mL), no matter if subjects were either healthy, or affected by SpA or uveitis. Similar results were found for Dkk-1. No differences between the groups with respect to the bone resorption marker CTX1 were found. In contrast, IHH levels were significantly (P<0.001) higher in the carriers of HLA-B27 than in the negative controls. Changes in key regulators of the Wnt pathway as well as IHH, a molecule regulating endochondral ossification, are found in HLA-B27 carriers, independent if they were healthy or affected by uveitis or SpA. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Bone morphogenetic proteins: from structure to clinical use

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Granjeiro J.M.

2005-01-01

Full Text Available Bone morphogenetic proteins (BMPs are multi-functional growth factors belonging to the transforming growth factor ß superfamily. Family members are expressed during limb development, endochondral ossification, early fracture, and cartilage repair. The activity of BMPs was first identified in the 1960s but the proteins responsible for bone induction were unknown until the purification and cloning of human BMPs in the 1980s. To date, about 15 BMP family members have been identified and characterized. The signal triggered by BMPs is transduced through serine/threonine kinase receptors, type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, namely: type IA and IB BMP receptors and type IA activin receptors. BMPs seem to be involved in the regulation of cell proliferation, survival, differentiation and apoptosis, but their hallmark is their ability to induce bone, cartilage, ligament, and tendon formation at both heterotopic and orthotopic sites. This suggests that, in the future, they may play a major role in the treatment of bone diseases. Several animal studies have illustrated the potential of BMPs to enhance spinal fusion, repair critical-size defects, accelerate union, and heal articular cartilage lesions. Difficulties in producing and purifying BMPs from bone tissue have prompted the attempts made by several laboratories, including ours, to express these proteins in the recombinant form in heterologous systems. This review focuses on BMP structure, molecular mechanisms of action and significance and potential applications in medical, dental and veterinary practice for the treatment of cartilage and bone-related diseases.

Study of differential properties of fibrochondrocytes and hyaline chondrocytes in growing rabbits.

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Huang, L; Li, M; Li, H; Yang, C; Cai, X

2015-02-01

We aimed to build a culture model of chondrocytes in vitro, and to study the differential properties between fibrochondrocytes and hyaline chondrocytes. Histological sections were stained with haematoxylin and eosin so that we could analyse the histological structure of the fibrocartilage and hyaline cartilage. Condylar fibrochondrocytes and femoral hyaline chondrocytes were cultured from four, 4-week-old, New Zealand white rabbits. The production of COL2A1, COL1OA1, SOX9 and aggrecan was detected by real time-q polymerase chain reaction (RT-qPCR) and immunoblotting and the differences between them were compared statistically. Histological structures obviously differed between fibrocartilage and hyaline cartilage. COL2A1 and SOX9 were highly expressed within cell passage 2 (P2) of both fibrochondrocytes and hyaline chondrocytes, and reduced significantly after cell passage 4 (P4). The mRNA expressions of COL2A1 (p=0.05), COL10A1 (p=0.04), SOX9 (p=0.03), and aggrecan (p=0.04) were significantly higher in hyaline chondrocytes than in fibrochondrocytes, whereas the expression of COL1A1 (p=0.02) was the opposite. Immunoblotting showed similar results. We have built a simple and effective culture model of chondrocytes in vitro, and the P2 of chondrocytes is recommended for further studies. Condylar fibrocartilage and femoral hyaline cartilage have unique biological properties, and the regulatory mechanisms of endochondral ossification for the condyle should be studied independently in the future. Copyright © 2014 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

C-Type Natriuretic Peptide Analog as Therapy for Achondroplasia.

Science.gov (United States)

Legeai-Mallet, Laurence

2016-01-01

Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development. At cellular level, Fgfr3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3, which correlate with an enhanced activation of its downstream signaling pathways. Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been conducted such as the C-type natriuretic peptide (CNP) analog (BMN111), intermittent parathyroid hormone injections, soluble FGFR3 therapy, and meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by downregulating the mitogen-activated protein kinase pathway, which is activated as a result of a FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+ mice mimicking ACH. In 2014, a clinical trial (phase 2) of BMN111 in pediatric patients with ACH has started. This first clinical trial marks the first big step towards real treatment for these patients. © 2016 S. Karger AG, Basel.

IHH Gene Mutations Causing Short Stature With Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy.

Science.gov (United States)

Vasques, Gabriela A; Funari, Mariana F A; Ferreira, Frederico M; Aza-Carmona, Miriam; Sentchordi-Montané, Lucia; Barraza-García, Jimena; Lerario, Antonio M; Yamamoto, Guilherme L; Naslavsky, Michel S; Duarte, Yeda A O; Bertola, Debora R; Heath, Karen E; Jorge, Alexander A L

2018-02-01

Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders. To investigate the cause of short stature and to determine the phenotype of patients with IHH mutations, including the response to recombinant human growth hormone (rhGH) therapy. We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants. We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6. Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH. Copyright © 2017 Endocrine Society

Effects of intermittent versus continuous parathyroid hormone administration on condylar chondrocyte proliferation and differentiation

International Nuclear Information System (INIS)

Liu, Qi; Wan, Qilong; Yang, Rongtao; Zhou, Haihua; Li, Zubing

2012-01-01

Highlights: ► Different PTH administration exerts different effects on condylar chondrocyte. ► Intermittent PTH administration suppresses condylar chondrocyte proliferation. ► Continuous PTH administration maintains condylar chondrocyte proliferating. ► Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presented enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.

Radiographic characteristics of the forelimb distal phalanx and microscopic morphology of the lateral palmar process in foals 3-32 weeks old

International Nuclear Information System (INIS)

Kaneps, A.J.; Stover, S.M.; O'Brien, T.R.; Pool, R.R.; Willits, N.H.

1995-01-01

Developmental morphology of the forelimb distal phalanges and lateral palmar processes of 9 Thoroughbred foals aged 3–32 weeks was assessed using radiography, microradiography and histology. For inclusion in the study, all distal phalanges had no pathologic radiographic abnormalities.Vascular channels that are characteristically found in the dorsal region of the distal phalanx were not evident radiographically in the palmar process. The proximal and distal angles of the palmar processes were separated by a lucent line continuous with the incisure in foals only through 12 weeks of age. The distal phalanges were triangular-shaped in foals 3–12 weeks of age, and were oval-shaped in older foals.The palmar aspect of the distal phalanx was the major contributor to growth of the distal phalanx in the sagittal plane, especially between 3 and 12 weeks of age. Growth of the lateral palmar process occurred through the means of endochondral ossification. The body and cortices of the lateral palmar process were composed of coarse cancellous bone. Porosity within the lateral palmar process was greater in regions sampled axial, compared to abaxial, to the parietal sulcus and did not change with age.A fracture was identified microradiographically and/or histologically in 9 of 18 (50%) and 10 of 17 (59%), respectively, of the lateral palmar processes examined. The fracture line was consistently associated with the parietal sulcus on the dorsal cortical surface and was always immediately abaxial to the deep digital flexor tendon attachment. No age-related morphological changes of the lateral palmar processes were identified with microradiography or histological examinations

An Essential Physiological Role for MCT8 in Bone in Male Mice.

Science.gov (United States)

Leitch, Victoria D; Di Cosmo, Caterina; Liao, Xiao-Hui; O'Boy, Sam; Galliford, Thomas M; Evans, Holly; Croucher, Peter I; Boyde, Alan; Dumitrescu, Alexandra; Weiss, Roy E; Refetoff, Samuel; Williams, Graham R; Bassett, J H Duncan

2017-09-01

T3 is an important regulator of skeletal development and adult bone maintenance. Thyroid hormone action requires efficient transport of T4 and T3 into target cells. We hypothesized that monocarboxylate transporter (MCT) 8, encoded by Mct8 on the X-chromosome, is an essential thyroid hormone transporter in bone. To test this hypothesis, we determined the juvenile and adult skeletal phenotypes of male Mct8 knockout mice (Mct8KO) and Mct8D1D2KO compound mutants, which additionally lack the ability to convert the prohormone T4 to the active hormone T3. Prenatal skeletal development was normal in both Mct8KO and Mct8D1D2KO mice, whereas postnatal endochondral ossification and linear growth were delayed in both Mct8KO and Mct8D1D2KO mice. Furthermore, bone mass and mineralization were decreased in adult Mct8KO and Mct8D1D2KO mice, and compound mutants also had reduced bone strength. Delayed bone development and maturation in Mct8KO and Mct8D1D2KO mice is consistent with decreased thyroid hormone action in growth plate chondrocytes despite elevated serum T3 concentrations, whereas low bone mass and osteoporosis reflects increased thyroid hormone action in adult bone due to elevated systemic T3 levels. These studies identify an essential physiological requirement for MCT8 in chondrocytes, and demonstrate a role for additional transporters in other skeletal cells during adult bone maintenance.

4D atlas of the mouse embryo for precise morphological staging.

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Wong, Michael D; van Eede, Matthijs C; Spring, Shoshana; Jevtic, Stefan; Boughner, Julia C; Lerch, Jason P; Henkelman, R Mark

2015-10-15

After more than a century of research, the mouse remains the gold-standard model system, for it recapitulates human development and disease and is quickly and highly tractable to genetic manipulations. Fundamental to the power and success of using a mouse model is the ability to stage embryonic mouse development accurately. Past staging systems were limited by the technologies of the day, such that only surface features, visible with a light microscope, could be recognized and used to define stages. With the advent of high-throughput 3D imaging tools that capture embryo morphology in microscopic detail, we now present the first 4D atlas staging system for mouse embryonic development using optical projection tomography and image registration methods. By tracking 3D trajectories of every anatomical point in the mouse embryo from E11.5 to E14.0, we established the first 4D atlas compiled from ex vivo 3D mouse embryo reference images. The resulting 4D atlas comprises 51 interpolated 3D images in this gestational range, resulting in a temporal resolution of 72 min. From this 4D atlas, any mouse embryo image can be subsequently compared and staged at the global, voxel and/or structural level. Assigning an embryonic stage to each point in anatomy allows for unprecedented quantitative analysis of developmental asynchrony among different anatomical structures in the same mouse embryo. This comprehensive developmental data set offers developmental biologists a new, powerful staging system that can identify and compare differences in developmental timing in wild-type embryos and shows promise for localizing deviations in mutant development. © 2015. Published by The Company of Biologists Ltd.

Endogenous Mouse Dicer Is an Exclusively Cytoplasmic Protein.

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Christian Much

2016-06-01

Full Text Available Dicer is a large multi-domain protein responsible for the ultimate step of microRNA and short-interfering RNA biogenesis. In human and mouse cell lines, Dicer has been shown to be important in the nuclear clearance of dsRNA as well as the establishment of chromatin modifications. Here we set out to unambiguously define the cellular localization of Dicer in mice to understand if this is a conserved feature of mammalian Dicer in vivo. To this end, we utilized an endogenously epitope tagged Dicer knock-in mouse allele. From primary mouse cell lines and adult tissues, we determined with certainty by biochemical fractionation and confocal immunofluorescence microscopy that endogenous Dicer is exclusively cytoplasmic. We ruled out the possibility that a fraction of Dicer shuttles to and from the nucleus as well as that FGF or DNA damage signaling induce Dicer nuclear translocation. We also explored Dicer localization during the dynamic and developmental context of embryogenesis, where Dicer is ubiquitously expressed and strictly cytoplasmic in all three germ layers as well as extraembryonic tissues. Our data exclude a direct role for Dicer in the nuclear RNA processing in the mouse.

Endogenous Mouse Dicer Is an Exclusively Cytoplasmic Protein.

Science.gov (United States)

Much, Christian; Auchynnikava, Tania; Pavlinic, Dinko; Buness, Andreas; Rappsilber, Juri; Benes, Vladimir; Allshire, Robin; O'Carroll, Dónal

2016-06-01

Dicer is a large multi-domain protein responsible for the ultimate step of microRNA and short-interfering RNA biogenesis. In human and mouse cell lines, Dicer has been shown to be important in the nuclear clearance of dsRNA as well as the establishment of chromatin modifications. Here we set out to unambiguously define the cellular localization of Dicer in mice to understand if this is a conserved feature of mammalian Dicer in vivo. To this end, we utilized an endogenously epitope tagged Dicer knock-in mouse allele. From primary mouse cell lines and adult tissues, we determined with certainty by biochemical fractionation and confocal immunofluorescence microscopy that endogenous Dicer is exclusively cytoplasmic. We ruled out the possibility that a fraction of Dicer shuttles to and from the nucleus as well as that FGF or DNA damage signaling induce Dicer nuclear translocation. We also explored Dicer localization during the dynamic and developmental context of embryogenesis, where Dicer is ubiquitously expressed and strictly cytoplasmic in all three germ layers as well as extraembryonic tissues. Our data exclude a direct role for Dicer in the nuclear RNA processing in the mouse.

Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes

Science.gov (United States)

Rowley, Jesse W.; Oler, Andrew J.; Tolley, Neal D.; Hunter, Benjamin N.; Low, Elizabeth N.; Nix, David A.; Yost, Christian C.; Zimmerman, Guy A.

2011-01-01

Inbred mice are a useful tool for studying the in vivo functions of platelets. Nonetheless, the mRNA signature of mouse platelets is not known. Here, we use paired-end next-generation RNA sequencing (RNA-seq) to characterize the polyadenylated transcriptomes of human and mouse platelets. We report that RNA-seq provides unprecedented resolution of mRNAs that are expressed across the entire human and mouse genomes. Transcript expression and abundance are often conserved between the 2 species. Several mRNAs, however, are differentially expressed in human and mouse platelets. Moreover, previously described functional disparities between mouse and human platelets are reflected in differences at the transcript level, including protease activated receptor-1, protease activated receptor-3, platelet activating factor receptor, and factor V. This suggests that RNA-seq is a useful tool for predicting differences in platelet function between mice and humans. Our next-generation sequencing analysis provides new insights into the human and murine platelet transcriptomes. The sequencing dataset will be useful in the design of mouse models of hemostasis and a catalyst for discovery of new functions of platelets. Access to the dataset is found in the “Introduction.” PMID:21596849

Dissection of the Mouse Pancreas for Histological Analysis and Metabolic Profiling.

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Veite-Schmahl, Michelle J; Regan, Daniel P; Rivers, Adam C; Nowatzke, Joseph F; Kennedy, Michael A

2017-08-19

We have been investigating the pancreas specific transcription factor, 1a cre-recombinase; lox-stop-lox- Kristen rat sarcoma, glycine to aspartic acid at the 12 codon (Ptf1a cre/+ ;LSL-Kras G12D/+ ) mouse strain as a model of human pancreatic cancer. The goal of our current studies is to identify novel metabolic biomarkers of pancreatic cancer progression. We have performed metabolic profiling of urine, feces, blood, and pancreas tissue extracts, as well as histological analyses of the pancreas to stage the cancer progression. The mouse pancreas is not a well-defined solid organ like in humans, but rather is a diffusely distributed soft tissue that is not easily identified by individuals unfamiliar with mouse internal anatomy or by individuals that have little or no experience performing mouse organ dissections. The purpose of this article is to provide a detailed step-wise visual demonstration to guide novices in the removal of the mouse pancreas by dissection. This article should be especially valuable to students and investigators new to research that requires harvesting of the mouse pancreas by dissection for metabolic profiling or histological analyses.

Using the mouse to model human disease: increasing validity and reproducibility

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Monica J. Justice

2016-02-01

Full Text Available Experiments that use the mouse as a model for disease have recently come under scrutiny because of the repeated failure of data, particularly derived from preclinical studies, to be replicated or translated to humans. The usefulness of mouse models has been questioned because of irreproducibility and poor recapitulation of human conditions. Newer studies, however, point to bias in reporting results and improper data analysis as key factors that limit reproducibility and validity of preclinical mouse research. Inaccurate and incomplete descriptions of experimental conditions also contribute. Here, we provide guidance on best practice in mouse experimentation, focusing on appropriate selection and validation of the model, sources of variation and their influence on phenotypic outcomes, minimum requirements for control sets, and the importance of rigorous statistics. Our goal is to raise the standards in mouse disease modeling to enhance reproducibility, reliability and clinical translation of findings.