Body/bone-marrow differential-temperature sensor

Science.gov (United States)

Anselmo, V. J.; Berdahl, C. M.

1978-01-01

Differential-temperature sensor developed to compare bone-marrow and body temperature in leukemia patients uses single stable amplifier to monitor temperature difference recorded by thermocouples. Errors are reduced by referencing temperatures to each other, not to separate calibration points.

Natural calcium isotonic composition of urine as a marker of bone mineral balance

Science.gov (United States)

Skulan, J.; Bullen, T.; Anbar, A.D.; Puzas, J.E.; Shackelford, L.; LeBlanc, A.; Smith, S.M.

2007-01-01

Background: We investigated whether changes in the natural isotopic composition of calcium in human urine track changes in net bone mineral balance, as predicted by a model of calcium isotopic behavior in vertebrates. If so, isotopic analysis of natural urine or blood calcium could be used to monitor short-term changes in bone mineral balance that cannot be detected with other techniques. Methods: Calcium isotopic compositions are expressed as ??44Ca, or the difference in parts per thousand between the 44Ca/40Ca of a sample and the 44Ca/ 40Ca of a standard reference material. ??44Ca was measured in urine samples from 10 persons who participated in a study of the effectiveness of countermeasures to bone loss in spaceflight, in which 17 weeks of bed rest was used to induce bone loss. Study participants were assigned to 1 of 3 treatment groups: controls received no treatment, one treatment group received alendronate, and another group performed resistive exercise. Measurements were made on urine samples collected before, at 2 or 3 points during, and after bed rest. Results: Urine ??44Ca values during bed rest were lower in controls than in individuals treated with alendronate (P bone mineral density data. Conclusion: Results confirm the predicted relationship between bone mineral balance and calcium isotopes, suggesting that calcium isotopic analysis of urine might be refined into a clinical and research tool. ?? 2007 American Association for Clinical Chemistry.

Empirical Differential Balancing for Nonlinear Systems

NARCIS (Netherlands)

Kawano, Yu; Scherpen, Jacquelien M.A.; Dochain, Denis; Henrion, Didier; Peaucelle, Dimitri

In this paper, we consider empirical balancing of nonlinear systems by using its prolonged system, which consists of the original nonlinear system and its variational system. For the prolonged system, we define differential reachability and observability Gramians, which are matrix valued functions

Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells

Science.gov (United States)

Kobayashi, Hideki; Butler, Jason M.; O'Donnell, Rebekah; Kobayashi, Mariko; Ding, Bi-Sen; Bonner, Bryant; Chiu, Vi K.; Nolan, Daniel J.; Shido, Koji; Benjamin, Laura; Rafii, Shahin

2010-01-01

Endothelial cells establish an instructive vascular niche that reconstitutes haematopoietic stem and progenitor cells (HSPCs) through release of specific paracrine growth factors, known as angiocrine factors. However, the mechanism by which endothelial cells balance the rate of proliferation and lineage-specific differentiation of HSPCs is unknown. Here, we demonstrate that Akt activation in endothelial cells, through recruitment of mTOR, but not the FoxO pathway, upregulates specific angiocrine factors that support expansion of CD34−Flt3− KLS HSPCs with long-term haematopoietic stem cell (LT-HSC) repopulation capacity. Conversely, co-activation of Akt-stimulated endothelial cells with p42/44 MAPK shifts the balance towards maintenance and differentiation of the HSPCs. Selective activation of Akt1 in the endothelial cells of adult mice increased the number of colony forming units in the spleen and CD34−Flt3− KLS HSPCs with LT-HSC activity in the bone marrow, accelerating haematopoietic recovery. Therefore, the activation state of endothelial cells modulates reconstitution of HSPCs through the upregulation of angiocrine factors, with Akt–mTOR-activated endothelial cells supporting the self-renewal of LT-HSCs and expansion of HSPCs, whereas MAPK co-activation favours maintenance and lineage-specific differentiation of HSPCs. PMID:20972423

Differential diagnosis of cystic bone tumors in childhood

Energy Technology Data Exchange (ETDEWEB)

Refior, H.J.; Stuerz, H.

1982-09-01

Skeletal changes leading to a suspicion of the presence of a tumour frequently occur in childhood with the roentgenological manifestation of a cyst. X-ray morphology can differ depending upon the localisation and the course. In childhood, however such findings are mainly classified as tumour-like bone lesions. This group comprises, inter alia, the juvenile bone cyst, the aneurysmatic bone cyst and fibrous dysplasia. However, it is necessary to exclude by differential diagnosis - even though the main age of manifestation is after completion of growth - genuine bone tumours with cystic phenomena, such as the giant cell tumour, chondroma or chondroblastoma. Verification of the diagnosis can be effected via radiologic-diagnostic methods such as tomography and angiography as well as computerized tomography. The use of scintigraphy of the skeleton can likewise be indicated. Numerous laboratory parameters can be used in individual cases to exclude certain diagnoses. Taking these aspects into consideration, the article reviews differential diagnosis of the most frequent skeletal affections in childhood. Great emphasis is given to the ranking and importance of the individual diagnostic methods.

Preliminary study of 24 h bone scintigraphy after dexamethason intervention for differentiating the benign from malignant bone lesions

International Nuclear Information System (INIS)

Fan Yang; Li Yaming; Han Chunqi; Li Deshun; Ma Aiping; Liang Chenrong; Sun Zhenqiu; Liu Hao; Sun Xiaorong; Yin Yafu

2001-01-01

Objective: To explore the clinical value of 24 h bone scintigraphy after dexamethason intervention for differentiating the benign and malignant bone lesions. Methods: Twenty patients with malignant bone lesion (242 foci) and 21 patients with benign bone lesion (102 foci) were randomly divided into non-intervention group and intervention group for the comparative study. The patients in the non-intervention group underwent bone scintigraphy 3 and 24 h after the tracer administration, while the patients in the intervention group were given dexamethason 6.75 mg orally after 3 h bone imaging, then underwent 24 h bone in aging. Different regions of interest were drawn in 3 and 24 h imaging, then the radionuclide uptake ratios (RUR) of 24 h to 3 h was calculated. Results: There were no significant differences in RUR of benign lesions between the non-intervention group and intervention group (q =0.94, P > 0.05). There were significant differences in RUR between the malignant lesions in the non-intervention group and that in the intervention group (q 20.10, P < 0.01); there were significant differences in RUR between the benign and the malignant lesions in the non-intervention group (q = 1.81, P < 0.05); and there were also significant differences in RUR between the benign and the malignant lesions in the intervention group (q = 16.39, P < 0.01). The sensitivity, specificity and accuracy of differentiating the benign and malignant bone lesions by RUR with non-intervention and intervention were 75.5%, 86.2%, 65.8% and 81.5%, 87.5%, 83.1%, respectively. Conclusions: Comparing with the routine bone imaging, 24 h bone scintigraphy after dexamethason intervention elevated the diagnosis efficiency for differentiation of the benign and malignant bone lesions. 24 h bone scintigraphy associated with dexamethason intervention is convenient and acceptable in differentiation of benign and malignant bone lesions, and it is proved to be of great value for clinical application

Osteoblast Differentiation and Bone Matrix Formation In Vivo and In Vitro.

Science.gov (United States)

Blair, Harry C; Larrouture, Quitterie C; Li, Yanan; Lin, Hang; Beer-Stoltz, Donna; Liu, Li; Tuan, Rocky S; Robinson, Lisa J; Schlesinger, Paul H; Nelson, Deborah J

2017-06-01

We review the characteristics of osteoblast differentiation and bone matrix synthesis. Bone in air breathing vertebrates is a specialized tissue that developmentally replaces simpler solid tissues, usually cartilage. Bone is a living organ bounded by a layer of osteoblasts that, because of transport and compartmentalization requirements, produce bone matrix exclusively as an organized tight epithelium. With matrix growth, osteoblasts are reorganized and incorporated into the matrix as living cells, osteocytes, which communicate with each other and surface epithelium by cell processes within canaliculi in the matrix. The osteoblasts secrete the organic matrix, which are dense collagen layers that alternate parallel and orthogonal to the axis of stress loading. Into this matrix is deposited extremely dense hydroxyapatite-based mineral driven by both active and passive transport and pH control. As the matrix matures, hydroxyapatite microcrystals are organized into a sophisticated composite in the collagen layer by nucleation in the protein lattice. Recent studies on differentiating osteoblast precursors revealed a sophisticated proton export network driving mineralization, a gene expression program organized with the compartmentalization of the osteoblast epithelium that produces the mature bone matrix composite, despite varying serum calcium and phosphate. Key issues not well defined include how new osteoblasts are incorporated in the epithelial layer, replacing those incorporated in the accumulating matrix. Development of bone in vitro is the subject of numerous projects using various matrices and mesenchymal stem cell-derived preparations in bioreactors. These preparations reflect the structure of bone to variable extents, and include cells at many different stages of differentiation. Major challenges are production of bone matrix approaching the in vivo density and support for trabecular bone formation. In vitro differentiation is limited by the organization and

Rapidly Assessing Changes in Bone Mineral Balance Using Natural Stable Calcium Isotopes

Science.gov (United States)

Morgan, J. L. L.; Gordon, G. W.; Romaniello, S. J.; Skulan, J. L.; Smith, S. M.; Anbar, A. D.

2011-01-01

We demonstrate that variations in the Ca isotope ratios in urine rapidly and quantitatively reflect changes in bone mineral balance. This variation occurs because bone formation depletes soft tissue of light Ca isotopes, while bone resorption releases that isotopically light Ca back into soft tissue. In a study of 12 individuals confined to bed rest, a condition known to induce bone resorption, we show that Ca isotope ratios shift in a direction consistent with net bone loss after just 7 days, long before detectible changes in bone density occur. Consistent with this interpretation, the Ca isotope variations track changes observed in N-teleopeptide, a bone resorption biomarker, while bone-specific alkaline phosphatase, a bone formation biomarker, is unchanged. Ca isotopes can in principle be used to quantify net changes in bone mass. Ca isotopes indicate an average loss of 0.62 +/- 0.16 % in bone mass over the course of this 30-day study. The Ca isotope technique should accelerate the pace of discovery of new treatments for bone disease and provide novel insights into the dynamics of bone metabolism.

Astronaut Bones: Stable Calcium Isotopes in Urine as a Biomarker of Bone Mineral Balance

Science.gov (United States)

Skulan, J.; Gordon, G. W.; Romaniello, S. J.; Anbar, A. D.; Smith, S. M.; Zwart, S.

2016-12-01

Bone loss is a common health concern, in conditions ranging from osteoporosis to cancer. Bone loss due to unloading is also an important health issue for astronauts. We demonstrate stable calcium isotopes, a tool developed in geochemistry, are capable of detecting real-time quantitative changes in net bone mineral balance (BMB) using serum and urine [1]. We validated this technique by comparing with DEXA and biomarker data in subjects during bed rest, a ground-based analog of space flight effects [2-4]. We now apply this tool to assess changes in astronauts' BMB before, during and after 4-6 month space missions. There is stable isotope fractionation asymmetry between bone formation and resorption. During bone formation there is a mass-dependent preference for "lighter" calcium isotopes to be removed from serum and incorporated into bone mineral. During bone resorption, there is no measurable isotopic discrimination between serum and bone. Hence, when bone formation rates exceed that of resorption, serum and urine become isotopically "heavy" due to the sequestration of "light" calcium in bone. Conversely, when bone resorption exceeds bone formation, serum and urine become isotopically "light" due to the release of the sequestered light calcium from bone. We measured Ca isotopes in urine of thirty International Space Station astronauts. Average Ca isotope values in astronauts' urine shift isotopically lighter during microgravity, consistent with negative net BMB. Within a month of return to Earth, astronauts returned to within error of their δ44Ca value prior to departure. Urine samples from astronauts testing bone loss countermeasures showed bisphosphonates provide a viable pharmacological countermeasure. Some, but not all, individuals appear able to resist bone loss through diet and intensive resistive exercise alone. This is a promising new technique for monitoring BMB in astronauts, and hopefully someday on the way to/from Mars, this also has important clinical

Mechanisms in endocrinology: micro-RNAs: targets for enhancing osteoblast differentiation and bone formation.

Science.gov (United States)

Taipaleenmäki, Hanna; Bjerre Hokland, Lea; Chen, Li; Kauppinen, Sakari; Kassem, Moustapha

2012-03-01

Osteoblast differentiation and bone formation (osteogenesis) are regulated by transcriptional and post-transcriptional mechanisms. Recently, a novel class of regulatory factors termed micro-RNAs (miRNAs) has been identified as playing an important role in the regulation of many aspects of osteoblast biology including proliferation, differentiation, metabolism and apoptosis. Also, preliminary data from animal disease models suggest that targeting miRNAs in bone can be a novel approach to increase bone mass. This review highlights the current knowledge of miRNA biology and their role in bone formation and discusses their potential use in future therapeutic applications for metabolic bone diseases.

BMP9-Induced Osteogenetic Differentiation and Bone Formation of Muscle-Derived Stem Cells

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Li Xiang

2012-01-01

Full Text Available Efficient osteogenetic differentiation and bone formation from muscle-derived stem cells (MDSCs should have potential clinical applications in treating nonunion fracture healing or bone defects. Here, we investigate osteogenetic differentiation ability of MDSCs induced by bone morphogenetic protein 9 (BMP9 in vitro and bone formation ability in rabbit radius defects repairing model. Rabbit's MDSCs were extracted by type I collagenase and trypsin methods, and BMP9 was introduced into MDSCs by infection with recombinant adenovirus. Effects of BMP9-induced osteogenetic differentiation of MDSCs were identified with alkaline phosphatase (ALP activity and expression of later marker. In stem-cell implantation assay, MDSCs have also shown valuable potential bone formation ability induced by BMP9 in rabbit radius defects repairing test. Taken together, our findings suggest that MDSCs are potentiated osteogenetic stem cells which can be induced by BMP9 to treat large segmental bone defects, nonunion fracture, and/or osteoporotic fracture.

Ethanol Extract of Atractylodes macrocephala Protects Bone Loss by Inhibiting Osteoclast Differentiation

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Youn-Hwan Hwang

2013-06-01

Full Text Available The rhizome of Atractylodes macrocephala has been used mainly in Traditional Chinese Medicine for invigorating the functions of the stomach and spleen. In the present study, we investigated the inhibitory effect of the 70% ethanol extract of the rhizome of Atractylodes macrocephala (AMEE on osteoclast differentiation. We found that AMEE inhibits osteoclast differentiation from its precursors induced by receptor activator of nuclear factor-κB ligand (RANKL, an essential cytokine required for osteoclast differentiation. AMEE attenuated RANKL-induced activation of NF-κB signaling pathway, subsequently inhibiting the induction of osteoclastogenic transcription factors, c-Fos and nuclear factor of activated T cells cytoplasmic 1. Consistent with the in vitro results, administration of AMEE protected RANKL-induced bone loss in mice. We also identified atractylenolide I and II as active constituents contributing to the anti-osteoclastogenic effect of AMEE. Taken together, our results demonstrate that AMEE has a protective effect on bone loss via inhibiting osteoclast differentiation and suggest that AMEE may be useful in preventing and treating various bone diseases associated with excessive bone resorption.

Methionine restriction alters bone morphology and affects osteoblast differentiation

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Amadou Ouattara

2016-12-01

Full Text Available Methionine restriction (MR extends the lifespan of a wide variety of species, including rodents, drosophila, nematodes, and yeasts. MR has also been demonstrated to affect the overall growth of mice and rats. The objective of this study was to evaluate the effect of MR on bone structure in young and aged male and female C57BL/6J mice. This study indicated that MR affected the growth rates of males and young females, but not aged females. MR reduced volumetric bone mass density (vBMD and bone mineral content (BMC, while bone microarchitecture parameters were decreased in males and young females, but not in aged females compared to control-fed (CF mice. However, when adjusted for bodyweight, the effect of MR in reducing vBMD, BMC and microarchitecture measurements was either attenuated or reversed suggesting that the smaller bones in MR mice is appropriate for its body size. In addition, CF and MR mice had similar intrinsic strength properties as measured by nanoindentation. Plasma biomarkers suggested that the low bone mass in MR mice could be due to increased collagen degradation, which may be influenced by leptin, IGF-1, adiponectin and FGF21 hormone levels. Mouse preosteoblast cell line cultured under low sulfur amino acid growth media attenuated gene expression levels of Col1al, Runx2, Bglap, Alpl and Spp1 suggesting delayed collagen formation and bone differentiation. Collectively, our studies revealed that MR altered bone morphology which could be mediated by delays in osteoblast differentiation. Keywords: Methionine restriction, Aged mice, Micro-computed tomography, Nanoindentation, MC3T3-E1 subclone 4

sup(99m)Tc-MDP bone scintigraphy: kinetics of captation and differential diagnosis

International Nuclear Information System (INIS)

Slosman, D.; Frey, P.; Donath, A.

1983-01-01

The differential diagnosis of bone pathology is approached by the study of local MDP kinetics during the first two hours after intravenous injection. The value of the ratio between the pathological and the contralateral side is constant in normal cases (flat curve), it decreases in infectious bone diseases, it passes through a maximum after 1 to 1 1/2 hour in inflammatory non-infectious involvement of bone and it keeps increasing in primary bone pathological conditions. This technique has become a very useful tool in approaching differential diagnosis

Water extract of Acer tegmentosum reduces bone destruction by inhibiting osteoclast differentiation and function.

Science.gov (United States)

Ha, Hyunil; Shim, Ki-Shuk; Kim, Taesoo; An, Hyosun; Lee, Chung-Jo; Lee, Kwang Jin; Ma, Jin Yeul

2014-04-01

The stem of Acer tegmentosum has been widely used in Korea for the treatment of hepatic disorders. In this study, we investigated the bone protective effect of water extract of the stem of Acer tegmentosum (WEAT). We found that WEAT inhibits osteoclast differentiation induced by receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. In osteoclast precursor cells, WEAT inhibited RANKL-induced activation of JNK, NF-κB, and cAMP response element-binding protein, leading to suppression of the induction of c-Fos and nuclear factor of activated T cells cytoplasmic 1, key transcription factors for osteoclast differentiation. In addition, WEAT inhibited bone resorbing activity of mature osteoclasts. Furthermore, the oral administration of WEAT reduced RANKL-induced bone resorption and trabecular bone loss in mice. Taken together, our study demonstrates that WEAT possesses a protective effect on bone destruction by inhibiting osteoclast differentiation and function.

Pharmacological activation of aldehyde dehydrogenase 2 promotes osteoblast differentiation via bone morphogenetic protein-2 and induces bone anabolic effect

Energy Technology Data Exchange (ETDEWEB)

Mittal, Monika; Pal, Subhashis; China, Shyamsundar Pal; Porwal, Konica [Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031 (India); Dev, Kapil [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Shrivastava, Richa [Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Raju, Kanumuri Siva Rama; Rashid, Mamunur [Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Trivedi, Arun Kumar; Sanyal, Sabyasachi [Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Wahajuddin, Muhammad [Pharmaceutics Division, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Bhaduria, Smrati [Division of Toxicology, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Maurya, Rakesh [Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226031 (India); Chattopadhyay, Naibedya, E-mail: n_chattopadhyay@cdri.res.in [Division of Endocrinology and Centre for Research in Anabolic Skeletal Targets in Health and Illness (ASTHI), CSIR-Central Drug Research Institute, Lucknow 226031 (India)

2017-02-01

Aldehyde dehydrogenases (ALDHs) are a family of enzymes involved in detoxifying aldehydes. Previously, we reported that an ALDH inhibitor, disulfiram caused bone loss in rats and among ALDHs, osteoblast expressed only ALDH2. Loss-of-function mutation in ALDH2 gene is reported to cause bone loss in humans which suggested its importance in skeletal homeostasis. We thus studied whether activating ALDH2 by N-(1, 3-benzodioxol-5-ylmethyl)-2, 6-dichlorobenzamide (alda-1) had osteogenic effect. We found that alda-1 increased and acetaldehyde decreased the differentiation of rat primary osteoblasts and expressions of ALDH2 and bone morphogenetic protein-2 (BMP-2). Silencing ALDH2 in osteoblasts abolished the alda-1 effects. Further, alda-1 attenuated the acetaldehyde-induced lipid-peroxidation and oxidative stress. BMP-2 is essential for bone regeneration and alda-1 increased its expression in osteoblasts. We then showed that alda-1 (40 mg/kg dose) augmented bone regeneration at the fracture site with concomitant increase in BMP-2 protein compared with control. The osteogenic dose (40 mg/kg) of alda-1 attained a bone marrow concentration that was stimulatory for osteoblast differentiation, suggesting that the tissue concentration of alda-1 matched its pharmacologic effect. In addition, alda-1 promoted modeling-directed bone growth and peak bone mass achievement, and increased bone mass in adult rats which reiterated its osteogenic effect. In osteopenic ovariectomized (OVX) rats, alda-1 reversed trabecular osteopenia with attendant increase in serum osteogenic marker (procollagen type I N-terminal peptide) and decrease in oxidative stress. Alda-1 has no effect on liver and kidney function. We conclude that activating ALDH2 by alda-1 had an osteoanabolic effect involving increased osteoblastic BMP-2 production and decreased OVX-induced oxidative stress. - Highlights: • Alda-1 induced osteoblast differentiation that involved upregulation of ALDH2 and BMP-2 • Alda-1

Bioenergetics during calvarial osteoblast differentiation reflect strain differences in bone mass.

Science.gov (United States)

Guntur, Anyonya R; Le, Phuong T; Farber, Charles R; Rosen, Clifford J

2014-05-01

Osteoblastogenesis is the process by which mesenchymal stem cells differentiate into osteoblasts that synthesize collagen and mineralize matrix. The pace and magnitude of this process are determined by multiple genetic and environmental factors. Two inbred strains of mice, C3H/HeJ and C57BL/6J, exhibit differences in peak bone mass and bone formation. Although all the heritable factors that differ between these strains have not been elucidated, a recent F1 hybrid expression panel (C3H × B6) revealed major genotypic differences in osteoblastic genes related to cellular respiration and oxidative phosphorylation. Thus, we hypothesized that the metabolic rate of energy utilization by osteoblasts differed by strain and would ultimately contribute to differences in bone formation. In order to study the bioenergetic profile of osteoblasts, we measured oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) first in a preosteoblastic cell line MC3T3-E1C4 and subsequently in primary calvarial osteoblasts from C3H and B6 mice at days 7, 14, and 21 of differentiation. During osteoblast differentiation in media containing ascorbic acid and β-glycerophosphate, all 3 cell types increased their oxygen consumption and extracellular acidification rates compared with the same cells grown in regular media. These increases are sustained throughout differentiation. Importantly, C3H calvarial osteoblasts had greater oxygen consumption rates than B6 consistent with their in vivo phenotype of higher bone formation. Interestingly, osteoblasts utilized both oxidative phosphorylation and glycolysis during the differentiation process although mature osteoblasts were more dependent on glycolysis at the 21-day time point than oxidative phosphorylation. Thus, determinants of oxygen consumption reflect strain differences in bone mass and provide the first evidence that during collagen synthesis osteoblasts use both glycolysis and oxidative phosphorylation to synthesize and

Constitutive β-catenin activation in osteoblasts impairs terminal osteoblast differentiation and bone quality

Energy Technology Data Exchange (ETDEWEB)

Bao, Quanwei; Chen, Sixu; Qin, Hao [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China); Feng, Jianquan [Department of Biomedical Sciences, Baylor College of Dentistry, Texas A& M Health Science Center, Dallas, TX 75246 (United States); Liu, Huayu; Liu, Daocheng; Li, Ang; Shen, Yue; Zhong, Xiaozheng; Li, Junfeng [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China); Zong, Zhaowen, E-mail: zongzhaowen@sina.cn [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China)

2017-01-01

Accumulating evidence suggests that Wnt/β-catenin signaling plays a central role in controlling bone mass. We previously reported that constitutive activation of β-catenin (CA-β-catenin) in osteoblasts potentially has side effects on the bone growth and bone remodeling process, although it could increase bone mass. The present study aimed to observe the effects of osteoblastic CA-β-catenin on bone quality and to investigate possible mechanisms of these effects. It was found that CA-β-catenin mice exhibited lower mineralization levels and disorganized collagen in long bones as confirmed by von Kossa staining and sirius red staining, respectively. Also, bone strength decreased significantly in CA-β-catenin mice. Then the effect of CA-β-catenin on biological functions of osteoblasts were investigated and it was found that the expression levels of osteocalcin, a marker for the late differentiation of osteoblasts, decreased in CA-β-catenin mice, while the expression levels of osterix and alkaline phosphatase, two markers for the early differentiation of osteoblasts, increased in CA-β-catenin mice. Furthermore, higher proliferation rate were revealed in osteoblasts that were isolated from CA-β-catenin mice. The Real-time PCR and western blot examination found that the expression level of c-myc and cyclin D1, two G1 progression-related molecules, increased in osteoblasts that were isolated from the CA-β-catenin mice, and the expression levels of CDK14 and cyclin Y, two mitotic-related molecules that can accelerate cells entering into S and G2/M phases, increased in osteoblasts that were isolated from the CA-β-catenin mice. In summary, osteoblastic CA-β-catenin kept osteoblasts in high proliferative state and impaired the terminal osteoblast differentiation, and this led to changed bone structure and decreased bone strength. - Highlights: • Wnt/β-catenin signaling plays a central role in controlling bone mass. • CA-β-catenin has side effects on the bone

Biglycan deficiency increases osteoclast differentiation and activity due to defective osteoblasts

DEFF Research Database (Denmark)

Bi, Yanming; Nielsen, Karina L; Kilts, Tina M

2006-01-01

to be independent of the differential production of soluble RANKL and OPG and, instead, due to a decrease in osteoblast maturation accompanied by increase in osteoblastic proliferation. In addition to the imbalance between differentiation and proliferation, there was a differential decrease in secretory leukocyte......Bone mass is maintained by a fine balance between bone formation by osteoblasts and bone resorption by osteoclasts. Although osteoblasts and osteoclasts have different developmental origins, it is generally believed that the differentiation, function, and survival of osteoclasts are regulated...... by osteogenic cells. We have previously shown that the extracellular matrix protein, biglycan (Bgn), plays an important role in the differentiation of osteoblast precursors. In this paper, we showed that Bgn is involved in regulating osteoclast differentiation through its effect on osteoblasts...

Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas

DEFF Research Database (Denmark)

Kim, Yung Hae; Larsen, Hjalte List; Rué, Paul

2015-01-01

Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine...

Frontal Bone Insufficiency in Gsk3β Mutant Mice.

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Heather Szabo-Rogers

Full Text Available The development of the mammalian skull is a complex process that requires multiple tissue interactions and a balance of growth and differentiation. Disrupting this balance can lead to changes in the shape and size of skull bones, which can have serious clinical implications. For example, insufficient ossification of the bony elements leads to enlarged anterior fontanelles and reduced mechanical protection of the brain. In this report, we find that loss of Gsk3β leads to a fully penetrant reduction of frontal bone size and subsequent enlarged frontal fontanelle. In the absence of Gsk3β the frontal bone primordium undergoes increased cell death and reduced proliferation with a concomitant increase in Fgfr2-IIIc and Twist1 expression. This leads to a smaller condensation and premature differentiation. This phenotype appears to be Wnt-independent and is not rescued by decreasing the genetic dose of β-catenin/Ctnnb1. Taken together, our work defines a novel role for Gsk3β in skull development.

Effects of ionizing radiation on differentiation of murine bone marrow cells into mast cells

International Nuclear Information System (INIS)

Murakami, Sho; Yoshino, Hironori; Ishikawa, Junya; Yamaguchi, Masaru; Tsujiguchi, Takakiyo; Nishiyama, Ayaka; Yokoyama, Kouki; Kashiwakura, Ikuo

2015-01-01

Mast cells, immune effector cells produced from bone marrow cells, play a major role in immunoglobulin E–mediated allergic responses. Ionizing radiation affects the functions of mast cells, which are involved in radiation-induced tissue damage. However, whether ionizing radiation affects the differential induction of mast cells is unknown. Here we investigated whether bone marrow cells of X-irradiated mice differentiated into mast cells. To induce mast cells, bone marrow cells from X-irradiated and unirradiated mice were cultured in the presence of cytokines required for mast cell induction. Although irradiation at 0.5 Gy and 2 Gy decreased the number of bone marrow cells 1 day post-irradiation, the cultured bone marrow cells of X-irradiated and unirradiated mice both expressed mast cell–related cell-surface antigens. However, the percentage of mast cells in the irradiated group was lower than in the unirradiated group. Similar decreases in the percentage of mast cells induced in the presence of X-irradiation were observed 10 days post irradiation, although the number of bone marrow cells in irradiated mice had recovered by this time. Analysis of mast cell function showed that degranulation of mast cells after immunoglobulin E–mediated allergen recognition was significantly higher in the X-irradiated group compared with in the unirradiated group. In conclusion, bone marrow cells of X-irradiated mice differentiated into mast cells, but ionizing radiation affected the differentiation efficiency and function of mast cells. (author)

Activation of GLP-1 Receptor Promotes Bone Marrow Stromal Cell Osteogenic Differentiation through β-Catenin

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Jingru Meng

2016-04-01

Full Text Available Glucagon-like peptide 1 (GLP-1 plays an important role in regulating bone remodeling, and GLP-1 receptor agonist shows a positive relationship with osteoblast activity. However, GLP-1 receptor is not found in osteoblast, and the mechanism of GLP-1 receptor agonist on regulating bone remodeling is unclear. Here, we show that the GLP-1 receptor agonist exendin-4 (Ex-4 promoted bone formation and increased bone mass and quality in a rat unloading-induced bone loss model. These functions were accompanied by an increase in osteoblast number and serum bone formation markers, while the adipocyte number was decreased. Furthermore, GLP-1 receptor was detected in bone marrow stromal cells (BMSCs, but not in osteoblast. Activation of GLP-1 receptor by Ex-4 promoted the osteogenic differentiation and inhibited BMSC adipogenic differentiation through regulating PKA/β-catenin and PKA/PI3K/AKT/GSK3β signaling. These findings reveal that GLP-1 receptor regulates BMSC osteogenic differentiation and provide a molecular basis for therapeutic potential of GLP-1 against osteoporosis.

Differentiation of Bone Marrow Mesenchymal Stem Cells in Osteoblasts and Adipocytes and its Role in Treatment of Osteoporosis.

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Wang, Cheng; Meng, Haoye; Wang, Xin; Zhao, Chenyang; Peng, Jing; Wang, Yu

2016-01-21

Osteoporosis is a systemic metabolic bone disorder characterized by a decrease in bone mass and degradation of the bone microstructure, leaving bones that are fragile and prone to fracture. Most osteoporosis treatments improve symptoms, but to date there is no quick and effective therapy. Bone marrow mesenchymal stem cells (BMMSCs) have pluripotent potential. In adults, BMMSCs differentiate mainly into osteoblasts and adipocytes in the skeleton. However, if this differentiation is unbalanced, it may lead to a decrease in bone mass. If the number of adipocyte cells increases and that of osteoblast cells decreases, osteoporosis can result. A variety of hormones and cytokines play an important role in the regulation of BMMSCs bidirectional differentiation. Therefore, a greater understanding of the regulation mechanism of BMMSC differentiation may provide new methods to prevent and treat osteoporosis. In addition, autologous, allogeneic BMMSCs or genetically modified BMMSC transplantation can effectively increase bone mass and density, increase bone mechanical strength, correct the imbalance in bone metabolism, and increase bone formation, and is expected to provide a new strategy and method for the treatment of osteoporosis.

Stable Calcium Isotopes in Urine as a Biomarker of Bone Mineral Balance in Spaceflight

Data.gov (United States)

National Aeronautics and Space Administration — The primary goal of this project was to demonstrate whether the relationship between bone mineral balance (BMB) and changes in the natural isotope composition of...

Differential expression of CCN-family members in primary human bone marrow-derived mesenchymal stem cells during osteogenic, chondrogenic and adipogenic differentiation

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Hendrich Christian

2005-03-01

Full Text Available Abstract Background The human cysteine rich protein 61 (CYR61, CCN1 as well as the other members of the CCN family of genes play important roles in cellular processes such as proliferation, adhesion, migration and survival. These cellular events are of special importance within the complex cellular interactions ongoing in bone remodeling. Previously, we analyzed the role of CYR61/CCN1 as an extracellular signaling molecule in human osteoblasts. Since mesenchymal stem cells of bone marrow are important progenitors for various differentiation pathways in bone and possess increasing potential for regenerative medicine, here we aimed to analyze the expression of CCN family members in bone marrow-derived human mesenchymal stem cells and along the osteogenic, the adipogenic and the chondrogenic differentiation. Results Primary cultures of human mesenchymal stem cells were obtained from the femoral head of patients undergoing total hip arthroplasty. Differentiation into adipocytes and osteoblasts was done in monolayer culture, differentiation into chondrocytes was induced in high density cell pellet cultures. For either pathway, established differentiation markers and CCN-members were analyzed at the mRNA level by RT-PCR and the CYR61/CCN1 protein was analyzed by immunocytochemistry. RT-PCR and histochemical analysis revealed the appropriate phenotype of differentiated cells (Alizarin-red S, Oil Red O, Alcian blue, alkaline phosphatase; osteocalcin, collagen types I, II, IX, X, cbfa1, PPARγ, aggrecan. Mesenchymal stem cells expressed CYR61/CCN1, CTGF/CCN2, CTGF-L/WISP2/CCN5 and WISP3/CCN6. The CYR61/CCN1 expression decreased markedly during osteogenic differentiation, adipogenic differentiation and chondrogenic differentiation. These results were confirmed by immuncytochemical analyses. WISP2/CCN5 RNA expression declined during adipogenic differentiation and WISP3/CCN6 RNA expression was markedly reduced in chondrogenic differentiation. Conclusion The

Novel anti-cancer strategy in bone tumors by targeting molecular and cellular modulators of bone resorption.

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Brounais, Bénédicte; Ruiz, Carmen; Rousseau, Julie; Lamoureux, François; Blanchard, Frédéric; Heymann, Dominique; Redini, Françoise

2008-11-01

Tumor cells alter the balanced process of bone formation and bone resorption mediated respectively by osteoblasts and osteoclasts, leading to the disruption of the normal equilibrium and resulting in a spectrum of osteolytic to osteoblastic lesions. This review will summarize research on molecules that play direct and essential roles in the differentiation and activity of osteoclasts, and the role of these molecules in bone destruction caused by cancer. Results from experimental models suggest that the Receptor Activator of NF-kB Ligand (RANKL), a member of the TNF superfamily is a common effector of bony lesions in osteolysis caused by primary and secondary bone tumors. Therefore, osteoclast represents an attractive target across a broad range of tumors that develop in bone. Elucidation of the mechanisms of RANKL interactions with its activator (RANK) and decoy (osteoprotegerin: OPG) receptors has enable the development of pharmacological inhibitors of RANKL (and of its signalling pathway) which have been recently patented, with potential for the treatment of cancer-induced bone disease. Blocking bone resorption by specific other drugs such as bisphosphonates, inhibitors of cathepsin K (the main enzyme involved in bone resorption mechanisms) or signalling pathways regulating osteoclast differentiation and activation is also a promising target for the treatment of osteolysis associated to bone tumors.

New factors controlling the balance between osteoblastogenesis and adipogenesis.

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Abdallah, Basem M; Kassem, Moustapha

2012-02-01

The majority of conditions associated with bone loss, including aging, are accompanied by increased marrow adiposity possibly due to shifting of the balance between osteoblast and adipocyte differentiation in bone marrow stromal (skeletal) stem cells (MSC). In order to study the relationship between osteoblastogenesis and adipogenesis in bone marrow, we have characterized cellular models of multipotent MSC as well as pre-osteoblastic and pre-adipocytic cell populations. Using these models, we identified two secreted factors in the bone marrow microenviroment: secreted frizzled-related protein 1 (sFRP-1) and delta-like1 (preadipocyte factor 1) (Dlk1/Pref-1). Both exert regulatory effects on osteoblastogenesis and adipogenesis. Our studies suggest a model for lineage fate determination of MSC that is regulated through secreted factors in the bone marrow microenvironment that mediate a cross-talk between lineage committed cell populations in addition to controlling differentiation choices of multipotent MSC. Copyright © 2011 Elsevier Inc. All rights reserved.

Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation.

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Kaneto, Carla Martins; Pereira Lima, Patrícia S; Prata, Karen Lima; Dos Santos, Jane Lima; de Pina Neto, João Monteiro; Panepucci, Rodrigo Alexandre; Noushmehr, Houtan; Covas, Dimas Tadeu; de Paula, Francisco José Alburquerque; Silva, Wilson Araújo

2017-06-01

Mesenchymal stem cells (MSCs) are precursors present in adult bone marrow that are able to differentiate into osteoblasts, adipocytes and chondroblasts that have gained great importance as a source for cell therapy. Recently, a number of studies involving the analysis of gene expression of undifferentiated MSCs and of MSCs in the differentiation into multiple lineage processes were observed but there is no information concerning the gene expression of MSCs from Osteogenesis Imperfecta (OI) patients. Osteogenesis Imperfecta is characterized as a genetic disorder in which a generalized osteopenia leads to excessive bone fragility and severe bone deformities. The aim of this study was to analyze gene expression profile during osteogenic differentiation from BMMSCs (Bone Marrow Mesenchymal Stem Cells) obtained from patients with Osteogenesis Imperfecta and from control subjects. Bone marrow samples were collected from three normal subjects and five patients with OI. Mononuclear cells were isolated for obtaining mesenchymal cells that had been expanded until osteogenic differentiation was induced. RNA was harvested at seven time points during the osteogenic differentiation period (D0, D+1, D+2, D+7, D+12, D+17 and D+21). Gene expression analysis was performed by the microarray technique and identified several differentially expressed genes. Some important genes for osteoblast differentiation had lower expression in OI patients, suggesting a smaller commitment of these patient's MSCs with the osteogenic lineage. Other genes also had their differential expression confirmed by RT-qPCR. An increase in the expression of genes related to adipocytes was observed, suggesting an increase of adipogenic differentiation at the expense osteogenic differentiation. Copyright © 2017. Published by Elsevier Masson SAS.

Osteoblast Differentiation and Bone Formation Gene Expression in Strontium-inducing Bone Marrow Mesenchymal Stem Cell

OpenAIRE

SILA-ASNA, MONNIPHA; BUNYARATVEJ, AHNOND; Maeda, Sakan; Kitaguchi, Hiromichi; BUNYARATAVEJ, NARONG

2007-01-01

Osteoblastic differentiation from human mesenchymal stem cell (hMSCs) is animportant step of bone formation. We studied the in vitro induction of hMSCs byusing strontium ranelate, a natural trace amount in water, food and human skeleton.The mRNA synthesis of various osteoblast specific genes was assessed by means ofreverse transcription polymerase chain reaction (RT-PCR). In the hMSCs culture,strontium ranelate could enhance the induction of hMSCs to differentiate intoosteoblasts. Cbfa1 gene ...

The effects and mechanisms of clinorotation on proliferation and differentiation in bone marrow mesenchymal stem cells

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Yan, Ming; Wang, Yongchun; Yang, Min; Liu, Yanwu; Qu, Bo; Ye, Zhengxu; Liang, Wei; Sun, Xiqing; Luo, Zhuojing

2015-01-01

Data from human and rodent studies have demonstrated that microgravity induces observed bone loss in real spaceflight or simulated experiments. The decrease of bone formation and block of maturation may play important roles in bone loss induced by microgravity. The aim of this study was to investigate the changes of proliferation and differentiation in bone marrow mesenchymal stem cells (BMSCs) induced by simulated microgravity and the mechanisms underlying it. We report here that clinorotation, a simulated model of microgravity, decreased proliferation and differentiation in BMSCs after exposure to 48 h simulated microgravity. The inhibited proliferation are related with blocking the cell cycle in G2/M and enhancing the apoptosis. While alterations of the osteoblast differentiation due to the decreased SATB2 expression induced by simulated microgravity in BMSCs. - Highlights: • Simulated microgravity inhibited proliferation and differentiation in BMSCs. • The decreased proliferation due to blocked cell cycle and enhanced the apoptosis. • The inhibited differentiation accounts for alteration of SATB2, Hoxa2 and Cbfa1

Effect of boron on osteogenic differentiation of human bone marrow stromal cells.

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Ying, Xiaozhou; Cheng, Shaowen; Wang, Wei; Lin, Zhongqin; Chen, Qingyu; Zhang, Wei; Kou, Dongquan; Shen, Yue; Cheng, Xiaojie; Rompis, Ferdinand An; Peng, Lei; Zhu Lu, Chuan

2011-12-01

Bone marrow stromal cells (BMSCs) have been well established as an ideal source of cell-based therapy for bone tissue engineering applications. Boron (B) is a notable trace element in humans; so far, the effects of boron on the osteogenic differentiation of BMSCs have not been reported. The aim of this study was to evaluate the effects of boron (0, 1, 10,100, and 1,000 ng/ml) on osteogenic differentiation of human BMSCs. In this study, BMSCs proliferation was analyzed by cell counting kit-8 (CCK8) assay, and cell osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity assay, Von Kossa staining, and real-time PCR. The results indicated that the proliferation of BMSCs was no different from the control group when added with B at the concentration of 1, 10, and 100 ng/ml respectively (P > 0.05); in contrast, 1,000 ng/ml B inhibited the proliferation of BMSCs at days 4, 7, and 14 (P < 0.05). By ALP staining, we discovered that BMSCs treated with 10 and 100 ng/ml B presented a higher ALP activity compared with control (P < 0.05). By real-time PCR, we detected the messenger RNA expression of ALP, osteocalcin, collagen type I, and bone morphogenetic proteins 7 were also increased in 10 and 100 ng/ml B treatment groups (P < 0.05). The calcium depositions were increased in 1 and 10 ng/ml B treatment groups (P < 0.05). Taken all together, it was the first time to report that B could increase osteogenic effect by stimulating osteogenic differentiation-related marker gene synthesis during the proliferation and differentiation phase in human BMSCs and could be a promising approach for enhancing osteogenic capacity of cell-based construction in bone tissue engineering.

Influence of bone marrow-derived mesenchymal stem cells pre-implantation differentiation approach on periodontal regeneration in vivo.

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Cai, Xinjie; Yang, Fang; Yan, Xiangzhen; Yang, Wanxun; Yu, Na; Oortgiesen, Daniel A W; Wang, Yining; Jansen, John A; Walboomers, X Frank

2015-04-01

The implantation of bone marrow-derived mesenchymal stem cells (MSCs) has previously been shown successful to achieve periodontal regeneration. However, the preferred pre-implantation differentiation strategy (e.g. maintenance of stemness, osteogenic or chondrogenic induction) to obtain optimal periodontal regeneration is still unknown. This in vivo study explored which differentiation approach is most suitable for periodontal regeneration. Mesenchymal stem cells were obtained from Fischer rats and seeded onto poly(lactic-co-glycolic acid)/poly(ɛ-caprolactone) electrospun scaffolds, and then pre-cultured under different in vitro conditions: (i) retention of multilineage differentiation potential; (ii) osteogenic differentiation approach; and (iii) chondrogenic differentiation approach. Subsequently, the cell-scaffold constructs were implanted into experimental periodontal defects of Fischer rats, with empty scaffolds as controls. After 6 weeks of implantation, histomorphometrical analyses were applied to evaluate the regenerated periodontal tissues. The chondrogenic differentiation approach showed regeneration of alveolar bone and ligament tissues. The retention of multilineage differentiation potential supported only ligament regeneration, while the osteogenic differentiation approach boosted alveolar bone regeneration. Chondrogenic differentiation of MSCs before implantation is a useful strategy for regeneration of alveolar bone and periodontal ligament, in the currently used rat model. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bone conditioned media (BCM) improves osteoblast adhesion and differentiation on collagen barrier membranes.

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Fujioka-Kobayashi, Masako; Caballé-Serrano, Jordi; Bosshardt, Dieter D; Gruber, Reinhard; Buser, Daniel; Miron, Richard J

2016-07-04

The use of autogenous bone chips during guided bone regeneration procedures has remained the gold standard for bone grafting due to its excellent combination of osteoconduction, osteoinduction and osteogenesis. Recent protocols established by our group have characterized specific growth factors and cytokines released from autogenous bone that have the potential to be harvested and isolated into bone conditioned media (BCM). Due to the advantageous osteo-promotive properties of BCM, the aims of the present study was to pre-coat collagen barrier membranes with BCM and investigate its effect on osteoblast adhesion, proliferation and differentiation for possible future clinical use. Scanning electron microscopy (SEM) was first used to qualitative assess BCM protein accumulation on the surface of collagen membranes. Thereafter, undifferentiated mouse ST2 stromal bone marrow cells were seeded onto BioGide porcine derived collagen barrier membranes (control) or barrier membranes pre-coated with BCM (test group). Control and BCM samples were compared for cell adhesion at 8 h, cell proliferation at 1, 3 and 5 days and real-time PCR at 5 days for osteoblast differentiation markers including Runx2, alkaline phosphatase (ALP), osteocalcin (OCN) and bone sialoprotein (BSP). Mineralization was further assessed with alizarin red staining at 14 days post seeding. SEM images demonstrated evidence of accumulated proteins found on the surface of collagen membranes following coating with BCM. Analysis of total cell numbers revealed that the additional pre-coating with BCM markedly increased cell attachment over 4 fold when compared to cells seeded on barrier membranes alone. No significant difference could be observed for cell proliferation at all time points. BCM significantly increased mRNA levels of osteoblast differentiation markers including ALP, OCN and BSP at 5 days post seeding. Furthermore, barrier membranes pre-coated with BCM demonstrated a 5-fold increase in alizarin

Organotins Are Potent Activators of PPARγ and Adipocyte Differentiation in Bone Marrow Multipotent Mesenchymal Stromal Cells

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Yanik, Susan C.; Baker, Amelia H.; Mann, Koren K.; Schlezinger, Jennifer J.

2011-01-01

Adipocyte differentiation in bone marrow is potentially deleterious to both bone integrity and lymphopoiesis. Here, we examine the hypothesis that organotins, common environmental contaminants that are dual ligands for peroxisome proliferator–activated receptor (PPAR) γ and its heterodimerization partner retinoid X receptor (RXR), are potent activators of bone marrow adipogenesis. A C57Bl/6-derived bone marrow multipotent mesenchymal stromal cell (MSC) line, BMS2, was treated with rosiglitazone, a PPARγ agonist, bexarotene, an RXR agonist, or a series of organotins. Rosiglitazone and bexarotene potently activated adipocyte differentiation; however, bexarotene had a maximal efficacy of only 20% of that induced by rosiglitazone. Organotins (tributyltin [TBT], triphenyltin, and dibutyltin) also stimulated adipocyte differentiation (EC50 of 10–20nM) but with submaximal, structure-dependent efficacy. In coexposures, both bexarotene and TBT enhanced rosiglitazone-induced adipogenesis. To investigate the contribution of PPARγ to TBT-induced adipogenesis, we examined expression of PPARγ2, as well as its transcriptional target FABP4. TBT-induced PPARγ2 and FABP4 protein expression with an efficacy intermediate between rosiglitazone and bexarotene, similar to lipid accumulation. A PPARγ antagonist and PPARγ-specific small hairpin RNA suppressed TBT-induced differentiation, although to a lesser extent than rosiglitazone-induced differentiation, suggesting that TBT may engage alternate pathways. TBT and bexarotene, but not rosiglitazone, also induced the expression of TGM2 (an RXR target) and ABCA1 (a liver X receptor target). The results show that an environmental contaminant, acting with the same potency as a therapeutic drug, induces PPARγ-dependent adipocyte differentiation in bone marrow MSCs. Activation of multiple nuclear receptor pathways by organotins may have significant implications for bone physiology. PMID:21622945

Donepezil prevents RANK-induced bone loss via inhibition of osteoclast differentiation by downregulating acetylcholinesterase

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Tsuyoshi Sato

2015-09-01

Conclusions: AChE promotes osteoclast differentiation in vitro. Donepezil inhibits osteoclast function in vitro and prevents bone loss by suppressing bone resorption in vivo, suggesting the possibility that donepezil reduces fracture risk in patients with Alzheimer's disease.

Synergetic effect of topological cue and periodic mechanical tension-stress on osteogenic differentiation of rat bone mesenchymal stem cells.

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Liu, Yao; Yang, Guang; Ji, Huanzhong; Xiang, Tao; Luo, En; Zhou, Shaobing

2017-06-01

Mesenchymal stem cells (MSCs) are able to self-renew and differentiate into tissues of mesenchymal origin, making them to be significant for cell-based therapies, such as metabolic bone diseases and bone repair. Regulating the differentiation of MSCs is significant for bone regeneration. Electrospun fibers mimicking natural extracellular matrix (ECM), is an effective artificial ECM to regulate the behaviors and fates of MSCs. The aligned electrospun fibers can modulate polar cell pattern of bone mesenchymal stem cells, which leads to more obvious osteogenic differentiation. Apart from the topographic effect of electrospun fibers, mechanical cues can also intervene the cell behaviors. In this study, the osteogenic differentiation of rat bone mesenchymal stem cells was evaluated, which were cultured on aligned/random electrospun fiber mats materials under mechanical tension intervention. Scanning electron microscope and immune-fluorescent staining were used to directly observe the polarity changing of cellular morphology and cytoskeleton. The results proved that aligned electrospun fibers could be more conducive to promote osteogenic differentiation of rat bone mesenchymal stem cells and this promotion of osteogenic differentiation was enhanced by tension intervention. These results were correlated to the quantitative real-time PCR assay. In general, culturing rat bone mesenchymal stem cells on electrospun fibers under the intervention of mechanical tension is an effective way to mimic a more real cellular microenvironment. Copyright © 2017 Elsevier B.V. All rights reserved.

Using Natural Stable Calcium Isotopes to Rapidly Assess Changes in Bone Mineral Balance Using a Bed Rest Model to Induce Bone Loss

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Morgan, J. L. L.; Skulan, J. L.; Gordon, G. E.; Smith, Scott M.; Romaniello, S. J.; Anbar, A. D.

2012-01-01

Metabolic bone diseases like osteoporosis result from the disruption of normal bone mineral balance (BMB) resulting in bone loss. During spaceflight astronauts lose substantial bone. Bed rest provides an analog to simulate some of the effects of spaceflight; including bone and calcium loss and provides the opportunity to evaluate new methods to monitor BMB in healthy individuals undergoing environmentally induced-bone loss. Previous research showed that natural variations in the Ca isotope ratio occur because bone formation depletes soft tissue of light Ca isotopes while bone resorption releases that isotopically light Ca back into soft tissue (Skulan et al, 2007). Using a bed rest model, we demonstrate that the Ca isotope ratio of urine shifts in a direction consistent with bone loss after just 7 days of bed rest, long before detectable changes in bone mineral density (BMD) occur. The Ca isotope variations tracks changes observed in urinary N-teleopeptide, a bone resorption biomarker. Bone specific alkaline phosphatase, a bone formation biomarker, is unchanged. The established relationship between Ca isotopes and BMB can be used to quantitatively translate the changes in the Ca isotope ratio to changes in BMD using a simple mathematical model. This model predicts that subjects lost 0.25 0.07% ( SD) of their bone mass from day 7 to day 30 of bed rest. Given the rapid signal observed using Ca isotope measurements and the potential to quantitatively assess bone loss; this technique is well suited to study the short-term dynamics of bone metabolism.

Nanoceramics on osteoblast proliferation and differentiation in bone tissue engineering.

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Sethu, Sai Nievethitha; Namashivayam, Subhapradha; Devendran, Saravanan; Nagarajan, Selvamurugan; Tsai, Wei-Bor; Narashiman, Srinivasan; Ramachandran, Murugesan; Ambigapathi, Moorthi

2017-05-01

Bone, a highly dynamic connective tissue, consist of a bioorganic phase comprising osteogenic cells and proteins which lies over an inorganic phase predominantly made of CaPO 4 (biological apatite). Injury to bone can be due to mechanical, metabolic or inflammatory agents also owing pathological conditions like fractures, osteomyelitis, osteolysis or cysts may arise in enameloid, chondroid, cementum, or chondroid bone which forms the intermediate tissues of the body. Bone tissue engineering (BTE) applies bioactive scaffolds, host cells and osteogenic signals for restoring damaged or diseased tissues. Various bioceramics used in BTE can be bioactive (like glass ceramics and hydroxyapatite bioactive glass), bioresorbable (like tricalcium phosphates) or bioinert (like zirconia and alumina). Limiting the size of these materials to nano-scale has resulted in a higher surface area to volume ratio thereby improving multi-functionality, solubility, surface catalytic activity, high heat and electrical conductivity. Nanoceramics have been found to induce osteoconduction, osteointegration, osteogenesis and osteoinduction. The present review aims at summarizing the interactions of nanoceramics and osteoblast/stem cells for promoting the proliferation and differentiation of the osteoblast cells by nanoceramics as superior bone substitutes in bone tissue engineering applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Legumain Regulates Differentiation Fate of Human Bone Marrow Stromal Cells and Is Altered in Postmenopausal Osteoporosis

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Abbas Jafari

2017-02-01

Full Text Available Secreted factors are a key component of stem cell niche and their dysregulation compromises stem cell function. Legumain is a secreted cysteine protease involved in diverse biological processes. Here, we demonstrate that legumain regulates lineage commitment of human bone marrow stromal cells and that its expression level and cellular localization are altered in postmenopausal osteoporotic patients. As shown by genetic and pharmacological manipulation, legumain inhibited osteoblast (OB differentiation and in vivo bone formation through degradation of the bone matrix protein fibronectin. In addition, genetic ablation or pharmacological inhibition of legumain activity led to precocious OB differentiation and increased vertebral mineralization in zebrafish. Finally, we show that localized increased expression of legumain in bone marrow adipocytes was inversely correlated with adjacent trabecular bone mass in a cohort of patients with postmenopausal osteoporosis. Our data suggest that altered proteolytic activity of legumain in the bone microenvironment contributes to decreased bone mass in postmenopausal osteoporosis.

Latexin is involved in bone morphogenetic protein-2-induced chondrocyte differentiation

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Kadouchi, Ichiro; Sakamoto, Kei; Tangjiao, Liu; Murakami, Takashi; Kobayashi, Eiji; Hoshino, Yuichi; Yamaguchi, Akira

2009-01-01

Latexin is the only known carboxypeptidase A inhibitor in mammals. We previously demonstrated that BMP-2 significantly induced latexin expression in Runx2-deficient mesenchymal cells (RD-C6 cells), during chondrocyte and osteoblast differentiation. In this study, we investigated latexin expression in the skeleton and its role in chondrocyte differentiation. Immunohistochemical studies revealed that proliferating and prehypertrophic chondrocytes expressed latexin during skeletogenesis and bone fracture repair. In the early phase of bone fracture, latexin mRNA expression was dramatically upregulated. BMP-2 upregulated the expression of the mRNAs of latexin, Col2a1, and the gene encoding aggrecan (Agc1) in a micromass culture of C3H10T1/2 cells. Overexpression of latexin additively stimulated the BMP-2-induced expression of the mRNAs of Col2a, Agc1, and Col10a1. BMP-2 treatment upregulated Sox9 expression, and Sox9 stimulated the promoter activity of latexin. These results indicate that latexin is involved in BMP-2-induced chondrocyte differentiation and plays an important role in skeletogenesis and skeletal regeneration.

Effects of developmental exposure to perfluorooctanoic acid (PFOA) on long bone morphology and bone cell differentiation

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Koskela, A., E-mail: antti.koskela@oulu.fi [Institute of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, Faculty of Medicine, University of Oulu, Oulu (Finland); Finnilä, M.A. [Research Unit of Medical Imaging, Physics and Technology, University of Oulu, Oulu (Finland); Korkalainen, M. [National Institute for Health and Welfare, Department of Health Protection, Kuopio (Finland); Spulber, S. [Department of Neuroscience, Karolinska Institutet, Stockholm (Sweden); Koponen, J. [National Institute for Health and Welfare, Department of Health Protection, Kuopio (Finland); Håkansson, H. [Institute of Environmental Medicine, Karolinska Institutet, Stockholm (Sweden); Tuukkanen, J. [Institute of Cancer Research and Translational Medicine, MRC Oulu and Department of Anatomy and Cell Biology, Faculty of Medicine, University of Oulu, Oulu (Finland); Viluksela, M. [National Institute for Health and Welfare, Department of Health Protection, Kuopio (Finland); Department of Environmental and Biological Sciences, University of Eastern Finland, Kuopio (Finland)

2016-06-15

Perfluorooctanoic acid (PFOA) is a ubiquitous and persistent environmental chemical, which has been used extensively due to its stability and surface tension-lowering properties. Toxicological effects include induction of neonatal mortality and reproductive toxicity. In this study, pregnant C57BL/6 mice were exposed orally to 0.3 mg PFOA/kg/day throughout pregnancy, and female offspring were studied at the age of 13 or 17 months. Morphometrical and biomechanical properties of femurs and tibias were analyzed with micro-computed tomography and 3-point bending, and bone PFOA concentrations were determined by mass spectrometry. The effects of PFOA on bone cell differentiation were studied in osteoclasts from C57BL/6 mice and in the MC3T3 pre-osteoblast cell line. PFOA exposed mice showed increased femoral periosteal area as well as decreased mineral density of tibias. Biomechanical properties of these bones were not affected. Bone PFOA concentrations were clearly elevated even at the age of 17 months. In osteoblasts, low concentrations of PFOA increased osteocalcin (OCN) expression and calcium secretion, but at PFOA concentrations of 100 μM and above osteocalcin (OCN) expression and calcium secretion were decreased. The number of osteoclasts was increased at all PFOA concentrations tested and resorption activity dose-dependently increased from 0.1–1.0 μM, but decreased at higher concentrations. The results show that PFOA accumulates in bone and is present in bones until the old age. PFOA has the potential to influence bone turnover over a long period of time. Therefore bone is a target tissue for PFOA, and altered bone geometry and mineral density seem to persist throughout the life of the animal. - Highlights: • Bone is a target tissue for PFOA both in vivo and in vitro. • Maternal exposure during pregnancy results in PFOA accumulation in bone of the offspring. • PFOA is present in bones until the old age. • PFOA causes mild alterations in bone morphometry

Effects of developmental exposure to perfluorooctanoic acid (PFOA) on long bone morphology and bone cell differentiation

International Nuclear Information System (INIS)

Koskela, A.; Finnilä, M.A.; Korkalainen, M.; Spulber, S.; Koponen, J.; Håkansson, H.; Tuukkanen, J.; Viluksela, M.

2016-01-01

Perfluorooctanoic acid (PFOA) is a ubiquitous and persistent environmental chemical, which has been used extensively due to its stability and surface tension-lowering properties. Toxicological effects include induction of neonatal mortality and reproductive toxicity. In this study, pregnant C57BL/6 mice were exposed orally to 0.3 mg PFOA/kg/day throughout pregnancy, and female offspring were studied at the age of 13 or 17 months. Morphometrical and biomechanical properties of femurs and tibias were analyzed with micro-computed tomography and 3-point bending, and bone PFOA concentrations were determined by mass spectrometry. The effects of PFOA on bone cell differentiation were studied in osteoclasts from C57BL/6 mice and in the MC3T3 pre-osteoblast cell line. PFOA exposed mice showed increased femoral periosteal area as well as decreased mineral density of tibias. Biomechanical properties of these bones were not affected. Bone PFOA concentrations were clearly elevated even at the age of 17 months. In osteoblasts, low concentrations of PFOA increased osteocalcin (OCN) expression and calcium secretion, but at PFOA concentrations of 100 μM and above osteocalcin (OCN) expression and calcium secretion were decreased. The number of osteoclasts was increased at all PFOA concentrations tested and resorption activity dose-dependently increased from 0.1–1.0 μM, but decreased at higher concentrations. The results show that PFOA accumulates in bone and is present in bones until the old age. PFOA has the potential to influence bone turnover over a long period of time. Therefore bone is a target tissue for PFOA, and altered bone geometry and mineral density seem to persist throughout the life of the animal. - Highlights: • Bone is a target tissue for PFOA both in vivo and in vitro. • Maternal exposure during pregnancy results in PFOA accumulation in bone of the offspring. • PFOA is present in bones until the old age. • PFOA causes mild alterations in bone morphometry

Usefulness of serum bone metabolic markers for the diagnosis of differentiated thyroid cancer with bone metastases

International Nuclear Information System (INIS)

Wu Xiaohui; Lu Hankui; Gao Yunchao; Yuan Zhibin

2007-01-01

Objective: Bone metabolic markers (BMM) are biochemical substances that reflect bone resorption or formation. Some of them have been found to be useful in the diagnosis and management of bone metastases. The aim of this study was to investigate the usefulness of two bone resorption markers: bone-specific alkaline phosphatase (B-ALP) and N-terminal procollagen propeptides of type I collagen (PINP), as well as two bone formation markers: cross linked N and C terminal telepeptides of type I collagen (NTX and CTX) in the detection of bone metastasis in patients with differentiated thyroid cancer (DTC). Methods: There were sixty-three DTC patients in this study, 33 cases with clinically confirmed bone metastases and 30 cases with no bone metastases. The extents of bone metastases (or extents of the disease, EOD) were classified into four grades (0, I, II and III) according to the clinical and imaging findings including 99 Tc m -MDP, 131 I whole body scans and others. Serum BMM levels were measured by chemiluminescence immunoassay for B-ALP, radioimmunoassay for PINP, ELISA for NTX and electrochemiluminescence immunoassay for CTX. Nonparametric Mann-Whitney U test, grade correlation analysis and receiver operator characteristic (ROC) curve were applied to analyze the correlation between BMM and DTC patients with bone metastases. Results: The serum levels of B-ALP, NTX and CTX were significantly higher in DTC patients with bone metastases than those in patients with no bone metastases (all P 0.05). The serum levels of all markers were correlated with EOD grades (r s =0.371-0.558, all P<0.01). B-ALP level was found to have significant difference between EOD 0 to I (P=0.012). The diagnostic sensitivity and specificity of B-ALP for detecting DTC with bone metastases were 71.1% and 76.7% respectively by ROC curve analysis, which were higher than those of the other three markers. Conclusions: Serum BMM levels of B-ALP, NTX and CTX were useful for the evaluation of DTC with

Sensitivity of tissue differentiation and bone healing predictions to tissue properties

NARCIS (Netherlands)

Isaksson, H.E.; Donkelaar, van C.C.; Ito, K.

2009-01-01

Computational models are employed as tools to investigate possible mechano-regulation pathways for tissue differentiation and bone healing. However, current models do not account for the uncertainty in input parameters, and often include assumptions about parameter values that are not yet

Safflower bud inhibits RANKL-induced osteoclast differentiation and prevents bone loss in ovariectomized mice.

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Choi, Joo-Hee; Lim, Seul-Ki; Kim, Dong-Il; Park, Min-Jung; Kim, Young-Kuk; Lee, An-Chul; Kim, Young-Min; Yang, Soo-Jin; Park, Jong-Hwan

2017-10-15

The powder and extract of safflower seeds are known to be effective in the prevention of bone loss in ovariectomized animals. However, the inhibitory effect and molecular mechanisms of safflower bud (SB), the germinated safflower, on bone destruction is unclear. The present study was designed to investigate the inhibitory effect and molecular mechanism of SB on osteoclastic differentiation and on bone loss in ovarietomized (OVX) mice. Osteoclastogenesis was determined by TRAP staining, F-actin ring formation, and bone resorption assay. NF-κB and MAPKs activation was analyzed by transfection assay and Western blot, respectively. Real-time PCR was performed to examine the expression of osteoclastogenesis-related genes. Histological changes, increases in TRAP-positive cells, and cathepsin K expression were examined in the metaphysis of OVX mice. Density of bone marrow was evaluated by µCT. SB inhibited the RANKL-induced differentiation of BMDMs into osteoclasts in a dose-dependent manner. F-actin ring formation and bone resorption were also reduced by SB in RANKL-treated BMDMs. In addition, SB decreased the activation of NF-κB and MAPKs and the expression of osteoclastogenesis-related genes in BMDMs treated with RANKL. Feeding of SB-included diet prevented bone loss in OVX mice. The number of TRAP-positive cells and level of protein expression of cathepsin K was reduced and bone mineral density was increased in the metaphysis of mice fed SB compared with OVX mice. These findings suggest that SB can be a preventive and therapeutic candidate for destructive bone diseases. Copyright © 2017. Published by Elsevier GmbH.

Bone remodelling: its local regulation and the emergence of bone fragility.

Science.gov (United States)

Martin, T John; Seeman, Ego

2008-10-01

Bone modelling prevents the occurrence of damage by adapting bone structure - and hence bone strength - to its loading circumstances. Bone remodelling removes damage, when it inevitably occurs, in order to maintain bone strength. This cellular machinery is successful during growth, but fails during advancing age because of the development of a negative balance between the volumes of bone resorbed and formed during remodelling by the basic multicellular unit (BMU), high rates of remodelling during midlife in women and late in life in both sexes, and a decline in periosteal bone formation. together resulting in bone loss and structural decay each time a remodelling event occurs. The two steps in remodelling - resorption of a volume of bone by osteoclasts and formation of a comparable volume by osteoblasts - are sequential, but the regulatory events leading to these two fully differentiated functions are not. Reparative remodelling is initiated by damage producing osteocyte apoptosis, which signals the location of damage via the osteocyte canalicular system to endosteal lining cells which forms the canopy of a bone-remodelling compartment (BRC). Within the BRC, local recruitment of osteoblast precursors from the lining cells, the marrow and circulation, direct contact with osteoclast precursors, osteoclastogenesis and molecular cross-talk between precursors, mature cells, cells of the immune system, and products of the resorbed matrix, titrate the birth, work and lifespan of the cells of this multicellular remodelling machinery to either remove or form a net volume of bone appropriate to the mechanical requirements.

Multilineage differentiation of porcine bone marrow stromal cells associated with specific gene expression pattern

DEFF Research Database (Denmark)

Zou, Lijin; Zou, Xuenong; Chen, Li

2007-01-01

There are increasing reports regarding differentiation of bone marrow stromal cells (BMSC) from human and various species of animals including pigs. The phenotype and function of BMSC along a mesenchymal lineage differentiation are well characterized by specific transcription factors and marker g...

Platelet-Poor and Platelet-Rich Plasma Stimulate Bone Lineage Differentiation in Periodontal Ligament Stem Cells.

Science.gov (United States)

Martínez, Constanza E; González, Sergio A; Palma, Verónica; Smith, Patricio C

2016-02-01

Plasma-derived fractions have been used as an autologous source of growth factors; however, limited knowledge concerning their biologic effects has hampered their clinical application. In this study, the authors analyze the content and specific effect of both platelet-rich plasma (PRP) and platelet-poor plasma (PPP) on osteoblastic differentiation using primary cultures of human periodontal ligament stem cells (HPLSCs). The authors evaluated the growth factor content of PRP and PPP using a proteome profiler array and enzyme-linked immunosorbent assay. HPLSCs were characterized by flow cytometry and differentiation assays. The effect of PRP and PPP on HPLSC bone differentiation was analyzed by quantifying calcium deposition after 14 and 21 days of treatment. Albeit at different concentrations, the two fractions had similar profiles of growth factors, the most representative being platelet-derived growth factor (PDGF) isoforms (PDGF-AA, -BB, and -AB), insulin-like growth factor binding protein (IGFBP)-2, and IGFBP-6. Both formulations exerted a comparable stimulus on osteoblastic differentiation even at low doses (2.5%), increasing calcium deposits in HPLSCs. PRP and PPP showed a similar protein profile and exerted comparable effects on bone differentiation. Further studies are needed to characterize and compare the effects of PPP and PRP on bone healing in vivo.

Peptide-laden mesoporous silica nanoparticles with promoted bioactivity and osteo-differentiation ability for bone tissue engineering.

Science.gov (United States)

Luo, Zuyuan; Deng, Yi; Zhang, Ranran; Wang, Mengke; Bai, Yanjie; Zhao, Qiang; Lyu, Yalin; Wei, Jie; Wei, Shicheng

2015-07-01

Combination of mesoporous silica materials and bioactive factors is a promising niche-mimetic solution as a hybrid bone substitution for bone tissue engineering. In this work, we have synthesized biocompatible silica-based nanoparticles with abundant mesoporous structure, and incorporated bone-forming peptide (BFP) derived from bone morphogenetic protein-7 (BMP-7) into the mesoporous silica nanoparticles (MSNs) to obtain a slow-release system for osteogenic factor delivery. The chemical characterization demonstrates that the small osteogenic peptide is encapsulated in the mesoporous successfully, and the nitrogen adsorption-desorption isotherms suggest that the peptide encapsulation has no influence on mesoporous structure of MSNs. In the cell experiment, the peptide-laden MSNs (p-MSNs) show higher MG-63 cell proliferation, spreading and alkaline phosphatase (ALP) activity than the bare MSNs, indicating good in vitro cytocompatibility. Simultaneously, the osteogenesis-related proteins expression and calcium mineral deposition disclose enhanced osteo-differentiation of human mesenchymal stem cells (hMSCs) under the stimulation of the p-MSNs, confirming that BFP released from MSNs could significantly promote the osteogenic differentiation of hMSCs, especially at 500μg/mL of p-MSNs concentration. The peptide-modified MSNs with better bioactivity and osteogenic differentiation make it a potential candidate as bioactive material for bone repairing, bone regeneration, and bio-implant coating applications. Copyright © 2015 Elsevier B.V. All rights reserved.

Kaempferol-immobilized titanium dioxide promotes formation of new bone: effects of loading methods on bone marrow stromal cell differentiation in vivo and in vitro.

Science.gov (United States)

Tsuchiya, Shuhei; Sugimoto, Keisuke; Kamio, Hisanobu; Okabe, Kazuto; Kuroda, Kensuke; Okido, Masazumi; Hibi, Hideharu

2018-01-01

Surface modification of titanium dioxide (TiO 2 ) implants promotes bone formation and shortens the osseointegration period. Kaempferol is a flavonoid that has the capacity to promote osteogenic differentiation in bone marrow stromal cells. The aim of this study was to promote bone formation around kaempferol immobilized on TiO 2 implants. There were four experimental groups. Alkali-treated TiO 2 samples (implants and discs) were used as a control and immersed in Dulbecco's phosphate-buffered saline (DPBS) (Al-Ti). For the coprecipitation sample (Al-cK), the control samples were immersed in DPBS containing 50 µg kaempferol/100% ethanol. For the adsorption sample (Al-aK), 50 µg kaempferol/100% ethanol was dropped onto control samples. The surface topography of the TiO 2 implants was observed by scanning electron microscopy with energy-dispersive X-ray spectroscopy, and a release assay was performed. For in vitro experiments, rat bone marrow stromal cells (rBMSCs) were cultured on each of the TiO 2 samples to analyze cell proliferation, alkaline phosphatase activity, calcium deposition, and osteogenic differentiation. For in vivo experiments, TiO 2 implants placed on rat femur bones were analyzed for bone-implant contact by histological methods. Kaempferol was detected on the surface of Al-cK and Al-aK. The results of the in vitro study showed that rBMSCs cultured on Al-cK and Al-aK promoted alkaline phosphatase activity, calcium deposition, and osteogenic differentiation. The in vivo histological analysis revealed that Al-cK and Al-aK stimulated new bone formation around implants. TiO 2 implant-immobilized kaempferol may be an effective tool for bone regeneration around dental implants.

Smurf1 Inhibits Osteoblast Differentiation, Bone Formation, and Glucose Homeostasis through Serine 148

Directory of Open Access Journals (Sweden)

Junko Shimazu

2016-04-01

Full Text Available The E3 ubiquitin ligase Smurf1 targets the master regulator of osteoblast differentiation, Runx2, for degradation, yet the function of Smurf1, if any, during osteoblast differentiation in vivo is ill defined. Here, we show that Smurf1 prevents osteoblast differentiation by decreasing Runx2 accumulation in osteoblasts. Remarkably, mice harboring a substitution mutation at serine 148 (S148 in Smurf1 that prevents its phosphorylation by AMPK (Smurf1ki/ki display a premature osteoblast differentiation phenotype that is equally severe as that of Smurf1−/− mice, as well as a high bone mass, and are also hyperinsulinemic and hypoglycemic. Consistent with the fact that Smurf1 targets the insulin receptor for degradation, there is, in Smurf1ki/ki mice, an increase in insulin signaling in osteoblasts that triggers a rise in the circulating levels of osteocalcin, a hormone that favors insulin secretion. These results identify Smurf1 as a determinant of osteoblast differentiation during the development of bone formation and glucose homeostasis post-natally and demonstrate the necessity of S148 for these functions.

Differentiation of malignant and degenerative bone lesions using dexamethasone interventional 3- and 24-hour bone scintigraphy

International Nuclear Information System (INIS)

Bhatnagar, A.; Mondal, A.; Kashyap, R.; Sharma, R.K.; Sharma, R.; Chakravarty, S.K.; Bihari, V.; Sawroop, K.; Chopra, M.K.; Soni, N.L.

1994-01-01

Seventy-seven adult patients with suspected skeletal metastases were divided into two groups. In group A (n=30), following intravenous administration of 20 mCi (740 MBq) of technetium-99m methylene diphosphonate ( 99m Tc-MDP), 3- and 24-h scintigraphy of bone lesions was performed. The 24/3 h lesion to bone background radiouptake ratio (RUR) was calculated for each lesion. In group B (n=47), the same procedure was followed with dexamethasone intervention (10 mg in 24 h) following the 3-h acquisition. In group A, after determination of the critical point, malignant and degenerative bone lesions could be separated with a sensitivity, specificity and accuracy of 0.76, 0.72 and 0.73, respectively. The mean RUR of the malignant lesions was 1.20± 0.23, and that of the benign lesions, 0.95± 0.15. In group B cases, significantly increased sensitivity, specificity and accuracy of 0.87, 0.94 and 0.92, respectively, were found (P<0.001). The mean RUR of the malignant lesions was 1.48± 0.34, and that of degenerative lesions, 0.88± 0.19. Dexamethasone interventional bone scintigraphy seems to be a new cost-effective method for differentiating malignant from degenerative bone lesions using the RUR. (orig.)

Antiosteoporotic Activity of Dioscorea alata L. cv. Phyto through Driving Mesenchymal Stem Cells Differentiation for Bone Formation

Directory of Open Access Journals (Sweden)

Kang-Yung Peng

2011-01-01

Full Text Available The aim of this study was to evaluate the effect of an ethanol extract of the rhizomes of Dioscorea alata L. cv. Phyto, Dispo85E, on bone formation and to investigate the mechanisms involved. Our results showed that Dispo85E increased the activity of alkaline phosphatase (ALP and bone nodule formation in primary bone marrow cultures. In addition, Dispo85E stimulated pluripotent C3H10T1/2 stem cells to differentiate into osteoblasts rather than adipocytes. Our in vivo data indicated that Dispo85E promotes osteoblastogenesis by increasing ALP activity and bone nodule formation in both intact and ovariectomized (OVX mice. Microcomputed tomography (μCT analysis also showed that Dispo85E ameliorates the deterioration of trabecular bone mineral density (tBMD, trabecular bone volume/total volume (BV/TV, and trabecular bone number (Tb.N in OVX mice. Our results suggested that Dispo85E is a botanical drug with a novel mechanism that drives the lineage-specific differentiation of bone marrow stromal cells and is a candidate drug for osteoporosis therapy.

The Src inhibitor dasatinib accelerates the differentiation of human bone marrow-derived mesenchymal stromal cells into osteoblasts

International Nuclear Information System (INIS)

Id Boufker, Hichame; Lagneaux, Laurence; Najar, Mehdi; Piccart, Martine; Ghanem, Ghanem; Body, Jean-Jacques; Journé, Fabrice

2010-01-01

The proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined. We evaluated the effects of dasatinib on bone marrow-derived mesenchymal stromal cells (MSC) differentiation into osteoblasts, in the presence or absence of a mixture of dexamethasone, ascorbic acid and β-glycerophosphate (DAG) for up to 21 days. The differentiation kinetics was assessed by evaluating mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers (receptor activator of nuclear factor kappa B ligand [RANKL], bone sialoprotein [BSP], osteopontin [OPN]). Dasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after, respectively, 7 and 14 days; it upregulated the expression of BSP and OPN genes independently of DAG; and it markedly downregulated the expression of RANKL gene and protein (decrease in RANKL/OPG ratio), the key factor that stimulates osteoclast differentiation and activity. Our results suggest a dual role for dasatinib in both (i) stimulating osteoblast differentiation leading to a direct increase in bone formation, and (ii) downregulating RANKL synthesis by osteoblasts leading to an indirect inhibition of osteoclastogenesis. Thus, dasatinib is a potentially interesting candidate drug for the treatment of osteolysis through its dual effect on bone metabolism

Benign bone-forming lesions: osteoma, osteoid osteoma, and osteoblastoma; Clinical, imaging, pathologic, and differential considerations

Energy Technology Data Exchange (ETDEWEB)

Greenspan, A. (Depts. of Radiology and Orthopedic Surgery, California Univ., Davis School of Medicine, Sacramento, CA (United States) Section of Musculoskeletal Radiology, UC Davis Medical Center, Sacramento, CA (United States))

1993-10-01

The benign bone lesions - osteoma, osteoid osteoma, and osteoblastoma - are characterized as bone-forming because tumor cells produce osteoid or mature bone. Osteoma is a slow-growing lesion most commonly seen in the paranasal sinuses and in the calvaria. When it occurs in the long bones, it is invariably juxtacortical and may need to be differentiated from, among others, parosteal osteosarcoma, sessile osteochondroma, and a matured juxtacortical focus of myositis ossificans. Osteoid osteoma and osteoblastoma appear histologically very similar. Their clinical presentations and distribution in the skeleton, however, are distinct: osteoid osteoma is usually accompanied by nocturnal pain promptly relieved by salicylates; osteoblastoma arises predominantly in the axial skeleton, spinal lesions constituting one-third of reported cases. This review focuses on the application of the various imaging modalities in the diagnosis, differential diagnosis, and evaluation of these lesions. Their histopathology also is discussed, and their treatment briefly outlined. (orig.)

Bone marker gene expression in calvarial bones: different bone microenvironments.

Science.gov (United States)

Al-Amer, Osama

2017-12-01

In calvarial mice, mesenchymal stem cells (MSCs) differentiate into osteoprogenitor cells and then differentiate into osteoblasts that differentiate into osteocytes, which become embedded within the bone matrix. In this case, the cells participating in bone formation include MSCs, osteoprogenitor cells, osteoblasts and osteocytes. The calvariae of C57BL/KaLwRijHsD mice consist of the following five bones: two frontal bones, two parietal bones and one interparietal bone. This study aimed to analyse some bone marker genes and bone related genes to determine whether these calvarial bones have different bone microenvironments. C57BL/KaLwRijHsD calvariae were carefully excised from five male mice that were 4-6 weeks of age. Frontal, parietal, and interparietal bones were dissected to determine the bone microenvironment in calvariae. Haematoxylin and eosin staining was used to determine the morphology of different calvarial bones under microscopy. TaqMan was used to analyse the relative expression of Runx2, OC, OSX, RANK, RANKL, OPG, N-cadherin, E-cadherin, FGF2 and FGFR1 genes in different parts of the calvariae. Histological analysis demonstrated different bone marrow (BM) areas between the different parts of the calvariae. The data show that parietal bones have the smallest BM area compared to frontal and interparietal bones. TaqMan data show a significant increase in the expression level of Runx2, OC, OSX, RANKL, OPG, FGF2 and FGFR1 genes in the parietal bones compared with the frontal and interparietal bones of calvariae. This study provides evidence that different calvarial bones, frontal, parietal and interparietal, contain different bone microenvironments.

CUDC-907 Promotes Bone Marrow Adipocytic Differentiation Through Inhibition of Histone Deacetylase and Regulation of Cell Cycle.

Science.gov (United States)

Ali, Dalia; Alshammari, Hassan; Vishnubalaji, Radhakrishnan; Chalisserry, Elna Paul; Hamam, Rimi; Alfayez, Musaad; Kassem, Moustapha; Aldahmash, Abdullah; Alajez, Nehad M

2017-03-01

The role of bone marrow adipocytes (BMAs) in overall energy metabolism and their effects on bone mass are currently areas of intensive investigation. BMAs differentiate from bone marrow stromal cells (BMSCs); however, the molecular mechanisms regulating BMA differentiation are not fully understood. In this study, we investigated the effect of CUDC-907, identified by screening an epigenetic small-molecule library, on adipocytic differentiation of human BMSCs (hBMSCs) and determined its molecular mechanism of action. Human bone marrow stromal cells exposed to CUDC-907 (500 nM) exhibited enhanced adipocytic differentiation (∼2.9-fold increase, P < 0.005) compared with that of control cells. Global gene expression and signaling pathway analyses of differentially expressed genes revealed a strong enrichment of genes involved in adipogenesis, cell cycle, and DNA replication. Chromatin immune precipitation combined with quantitative polymerase chain reaction showed significant increase in H3K9ac epigenetic marker in the promoter regions of AdipoQ, FABP4, PPARγ, KLF15, and CEBPA in CUDC-907-treated hBMSCs. Follow-up experiments corroborated that the inhibition of histone deacetylase (HDAC) activity enhanced adipocytic differentiation, while the inhibition of PI3K decreased adipocytic differentiation. In addition, CUDC-907 arrested hBMSCs in the G0-G1 phase of the cell cycle and reduced the number of S-phase cells. Our data reveal that HDAC, PI3K, and cell cycle genes are important regulators of BMA formation and demonstrate that adipocyte differentiation of hBMSCs is associated with complex changes in a number of epigenetic and genetic pathways, which can be targeted to regulate BMA formation.

Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance.

Science.gov (United States)

Stern, Tomer; Aviram, Rona; Rot, Chagai; Galili, Tal; Sharir, Amnon; Kalish Achrai, Noga; Keller, Yosi; Shahar, Ron; Zelzer, Elazar

2015-08-01

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of

Isometric Scaling in Developing Long Bones Is Achieved by an Optimal Epiphyseal Growth Balance

Science.gov (United States)

Stern, Tomer; Aviram, Rona; Rot, Chagai; Galili, Tal; Sharir, Amnon; Kalish Achrai, Noga; Keller, Yosi; Shahar, Ron; Zelzer, Elazar

2015-01-01

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of

A well-balanced diet combined or not with exercise induces fat mass loss without any decrease of bone mass despite bone micro-architecture alterations in obese rat.

Science.gov (United States)

Gerbaix, Maude; Metz, Lore; Mac-Way, Fabrice; Lavet, Cédric; Guillet, Christelle; Walrand, Stéphane; Masgrau, Aurélie; Vico, Laurence; Courteix, Daniel

2013-04-01

The association of a well-balanced diet with exercise is a key strategy to treat obesity. However, weight loss is linked to an accelerated bone loss. Furthermore, exercise is known to induce beneficial effects on bone. We investigated the impact of a well-balanced isoenergetic reducing diet (WBR) and exercise on bone tissue in obese rats. Sixty male rats had previously been fed with a high fat/high sucrose diet (HF/HS) for 4months to induce obesity. Then, 4 regimens were initiated for 2months: HF/HS diet plus exercise (treadmill: 50min/day, 5days/week), WBR diet plus exercise, HF/HS diet plus inactivity and WBR diet plus inactivity. Body composition and total BMD were assessed using DXA and visceral fat mass was weighed. Tibia densitometry was assessed by Piximus. Bone histomorphometry was performed on the proximal metaphysis of tibia and on L2 vertebrae (L2). Trabecular micro-architectural parameters were measured on tibia and L2 by 3D microtomography. Plasma concentration of osteocalcin and CTX were measured. Both WBR diet and exercise had decreased global weight, global fat and visceral fat mass (pdiet alone failed to alter total and tibia bone mass and BMD. However, Tb.Th, bone volume density and degree of anisotropy of tibia were decreased by the WBR diet (pdiet had involved a significant lower MS/BS and BFR/BS in L2 (pdiet inducing weight and fat mass losses did not affected bone mass and BMD of obese rats despite alterations of their bone micro-architecture. The moderate intensity exercise performed had improved the tibia BMD of obese rats without any trabecular and cortical adaptation. Copyright © 2013 Elsevier Inc. All rights reserved.

Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells.

Science.gov (United States)

Garba, Abubakar; Acar, Delphine D; Roukaerts, Inge D M; Desmarets, Lowiese M B; Devriendt, Bert; Nauwynck, Hans J

2017-09-01

Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell

Utility of unenhanced fat-suppressed T1-weighted MRI in children with sickle cell disease -- can it differentiate bone infarcts from acute osteomyelitis?

Science.gov (United States)

Delgado, Jorge; Bedoya, Maria A; Green, Abby M; Jaramillo, Diego; Ho-Fung, Victor

2015-12-01

Children with sickle cell disease (SCD) are at risk of bone infarcts and acute osteomyelitis. The clinical differentiation between a bone infarct and acute osteomyelitis is a diagnostic challenge. Unenhanced T1-W fat-saturated MR images have been proposed as a potential tool to differentiate bone infarcts from osteomyelitis. To evaluate the reliability of unenhanced T1-W fat-saturated MRI for differentiation between bone infarcts and acute osteomyelitis in children with SCD. We retrospectively reviewed the records of 31 children (20 boys, 11 girls; mean age 10.6 years, range 1.1-17.9 years) with SCD and acute bone pain who underwent MR imaging including unenhanced T1-W fat-saturated images from 2005 to 2010. Complete clinical charts were reviewed by a pediatric hematologist with training in infectious diseases to determine a clinical standard to define the presence or absence of osteomyelitis. A pediatric radiologist reviewed all MR imaging and was blinded to clinical information. Based on the signal intensity in T1-W fat-saturated images, the children were further classified as positive for osteomyelitis (low bone marrow signal intensity) or positive for bone infarct (high bone marrow signal intensity). Based on the clinical standard, 5 children were classified as positive for osteomyelitis and 26 children as positive for bone infarct (negative for osteomyelitis). The bone marrow signal intensity on T1-W fat-saturated imaging was not significant for the differentiation between bone infarct and osteomyelitis (P = 0.56). None of the additional evaluated imaging parameters on unenhanced MRI proved reliable in differentiating these diagnoses. The bone marrow signal intensity on unenhanced T1-W fat-saturated MR images is not a reliable criterion to differentiate bone infarcts from osteomyelitis in children.

Utility of unenhanced fat-suppressed T1-weighted MRI in children with sickle cell disease - can it differentiate bone infarcts from acute osteomyelitis?

International Nuclear Information System (INIS)

Delgado, Jorge; Bedoya, Maria A.; Green, Abby M.; Jaramillo, Diego; Ho-Fung, Victor

2015-01-01

Children with sickle cell disease (SCD) are at risk of bone infarcts and acute osteomyelitis. The clinical differentiation between a bone infarct and acute osteomyelitis is a diagnostic challenge. Unenhanced T1-W fat-saturated MR images have been proposed as a potential tool to differentiate bone infarcts from osteomyelitis. To evaluate the reliability of unenhanced T1-W fat-saturated MRI for differentiation between bone infarcts and acute osteomyelitis in children with SCD. We retrospectively reviewed the records of 31 children (20 boys, 11 girls; mean age 10.6 years, range 1.1-17.9 years) with SCD and acute bone pain who underwent MR imaging including unenhanced T1-W fat-saturated images from 2005 to 2010. Complete clinical charts were reviewed by a pediatric hematologist with training in infectious diseases to determine a clinical standard to define the presence or absence of osteomyelitis. A pediatric radiologist reviewed all MR imaging and was blinded to clinical information. Based on the signal intensity in T1-W fat-saturated images, the children were further classified as positive for osteomyelitis (low bone marrow signal intensity) or positive for bone infarct (high bone marrow signal intensity). Based on the clinical standard, 5 children were classified as positive for osteomyelitis and 26 children as positive for bone infarct (negative for osteomyelitis). The bone marrow signal intensity on T1-W fat-saturated imaging was not significant for the differentiation between bone infarct and osteomyelitis (P = 0.56). None of the additional evaluated imaging parameters on unenhanced MRI proved reliable in differentiating these diagnoses. The bone marrow signal intensity on unenhanced T1-W fat-saturated MR images is not a reliable criterion to differentiate bone infarcts from osteomyelitis in children. (orig.)

Utility of unenhanced fat-suppressed T1-weighted MRI in children with sickle cell disease - can it differentiate bone infarcts from acute osteomyelitis?

Energy Technology Data Exchange (ETDEWEB)

Delgado, Jorge; Bedoya, Maria A. [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Green, Abby M. [The Children' s Hospital of Philadelphia, Division of Oncology, Philadelphia, PA (United States); Jaramillo, Diego; Ho-Fung, Victor [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA (United States)

2015-12-15

Children with sickle cell disease (SCD) are at risk of bone infarcts and acute osteomyelitis. The clinical differentiation between a bone infarct and acute osteomyelitis is a diagnostic challenge. Unenhanced T1-W fat-saturated MR images have been proposed as a potential tool to differentiate bone infarcts from osteomyelitis. To evaluate the reliability of unenhanced T1-W fat-saturated MRI for differentiation between bone infarcts and acute osteomyelitis in children with SCD. We retrospectively reviewed the records of 31 children (20 boys, 11 girls; mean age 10.6 years, range 1.1-17.9 years) with SCD and acute bone pain who underwent MR imaging including unenhanced T1-W fat-saturated images from 2005 to 2010. Complete clinical charts were reviewed by a pediatric hematologist with training in infectious diseases to determine a clinical standard to define the presence or absence of osteomyelitis. A pediatric radiologist reviewed all MR imaging and was blinded to clinical information. Based on the signal intensity in T1-W fat-saturated images, the children were further classified as positive for osteomyelitis (low bone marrow signal intensity) or positive for bone infarct (high bone marrow signal intensity). Based on the clinical standard, 5 children were classified as positive for osteomyelitis and 26 children as positive for bone infarct (negative for osteomyelitis). The bone marrow signal intensity on T1-W fat-saturated imaging was not significant for the differentiation between bone infarct and osteomyelitis (P = 0.56). None of the additional evaluated imaging parameters on unenhanced MRI proved reliable in differentiating these diagnoses. The bone marrow signal intensity on unenhanced T1-W fat-saturated MR images is not a reliable criterion to differentiate bone infarcts from osteomyelitis in children. (orig.)

Acid Balance, Dietary Acid Load, and Bone Effects—A Controversial Subject

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Lynda Frassetto

2018-04-01

Full Text Available Modern Western diets, with higher contents of animal compared to fruits and vegetable products, have a greater content of acid precursors vs. base precursors, which results in a net acid load to the body. To prevent inexorable accumulation of acid in the body and progressively increasing degrees of metabolic acidosis, the body has multiple systems to buffer and titrate acid, including bone which contains large quantities of alkaline salts of calcium. Both in vitro and in vivo studies in animals and humans suggest that bone base helps neutralize part of the dietary net acid load. This raises the question of whether decades of eating a high acid diet might contribute to the loss of bone mass in osteoporosis. If this idea is true, then additional alkali ingestion in the form of net base-producing foods or alkalinizing salts could potentially prevent this acid-related loss of bone. Presently, data exists that support both the proponents as well as the opponents of this hypothesis. Recent literature reviews have tended to support either one side or the other. Assuming that the data cited by both sides is correct, we suggest a way to reconcile the discordant findings. This overview will first discuss dietary acids and bases and the idea of changes in acid balance with increasing age, then review the evidence for and against the usefulness of alkali therapy as a treatment for osteoporosis, and finally suggest a way of reconciling these two opposing points of view.

Erk1 positively regulates osteoclast differentiation and bone resorptive activity.

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Yongzheng He

Full Text Available The extracellular signal-regulated kinases (ERK1 and 2 are widely-expressed and they modulate proliferation, survival, differentiation, and protein synthesis in multiple cell lineages. Altered ERK1/2 signaling is found in several genetic diseases with skeletal phenotypes, including Noonan syndrome, Neurofibromatosis type 1, and Cardio-facio-cutaneous syndrome, suggesting that MEK-ERK signals regulate human skeletal development. Here, we examine the consequence of Erk1 and Erk2 disruption in multiple functions of osteoclasts, specialized macrophage/monocyte lineage-derived cells that resorb bone. We demonstrate that Erk1 positively regulates osteoclast development and bone resorptive activity, as genetic disruption of Erk1 reduced osteoclast progenitor cell numbers, compromised pit formation, and diminished M-CSF-mediated adhesion and migration. Moreover, WT mice reconstituted long-term with Erk1(-/- bone marrow mononuclear cells (BMMNCs demonstrated increased bone mineral density as compared to recipients transplanted with WT and Erk2(-/- BMMNCs, implicating marrow autonomous, Erk1-dependent osteoclast function. These data demonstrate Erk1 plays an important role in osteoclast functions while providing rationale for the development of Erk1-specific inhibitors for experimental investigation and/or therapeutic modulation of aberrant osteoclast function.

Natural Ca Isotope Composition of Urine as a Rapid Measure of Bone Mineral Balance

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Skulan, J.; Gordon, G. W.; Morgan, J.; Romaniello, S. J.; Smith, S. M.; Anbar, A. D.

2011-12-01

Naturally occurring stable Ca isotope variations in urine are emerging as a powerful tool to detect changes in bone mineral balance. Bone formation depletes soft tissue of light Ca isotopes while bone resorption releases isotopically light Ca into soft tissue. Previously published work found that variations in Ca isotope composition could be detected at 4 weeks of bed rest in a 90-day bed rest study (data collected at 4, 8 and 12 weeks). A new 30-day bed rest study involved 12 patients on a controlled diet, monitored for 7 days prior to bed rest and 7 days post bed rest. Samples of urine, blood and food were collected throughout the study. Four times daily blood samples and per void urine samples were collected to monitor diurnal or high frequency variations. An improved chemical purification protocol, followed by measurement using multiple collector inductively coupled plasma mass spectrometry (MC-ICP-MS) allowed accurate and precise determinations of mass-dependent Ca isotope variations in these biological samples to better than ±0.2% (δ44/42Ca) on studies as seen by X-ray measurements. This Ca isotope technique should accelerate the pace of discovery of new treatments for bone disease and provide novel insights into the dynamics of bone metabolism.

SIRT3/SOD2 maintains osteoblast differentiation and bone formation by regulating mitochondrial stress

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Gao, Jing; Feng, Zhihui; Wang, Xueqiang; Zeng, Mengqi; Liu, Jing; Han, Shujun; Xu, Jie; Chen, Lei; Cao, Ke; Long, Jiangang; Li, Zongfang; Shen, Weili; Liu, Jiankang

2017-01-01

Recent studies have revealed robust metabolic changes during cell differentiation. Mitochondria, the organelles where many vital metabolic reactions occur, may play an important role. Here, we report the involvement of SIRT3-regulated mitochondrial stress in osteoblast differentiation and bone formation. In both the osteoblast cell line MC3T3-E1 and primary calvarial osteoblasts, robust mitochondrial biogenesis and supercomplex formation were observed during differentiation, accompanied by in...

Arctigenin suppresses receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow-derived macrophages.

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Kim, A-Ram; Kim, Hyuk Soon; Lee, Jeong Min; Choi, Jung Ho; Kim, Se Na; Kim, Do Kyun; Kim, Ji Hyung; Mun, Se Hwan; Kim, Jie Wan; Jeon, Hyun Soo; Kim, Young Mi; Choi, Wahn Soo

2012-05-05

Osteoclasts, multinucleated bone-resorbing cells, are closely associated with bone diseases such as rheumatoid arthritis and osteoporosis. Osteoclasts are derived from hematopoietic precursor cells, and their differentiation is mediated by two cytokines, including macrophage colony stimulating factor and receptor activator of nuclear factor κB ligand (RANKL). Previous studies have shown that arctigenin exhibits an anti-inflammatory effect. However, the effect of arctigenin on osteoclast differentiation is yet to be elucidated. In this study, we found that arctigenin inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages in a dose-dependent manner and suppressed RANKL-mediated bone resorption. Additionally, the expression of typical marker proteins, such as NFATc1, c-Fos, TRAF6, c-Src, and cathepsin K, were significantly inhibited. Arctigenin inhibited the phosphorylation of Erk1/2, but not p38 and JNK, in a dose-dependent manner. Arctigenin also dramatically suppressed immunoreceptor tyrosine-based activation motif-mediated costimulatory signaling molecules, including Syk and PLCγ2, and Gab2. Notably, arctigenin inhibited the activation of Syk through RANKL stimulation. Furthermore, arctigenin prevented osteoclast differentiation in the calvarial bone of mice following stimulation with lipopolysaccharide. Our results show that arctigenin inhibits osteoclast differentiation in vitro and in vivo. Therefore, arctigenin may be useful for treating rheumatoid arthritis and osteoporosis. Copyright © 2012 Elsevier B.V. All rights reserved.

Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation.

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Tian, Fei; Wu, Mengrui; Deng, Lianfu; Zhu, Guochun; Ma, Junqing; Gao, Bo; Wang, Lin; Li, Yi-Ping; Chen, Wei

2014-07-01

Core binding factor beta (Cbfβ) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbfβ regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbfβ-deficient (Cbfβ(f/f) Prx1-Cre) mice were generated to study the role of Cbfβ in postnatal cartilage and bone development. These mutant mice survived to adulthood but exhibited severe sternum and limb malformations. Sternum ossification was largely delayed in the Cbfβ(f/f) Prx1-Cre mice and the xiphoid process was noncalcified and enlarged. In newborn and 7-day-old Cbfβ(f/f) Prx1-Cre mice, the resting zone was dramatically elongated, the proliferation zone and hypertrophic zone of the growth plates were drastically shortened and disorganized, and trabecular bone formation was reduced. Moreover, in 1-month-old Cbfβ(f/f) Prx1-Cre mice, the growth plates were severely deformed and trabecular bone was almost absent. In addition, Cbfβ deficiency impaired intramembranous bone formation both in vivo and in vitro. Interestingly, although the expression of Indian hedgehog (Ihh) was largely reduced, the expression of parathyroid hormone-related protein (PTHrP) receptor (PPR) was dramatically increased in the Cbfβ(f/f) Prx1-Cre growth plate, indicating that that Cbfβ deficiency disrupted the Ihh-PTHrP negative regulatory loop. Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbfβ complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbfβ complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbfβ-deficient chondrocytes. Taken together, our study reveals not only that Cbfβ is essential for chondrocyte

Investigation of bone and mineral metabolism in hyperthyroidism before and after treatment using calcitonin, 47Ca and balance studies

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Hendriks, J.Th.A.M.; Smeenk, D.

1979-01-01

Seventeen normocalcaemic patients with severe hyperthyroidism were examined before therapy was initiated; 9 were re-examined about 1 year later. Studies with 47 Ca under balance conditions and with calcitonin demonstrated a high rate of bone resorption in untreated patients. As a result of the increased bone turnover, the reaction to 6 MRC units of porcine calcitonin iv was more marked in the untreated than in the treated patients, or the control group. In contrast to the normal diurnal pattern for PO 4 , it was found that during fasting the plasma PO 4 level increases in the morning in patients with hyperthyroidism. This increase which was not suppressed by the administered dose of calcitonin developed in spite of an elevated urinary PO 4 excretion. After treatment, the serum Ca concentration as well as the urinary and faecal Ca excretion was decreased. The Ca balance improved; the rapidly-exchangeable Ca pool returned to normal. The slowly-exchangeable and the total Ca pools, however, remained enlarged. The rate of bone resorption normalized. The accretion rate on the other hand remained elevated. This is attributed to continued enhancement of bone formation to compensate for the previous loss of bony tissue. (author)

MicroRNA-9 promotes the neuronal differentiation of rat bone marrow mesenchymal stem cells by activating autophagy

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Guang-yu Zhang

2015-01-01

Full Text Available MicroRNA-9 (miR-9 has been shown to promote the differentiation of bone marrow mesenchymal stem cells into neuronal cells, but the precise mechanism is unclear. Our previous study confirmed that increased autophagic activity improved the efficiency of neuronal differentiation in bone marrow mesenchymal stem cells. Accumulating evidence reveals that miRNAs adjust the autophagic pathways. This study used miR-9-1 lentiviral vector and miR-9-1 inhibitor to modulate the expression level of miR-9. Autophagic activity and neuronal differentiation were measured by the number of light chain-3 (LC3-positive dots, the ratio of LC3-II/LC3, and the expression levels of the neuronal markers enolase and microtubule-associated protein 2. Results showed that LC3-positive dots, the ratio of LC3-II/LC3, and expression of neuron specific enolase and microtubule-associated protein 2 increased in the miR-9 + group. The above results suggest that autophagic activity increased and bone marrow mesenchymal stem cells were prone to differentiate into neuronal cells when miR-9 was overexpressed, demonstrating that miR-9 can promote neuronal differentiation by increasing autophagic activity.

The inhibitory effect of vitamin K on RANKL-induced osteoclast differentiation and bone resorption.

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Wu, Wei-Jie; Kim, Min Seuk; Ahn, Byung-Yong

2015-10-01

To further understand the correlation between vitamin K and bone metabolism, the effects of vitamins K1, menaquinone-4 (MK-4), and menaquinone-7 (MK-7) on RANKL-induced osteoclast differentiation and bone resorption were comparatively investigated. Vitamin K2 groups (MK-4 and MK-7) were found to significantly inhibit RANKL-medicated osteoclast cell formation of bone marrow macrophages (BMMs) in a dose-dependent manner, without any evidence of cytotoxicity. The mRNA expression of specific osteoclast differentiation markers, such as c-Fos, NFATc1, OSCAR, and TRAP, as well as NFATc1 protein expression and TRAP activity in RANKL-treated BMMs were inhibited by vitamin K2, although MK-4 exhibited a significantly greater efficiency compared to MK-7. In contrast, the same dose of vitamin K1 had no inhibitory effect on RANKL-induced osteoclast cell formation, but increased the expression of major osteoclastogenic genes. Interestingly, vitamins K1, MK-4 and MK-7 all strongly inhibited osteoclastic bone resorption (p vitamins K1, MK-4 and MK-7 have anti-osteoporotic properties, while their regulation effects on osteoclastogenesis are somewhat different.

Combined VEGF and LMP-1 delivery enhances osteoprogenitor cell differentiation and ectopic bone formation.

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Wang, Xiuli; Cui, Fuai; Madhu, Vedavathi; Dighe, Abhijit S; Balian, Gary; Cui, Quanjun

2011-02-01

A novel strategy to enhance bone repair is to combine angiogenic factors and osteogenic factors. We combined vascular endothelial growth factor (VEGF) and LIM mineralization protein-1 (LMP-1) by using an internal ribosome entry site to link the genes within a single plasmid. We then evaluated the effects on osteoblastic differentiation in vitro and ectopic bone formation in vivo with a subcutaneously placed PLAGA scaffold loaded with a cloned mouse osteoprogenitor cell line, D1, transfected with plasmids containing VEGF and LMP-1 genes. The cells expressing both genes elevated mRNA expression of RunX2 and β-catenin and alkaline phosphatase activity compared to cells from other groups. In vivo, X-ray and micro-CT analysis of the retrieved implants revealed more ectopic bone formation at 2 and 3 weeks but not at 4 weeks compared to other groups. The results indicate that the combination of the therapeutic growth factors potentiates cell differentiation and may promote osteogenesis.

Enhanced adipogenic differentiation of bovine bone marrow-derived mesenchymal stem cells

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Until now, the isolation and characterization of bovine bone marrow-derived mesenchymal stem cells (bBM-MSCs) have not been established, which prompted us to optimize the differentiation protocol for bBM-MSCs. In this study, bBM-MSCs were freshly isolated from three 6-month-old cattle and used for p...

Involvement of multiple myeloma cell-derived exosomes in osteoclast differentiation

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Raimondi, Lavinia; De Luca, Angela; Amodio, Nicola; Manno, Mauro; Raccosta, Samuele; Taverna, Simona; Bellavia, Daniele; Naselli, Flores; Fontana, Simona; Schillaci, Odessa; Giardino, Roberto; Fini, Milena; Tassone, Pierfrancesco; Santoro, Alessandra; De Leo, Giacomo; Giavaresi, Gianluca; Alessandro, Riccardo

2015-01-01

Bone disease is the most frequent complication in multiple myeloma (MM) resulting in osteolytic lesions, bone pain, hypercalcemia and renal failure. In MM bone disease the perfect balance between bone-resorbing osteoclasts (OCs) and bone-forming osteoblasts (OBs) activity is lost in favour of OCs, thus resulting in skeletal disorders. Since exosomes have been described for their functional role in cancer progression, we here investigate whether MM cell-derived exosomes may be involved in OCs differentiation. We show that MM cells produce exosomes which are actively internalized by Raw264.7 cell line, a cellular model of osteoclast formation. MM cell-derived exosomes positively modulate pre-osteoclast migration, through the increasing of CXCR4 expression and trigger a survival pathway. MM cell-derived exosomes play a significant pro-differentiative role in murine Raw264.7 cells and human primary osteoclasts, inducing the expression of osteoclast markers such as Cathepsin K (CTSK), Matrix Metalloproteinases 9 (MMP9) and Tartrate-resistant Acid Phosphatase (TRAP). Pre-osteoclast treated with MM cell-derived exosomes differentiate in multinuclear OCs able to excavate authentic resorption lacunae. Similar results were obtained with exosomes derived from MM patient's sera. Our data indicate that MM-exosomes modulate OCs function and differentiation. Further studies are needed to identify the OCs activating factors transported by MM cell-derived exosomes. PMID:25944696

The role of apparent diffusion coefficient in the differentiation between benign and malignant bone tumors

International Nuclear Information System (INIS)

Liu Jicun; Cui Jianling; Li Shiling; Guo Zhiping; Ma Xiaohui

2009-01-01

Objective: To explore the role of apparent diffusion coefficient (ADC) value of diffusion-weighted imaging (DWI) in the differentiation between benign and malignant bone tumors. Methods: Echo planar imaging DWI was performed in 18 patients with benign tumor or tumorous lesion and 26 patients with malignant tumor of bone. Three b-values (0, 500 and 1000 s/mm 2 ) were applied. The lowest, highest, and whole ADC values were measured for each lesion, respectively. Results: The lowest ADC values of benign bone tumor [mean (1.28 ± 0.49)x10 -3 mm 2 /s] were significantly higher than that of malignant tumor [ mean (0.92 ± 0.35) x10 -3 mm 2 /s,t =2.839,P -3 mm 2 /s] were significantly higher than that of malignant tumor [ mean (1.21 ± 0.36)x10 -3 mm 2 /s, t =3.092, P -3 mm 2 /s] and malignant bone tumor [ mean (1.71 ± 0.65)x10 -3 mm 2 /s, t = 1.669, P > 0.05]. Excluding cases of bone cyst and aneurismal bone cyst, the lowest, highest, and whole ADC values of benign bone tumor waw (1.11 ± 0.31)x10 -3 mm 2 /s, (1.88 ± 0.49)x10 -3 mm 2 /s, and (1.45 ± 0.35)x10 -3 mm 2 /s, respectively. There was no significant difference for the lowest, highest, or whole ADC values between benign and malignant bone tumor (t =1.728, 0.964, and 2.012, respectively, P> 0.05). Conclusion: ADC value is useless for the differentiation between benign and malignant bone tumors. (authors)

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration.

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Aquino-Martínez, Rubén; Angelo, Alcira P; Pujol, Francesc Ventura

2017-11-16

Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC) recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca 2+ -containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO 4 ) on MSC migration. In addition, to evaluate the influence of CaSO 4 on MSC differentiation and the potential molecular mechanisms involved. A circular calvarial bone defect (5 mm diameter) was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO 4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO 4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO 4 treatment was also evaluated by qPCR. CaSO 4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO 4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO 4 -containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO 4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO 4 effects on MSC migration. Specific CaSO 4 concentrations induce bone regeneration of calvarial defects in part by acting on the host's undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO 4 regulates BMP-2-induced MSC migration by differentially activating the PI3

Instability of Employment and the Lack of Work Life Balance: From the viewpoint of compensating wage differentials (Japanese)

OpenAIRE

MORIKAWA Masayuki

2010-01-01

The purpose of this paper is to present survey-based evidence on the compensating wage differentials for the instability of employment and the lack of work-life-balance in Japan. First, we present facts on the individual evaluation of the size of fair compensating differentials. Then we estimate the effects of working hours and wages on the job satisfaction index. The fair compensating wage differentials for the instability of employment and lack of work-life-balance are both between 10% and ...

Function of Matrix IGF-1 in Coupling Bone Resorption and Formation

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Crane, Janet L.; Cao, Xu

2013-01-01

Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space and time dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of MSCs and HSCs and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis. PMID:24068256

Function of matrix IGF-1 in coupling bone resorption and formation.

Science.gov (United States)

Crane, Janet L; Cao, Xu

2014-02-01

Balancing bone resorption and formation is the quintessential component for the prevention of osteoporosis. Signals that determine the recruitment, replication, differentiation, function, and apoptosis of osteoblasts and osteoclasts direct bone remodeling and determine whether bone tissue is gained, lost, or balanced. Therefore, understanding the signaling pathways involved in the coupling process will help develop further targets for osteoporosis therapy, by blocking bone resorption or enhancing bone formation in a space- and time-dependent manner. Insulin-like growth factor type 1 (IGF-1) has long been known to play a role in bone strength. It is one of the most abundant substances in the bone matrix, circulates systemically and is secreted locally, and has a direct relationship with bone mineral density. Recent data has helped further our understanding of the direct role of IGF-1 signaling in coupling bone remodeling which will be discussed in this review. The bone marrow microenvironment plays a critical role in the fate of mesenchymal stem cells and hematopoietic stem cells and thus how IGF-1 interacts with other factors in the microenvironment are equally important. While previous clinical trials with IGF-1 administration have been unsuccessful at enhancing bone formation, advances in basic science studies have provided insight into further mechanisms that should be considered for future trials. Additional basic science studies dissecting the regulation and the function of matrix IGF-1 in modeling and remodeling will continue to provide further insight for future directions for anabolic therapies for osteoporosis.

SHP1 Regulates Bone Mass by Directing Mesenchymal Stem Cell Differentiation

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Menghui Jiang

2016-07-01

Full Text Available Osteoblasts and adipocytes are derived from a common precursor, mesenchymal stem cells (MSCs. Alterations in the normal fate of differentiating MSCs are involved in the development of obesity and osteoporosis. Here, we report that viable motheaten (mev mice, which are deficient in the SH2-domain-containing phosphatase-1 (SHP1, develop osteoporosis spontaneously. Consistently, MSCs from mev/mev mice exhibit significantly reduced osteogenic potential and greatly increased adipogenic potential. When MSCs were transplanted into nude mice, SHP1-deficient MSCs resulted in diminished bone formation compared with wild-type MSCs. SHP1 was found to bind to GSK3β and suppress its kinase activity by dephosphorylating pY216, thus resulting in β-catenin stabilization. Mice, in which SHP1 was deleted in MSCs using SHP1fl/flDermo1-cre, displayed significantly decreased bone mass and increased adipose tissue. Taken together, these results suggest a possible role for SHP1 in controlling tissue homeostasis through modulation of MSC differentiation via Wnt signaling regulation.

Bone tumors with an associated pathologic fracture: Differentiation between benign and malignant status using radiologic findings

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Bae, Ji Hyun; Lee, In Sook; Song, You Seon; Kim, Jeung Il; Lee, Moon Sung; Lee, Young Hwan; Song, Jong Woon

2015-01-01

To determine whether benign and malignant bone tumors with associated pathologic fractures can be differentiated using radiologic findings. Seventy-eight patients (47 men and 31 women, age range: 1-93 years) with a bone tumor and an associated pathologic fracture from 2004 to 2013 constituted the retrospective study cohort. The tumor size, margin, and enhancement patterns; the presence of sclerotic margin, the peritumoral bone marrow, soft tissue edema, extra-osseous soft tissue mass, intratumoral cystic/hemorrhagic/necrotic regions, mineralization/sclerotic regions, periosteal reaction and its appearance; and cortical change and its appearance were evaluated on all images. Differences between the imaging characteristics of malignant and benign pathologic fractures were compared using Pearson's chi-square test and the 2-sample t-test. There were 22 benign and 56 malignant bone tumors. Some factors were found to significantly differentiate between benign and malignant tumors; specifically, ill-defined tumor margin, the presence of sclerotic tumor margin and an extra-osseous soft tissue mass, the absence of cystic/necrotic/hemorrhagic portions in a mass, the homogeneous enhancement pattern, and the presence of a displaced fracture and of underlying cortical change were suggestive of malignant pathologic fractures. Some imaging findings were helpful for differentiating between benign and malignant pathologic fractures

Bone tumors with an associated pathologic fracture: Differentiation between benign and malignant status using radiologic findings

Energy Technology Data Exchange (ETDEWEB)

Bae, Ji Hyun; Lee, In Sook; Song, You Seon [Pusan National University School of Medicine, Pusan National University Hospital, Busan (Korea, Republic of); Kim, Jeung Il [Dept. of Radiology, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu (Korea, Republic of); Lee, Moon Sung [Dept. of Radiology, Keimyung University College of Medicine, Dongsan Medical Center, Daegu (Korea, Republic of); Lee, Young Hwan [Dept. of Radiology, Catholic University of Daegu College of Medicine, Daegu Catholic University Hospital, Daegu (Korea, Republic of); Song, Jong Woon [Dept. of Radiology, Inje University College of Medicine, Haeundae Paik Hospital, Busan (Korea, Republic of)

2015-10-15

To determine whether benign and malignant bone tumors with associated pathologic fractures can be differentiated using radiologic findings. Seventy-eight patients (47 men and 31 women, age range: 1-93 years) with a bone tumor and an associated pathologic fracture from 2004 to 2013 constituted the retrospective study cohort. The tumor size, margin, and enhancement patterns; the presence of sclerotic margin, the peritumoral bone marrow, soft tissue edema, extra-osseous soft tissue mass, intratumoral cystic/hemorrhagic/necrotic regions, mineralization/sclerotic regions, periosteal reaction and its appearance; and cortical change and its appearance were evaluated on all images. Differences between the imaging characteristics of malignant and benign pathologic fractures were compared using Pearson's chi-square test and the 2-sample t-test. There were 22 benign and 56 malignant bone tumors. Some factors were found to significantly differentiate between benign and malignant tumors; specifically, ill-defined tumor margin, the presence of sclerotic tumor margin and an extra-osseous soft tissue mass, the absence of cystic/necrotic/hemorrhagic portions in a mass, the homogeneous enhancement pattern, and the presence of a displaced fracture and of underlying cortical change were suggestive of malignant pathologic fractures. Some imaging findings were helpful for differentiating between benign and malignant pathologic fractures.

Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions

International Nuclear Information System (INIS)

Ren Hongying; Cao Ying; Zhao, Qinjun; Li Jing; Zhou Cixiang; Liao Lianming; Jia Mingyue; Zhao Qian; Cai Huiguo; Han Zhongchao; Yang Renchi; Chen Guoqiang; Zhao, R.C.

2006-01-01

Low oxygen tension is a potent differentiation inducer of numerous cell types and an effective stimulus of many gene expressions. Here, we described that under 8% O 2 , bone marrow stromal cells (MSCs) exhibited proliferative and morphologic changes. The level of differentiated antigen H-2Dd and the number of G 2 /S/M phase cells increased evidently under 8% O 2 condition. Also, the proportion of wide, flattened, and epithelial-like cells (which were alkaline phosphatase staining positive) in MSCs increased significantly. When cultured in adipogenic medium, there was a 5- to 6-fold increase in the number of lipid droplets under hypoxic conditions compared with that in normoxic culture. We also demonstrated the existence of MSC differentiation under hypoxic conditions by electron microscopy. Expression of Oct4 was inhibited under 8% O 2 condition, but after adipocyte differentiation in normoxic culture and hypoxia-mimicking agents cobalt chloride (CoCl 2 ) and deferoxamine mesylate (DFX) treatments, Oct4 was still expressed in MSCs. These results indicate hypoxia accelerates MSC differentiation and hypoxia and hypoxia-mimicking agents exert different effects on MSC differentiation

Ginsenoside Re Promotes Osteoblast Differentiation in Mouse Osteoblast Precursor MC3T3-E1 Cells and a Zebrafish Model

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Hye-Min Kim

2016-12-01

Full Text Available Bone homeostasis is tightly regulated to balance bone formation and bone resorption. Many anabolic drugs are used as bone-targeted therapeutic agents for the promotion of osteoblast-mediated bone formation or inhibition of osteoclast-mediated bone resorption. Previous studies showed that ginsenoside Re has the effect of the suppression of osteoclast differentiation in mouse bone-marrow derived macrophages and zebrafish. Herein, we investigated whether ginsenoside Re affects osteoblast differentiation and mineralization in in vitro and in vivo models. Mouse osteoblast precursor MC3T3-E1 cells were used to investigate cell viability, alkaline phosphatase (ALP activity, and mineralization. In addition, we examined osteoblastic signaling pathways. Ginsenoside Re affected ALP activity without cytotoxicity, and we also observed the stimulation of osteoblast differentiation through the activation of osteoblast markers including runt-related transcription factor 2, type 1 collagen, ALP, and osteocalcin in MC3T3-E1 cells. Moreover, Alizarin red S staining indicated that ginsenoside Re increased osteoblast mineralization in MC3T3-E1 cells and zebrafish scales compared to controls. These results suggest that ginsenoside Re promotes osteoblast differentiation as well as inhibits osteoclast differentiation, and it could be a potential therapeutic agent for bone diseases.

Differential diagnosis of metastases in bone scans: chemotherapy induced bone necrosis

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Reuland, P.

1999-01-01

Aim: Influenced by the incorrect diagnosis of a bone metastasis caused by bone necrosis we evaluated reasons and frequency of bone necrosis in patients referred for bone scanning in follow-up of tumors. Methods: Bone scans performed within two years on patients with primary bone tumors or tumors metastatic to bone were reviewed in respect to the final diagnosis bone necrosis. Results: We found the cases of three young patients who presented the appearance of hot spots on bone scintigrams which were finally diagnosed as bone necrosis. In two cases the diagnosis was based on histological findings, in one case the diagnosis was made evident by follow-up. All the three patients had been treated by chemotherapy and presented no other reason for the development of bone necrosis. Enhanced tracer uptake in all sites decreased within eight weeks up to two years without therapy. Conclusion: Single and multiple hot spots after chemotherapy may be originated by bone necrosis but mimikry metastases. (orig.) [de

The effect of serum vitamin D level and bone mineral density on balance and the risk of falling in postmenopausal women

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Ayşegül Küçükali Türkyılmaz

2013-01-01

Full Text Available Objective: The aim of this study was to investigate the effect of bone mineral density and vitamin D level on the risk of falling and balance in postmenopausal women.Methods: The age ranged from 44 to 67 (57.25±7.27 years, 133 postmenopausal women were enrolled. Age, height, weight, socio-demographic information, history of falling and fracture in last year, risk factors for osteoporosis, and menopause duration were recorded. Serum 25OHD3 level and bone mineral density (BMD of participants were measured. Postural balance function and the risk of falling were evaluated by time-up and go test (TUG, and Berg balance scale (BBS. Patients were divided into 4 groups; group 1: low vitamin D and osteoporosis, group 2: only low vitamin D, group 3: only osteoporotic, group 4: normal. Results: There was significant difference between the groups according to TUG (p<0.001. There were significant differences between group 1 and 2, group 1 and 4, group 3 and 4 (each, p= 0.001. There was significant difference between the groups according to BBS (p<0.001. Significant differences were found between group 1 and 2, group 1 and 4, group 2 (each, p<0.001 and 3 (p= 0.002, group 3 and 4 (p<0.001. There were negative correlations between TUG, L1-L4 and femoral neck BMD (r=-0.488, p<0.001 and r =-0.462, p<0.001, respectively. There were positive correlations between BBS, L1-L4 and femoral neck BMD (r=-0.488, p<0.001 and r=-0.462, p<0.001, respectively. Conclusion: We concluded that whereas vitamin D level had no effect on balance and the risk of falling, whereas osteoporosis had effects both on balance and risk of falling. Key words: Vitamin D, bone mineral density, balance, risk of falling

Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassified arthritis

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Duer, Anne; Østergaard, M; Hørslev-Petersen, K

2008-01-01

OBJECTIVES: To investigate the value in clinical practice of hand magnetic resonance imaging (MRI) and whole body bone scintigraphy in the differential diagnosis of patients with unclassified arthritis. METHODS: 41 patients with arthritis (> or = 2 swollen joints, > 6 months' duration) which...... to psoriatic arthritis (RF negative + psoriasis); one to non-specific self-limiting arthritis). No patients classified as non-RA at baseline had fulfilled the ACR criteria after 2 years. The presence of MRI synovitis, MRI erosion and bone scintigraphic pattern compatible with RA showed 100% specificity...

Silk fibroin/chitosan thin film promotes osteogenic and adipogenic differentiation of rat bone marrow-derived mesenchymal stem cells.

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Li, Da-Wei; He, Jin; He, Feng-Li; Liu, Ya-Li; Liu, Yang-Yang; Ye, Ya-Jing; Deng, Xudong; Yin, Da-Chuan

2018-04-01

As a biodegradable polymer thin film, silk fibroin/chitosan composite film overcomes the defects of pure silk fibroin and chitosan films, respectively, and shows remarkable biocompatibility, appropriate hydrophilicity and mechanical properties. Silk fibroin/chitosan thin film can be used not only as metal implant coating for bone injury repair, but also as tissue engineering scaffold for skin, cornea, adipose, and other soft tissue injury repair. However, the biocompatibility of silk fibroin/chitosan thin film for mesenchymal stem cells, a kind of important seed cell of tissue engineering and regenerative medicine, is rarely reported. In this study, silk fibroin/chitosan film was prepared by solvent casting method, and the rat bone marrow-derived mesenchymal stem cells were cultured on the silk fibroin/chitosan thin film. Osteogenic and adipogenic differentiation of rat bone marrow-derived mesenchymal stem cells were induced, respectively. The proliferation ability, osteogenic and adipogenic differentiation abilities of rat bone marrow-derived mesenchymal stem cells were systematically compared between silk fibroin/chitosan thin film and polystyrene tissue culture plates. The results showed that silk fibroin/chitosan thin film not only provided a comparable environment for the growth and proliferation of rat bone marrow-derived mesenchymal stem cells but also promoted their osteogenic and adipogenic differentiation. This work provided information of rat bone marrow-derived mesenchymal stem cells behavior on silk fibroin/chitosan thin film and extended the application of silk fibroin/chitosan thin film. Based on the results, we suggested that the silk fibroin/chitosan thin film could be a promising material for tissue engineering of bone, cartilage, adipose, and skin.

Treatment with at Homeopathic Complex Medication Modulates Mononuclear Bone Marrow Cell Differentiation

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Beatriz Cesar

2011-01-01

Full Text Available A homeopathic complex medication (HCM, with immunomodulatory properties, is recommended for patients with depressed immune systems. Previous studies demonstrated that the medication induces an increase in leukocyte number. The bone marrow microenvironment is composed of growth factors, stromal cells, an extracellular matrix and progenitor cells that differentiate into mature blood cells. Mice were our biological model used in this research. We now report in vivo immunophenotyping of total bone marrow cells and ex vivo effects of the medication on mononuclear cell differentiation at different times. Cells were examined by light microscopy and cytokine levels were measured in vitro. After in vivo treatment with HCM, a pool of cells from the new marrow microenvironment was analyzed by flow cytometry to detect any trend in cell alteration. The results showed decreases, mainly, in CD11b and TER-119 markers compared with controls. Mononuclear cells were used to analyze the effects of ex vivo HCM treatment and the number of cells showing ring nuclei, niche cells and activated macrophages increased in culture, even in the absence of macrophage colony-stimulating factor. Cytokines favoring stromal cell survival and differentiation in culture were induced in vitro. Thus, we observe that HCM is immunomodulatory, either alone or in association with other products.

A pilot study of the feasibility of long-term human bone balance during perimenopause using a 41Ca tracer

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Hui, S.K.; Prior, J.; Gelbart, Z.; Johnson, R.R.; Lentle, B.C.; Paul, M.

2007-01-01

The mechanisms governing calcium fluxes during bone remodeling processes in perimenopausal women are poorly known. Despite higher, albeit erratic, estradiol levels in perimenopause, spine bone loss is greater than during the first five years past the final menstrual flow when estradiol becomes low. Understanding changes during this dynamic transition are important to prevent fragility fractures in midlife and older women. The exploration of long-lived 41 Ca (T 1/2 = 1.04 x 10 5 yrs) tracer measurements using accelerator mass spectrometry (AMS) leads to the possibility of monitoring bone remodeling balance. With this new technology, we explored a pilot long-term feasibility study of bone health by measuring the 41 Ca trace element in urine for six years from premenopausal to later perimenopausal phases in one midlife woman. We measured bone mineral density in parallel

Trans-differentiation via Epigenetics: A New Paradigm in the Bone Regeneration.

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Cho, Young-Dan; Ryoo, Hyun-Mo

2018-02-01

In regenerative medicine, growing cells or tissues in the laboratory is necessary when damaged cells can not heal by themselves. Acquisition of the required cells from the patient's own cells or tissues is an ideal option without additive side effects. In this context, cell reprogramming methods, including the use of induced pluripotent stem cells (iPSCs) and trans-differentiation, have been widely studied in regenerative research. Both approaches have advantages and disadvantages, and the possibility of de-differentiation because of the epigenetic memory of iPSCs has strengthened the need for controlling the epigenetic background for successful cell reprogramming. Therefore, interest in epigenetics has increased in the field of regenerative medicine. Herein, we outline in detail the cell trans-differentiation method using epigenetic modification for bone regeneration in comparison to the use of iPSCs.

Differentiation of bone marrow cells with irradiated bone in vitro

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Toshiyuki Tominaga; Moritoshi Itoman; Izumi, T.; Wakita, R.; Uchino, M.

1999-01-01

Disease transmission or infection is an important issue in bone allograft, and irradiation is used for sterilization of graft bones. One of the advantages of bone allograft over biomaterials is that graft bones have osteoinductive factors such as growth factors. Irradiation is reported to decrease the osteoinductive activity in vivo. We investigated the osteoinductive activity of irradiated bone by alkaline phosphatase (ALP) activity in rat bone marrow cell culture. Bones (tibias and femurs of 12-week-old Wistar rats) were cleaned of adhering soft tissue, and the marrow was removed by washing. The bones were defatted, lyophilized, and cut into uniform 70 mg fragments. Then the Bone fragments were irradiated at either 10, 20, 25, 30, 40, or 50 kGy at JAERI. Bone marrow cells were isolated from tibias and femurs of 4-week-old Wistar rats. Cells were plated in tissue culture flask. When primary cultures reached confluence, cells were passaged (4 x 103 cell / cm2) to 6 wells plates. The culture medium consisted of minimum essential medium, 10% fetal bovine serum, ascorbic acid, and antibiotics. At confluence, a cell culture insert was set in the well, and an irradiated bone fragment was placed in it. Then, medium was supplemented with 10 mM ?-glycerophosphate and 1 x 10-8 M dexamethasone. Culture wells were stained by naphthol AS-MX phosphate, N,N-dimethyl formamide, Red violet LB salt on day 0, 7, 14. The density of ALP staining was analyzed by a personal computer. Without bones, ALP staining increased by 50% on day 7 and by 100% on day 14, compared with that on day 0. The other side, with bones irradiated at 30 kGy or lower, ALP staining increased by 150% on day 7, and by 180% on day 14, compared with that on day 0. In the groups of irradiated bones of 40 kGy or higher, the increase in ALP staining was less prominent compared with the groups of irradiated bones of 30 kGy or lower. In the groups of 0-30 kGy irradiation, ALP staining increased in the early period

Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

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Rubén Aquino-Martínez

2017-11-01

Full Text Available Abstract Background Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca2+-containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO4 on MSC migration. In addition, to evaluate the influence of CaSO4 on MSC differentiation and the potential molecular mechanisms involved. Methods A circular calvarial bone defect (5 mm diameter was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO4 treatment was also evaluated by qPCR. Results CaSO4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO4-containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO4 effects on MSC migration. Conclusions Specific CaSO4 concentrations induce bone regeneration of calvarial defects in part by acting on the host’s undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO4 regulates BMP-2-induced

Intrinsic Sex-Linked Variations in Osteogenic and Adipogenic Differentiation Potential of Bone Marrow Multipotent Stromal Cells.

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Bragdon, Beth; Burns, Robert; Baker, Amelia H; Belkina, Anna C; Morgan, Elise F; Denis, Gerald V; Gerstenfeld, Louis C; Schlezinger, Jennifer J

2015-02-01

Bone formation and aging are sexually dimorphic. Yet, definition of the intrinsic molecular differences between male and female multipotent mesenchymal stromal cells (MSCs) in bone is lacking. This study assessed sex-linked differences in MSC differentiation in 3-, 6-, and 9-month-old C57BL/6J mice. Analysis of tibiae showed that female mice had lower bone volume fraction and higher adipocyte content in the bone marrow compared to age-matched males. While both males and females lost bone mass in early aging, the rate of loss was higher in males. Similar expression of bone- and adipocyte-related genes was seen in males and females at 3 and 9 months, while at 6 months, females exhibited a twofold greater expression of these genes. Under osteogenic culture conditions, bone marrow MSCs from female 3- and 6-month-old mice expressed similar levels of bone-related genes, but significantly greater levels of adipocyte-related genes, than male MSCs. Female MSCs also responded to rosiglitazone-induced suppression of osteogenesis at a 5-fold lower (10 nM) concentration than male MSCs. Female MSCs grown in estrogen-stripped medium showed similar responses to rosiglitazone as MSCs grown in serum containing estrogen. MSCs from female mice that had undergone ovariectomy before sexual maturity also were sensitive to rosiglitazone-induced effects on osteogenesis. These results suggest that female MSCs are more sensitive to modulation of differentiation by PPARγ and that these differences are intrinsic to the sex of the animal from which the MSCs came. These results also may explain the sensitivity of women to the deleterious effects of rosiglitazone on bone. © 2014 Wiley Periodicals, Inc.

Leishmania donovani infection induces anemia in hamsters by differentially altering erythropoiesis in bone marrow and spleen.

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William P Lafuse

Full Text Available Leishmania donovani is a parasite that causes visceral leishmaniasis by infecting and replicating in macrophages of the bone marrow, spleen, and liver. Severe anemia and leucopenia is associated with the disease. Although immune defense mechanisms against the parasite have been studied, we have a limited understanding of how L. donovani alters hematopoiesis. In this study, we used Syrian golden hamsters to investigate effects of L. donovani infection on erythropoiesis. Infection resulted in severe anemia and leucopenia by 8 weeks post-infection. Anemia was associated with increased levels of serum erythropoietin, which indicates the hamsters respond to the anemia by producing erythropoietin. We found that infection also increased numbers of BFU-E and CFU-E progenitor populations in the spleen and bone marrow and differentially altered erythroid gene expression in these organs. In the bone marrow, the mRNA expression of erythroid differentiation genes (α-globin, β-globin, ALAS2 were inhibited by 50%, but mRNA levels of erythroid receptor (c-kit, EpoR and transcription factors (GATA1, GATA2, FOG1 were not affected by the infection. This suggests that infection has a negative effect on differentiation of erythroblasts. In the spleen, erythroid gene expression was enhanced by infection, indicating that the anemia activates a stress erythropoiesis response in the spleen. Analysis of cytokine mRNA levels in spleen and bone marrow found that IFN-γ mRNA is highly increased by L. donovani infection. Expression of the IFN-γ inducible cytokine, TNF-related apoptosis-inducing ligand (TRAIL, was also up-regulated. Since TRAIL induces erythroblasts apoptosis, apoptosis of bone marrow erythroblasts from infected hamsters was examined by flow cytometry. Percentage of erythroblasts that were apoptotic was significantly increased by L. donovani infection. Together, our results suggest that L. donovani infection inhibits erythropoiesis in the bone marrow by

Differential diagnosis of metastatic bone disease and benign bone disease on spine SPECT in patients with low back pain

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Lee, Seung Hun; Choi, Yun Young; Cho, Suk Shin

2001-01-01

One or more abnormal vertebrae detected on bone scintigraphy is a common finding in clinical practice, and it could pose a diagnostic dilemma especially in cancer patients, as either metastasis or benign disease may cause scintigraphic abnormality. The purpose of this study was to determine whether additional spine SPECT has a role in differentiating malignant from benign lesions in patients with back pain. We reviewed spine SPECT studies obtained over a three-year period in 108 patients. Among them, forty-five patients with abnormal SPECT and clinically followed records were evaluated (20 cancer patients were included). Uptake patterns were classified as follows: 1. Body: diffusely increased uptake, linear increased uptake of end plate, segmental increased uptake, and cold defect, 2 Posterior element; posterior to body (pedicle), posterior to intervertebral disc space (facet joint), and spinous process. Lesions were correlated with radiological findings and with final diagnosis. Sixty-nine bone lesions were detected on SPECT images, including 18 metastases, 28 degenerative diseases and 21 compression fractures. Cold defect (6) and segmental increased uptake (5) were dominant findings in metastasis: linear increased uptake (12), and facet joint uptake (15) were in degenerative change; and diffuse increased uptake (9), and linear increased uptake (9) were in compression fracture. Cold defect and segmental increased uptake of body were characteristic findings of metastasis, but care should be taken because compression fracture also shows segmental increased uptake in some cases. Degenerative disease was easily diagnosed because of the typical finding of linear increased uptake of end plate and facet joint. Therefore, additional bone SPECT after planar bone scan would be helpful for differentiating metastasis from benign condition in cancer patients

Spaceflight-induced vertebral bone loss in ovariectomized rats is associated with increased bone marrow adiposity and no change in bone formation

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Keune, Jessica A; Philbrick, Kenneth A; Branscum, Adam J; Iwaniec, Urszula T; Turner, Russell T

2016-01-01

There is often a reciprocal relationship between bone marrow adipocytes and osteoblasts, suggesting that marrow adipose tissue (MAT) antagonizes osteoblast differentiation. MAT is increased in rodents during spaceflight but a causal relationship between MAT and bone loss remains unclear. In the present study, we evaluated the effects of a 14-day spaceflight on bone mass, bone resorption, bone formation, and MAT in lumbar vertebrae of ovariectomized (OVX) rats. Twelve-week-old OVX Fischer 344 rats were randomly assigned to a ground control or flight group. Following flight, histological sections of the second lumbar vertebrae (n=11/group) were stained using a technique that allowed simultaneous quantification of cells and preflight fluorochrome label. Compared with ground controls, rats flown in space had 32% lower cancellous bone area and 306% higher MAT. The increased adiposity was due to an increase in adipocyte number (224%) and size (26%). Mineral apposition rate and osteoblast turnover were unchanged during spaceflight. In contrast, resorption of a preflight fluorochrome and osteoclast-lined bone perimeter were increased (16% and 229%, respectively). The present findings indicate that cancellous bone loss in rat lumbar vertebrae during spaceflight is accompanied by increased bone resorption and MAT but no change in bone formation. These findings do not support the hypothesis that increased MAT during spaceflight reduces osteoblast activity or lifespan. However, in the context of ovarian hormone deficiency, bone formation during spaceflight was insufficient to balance increased resorption, indicating defective coupling. The results are therefore consistent with the hypothesis that during spaceflight mesenchymal stem cells are diverted to adipocytes at the expense of forming osteoblasts. PMID:28725730

Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence.

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Yang, Fan; Yang, Lei; Li, Yuan; Yan, Gege; Feng, Chao; Liu, Tianyi; Gong, Rui; Yuan, Ye; Wang, Ning; Idiiatullina, Elina; Bikkuzin, Timur; Pavlov, Valentin; Li, Yang; Dong, Chaorun; Wang, Dawei; Cao, Yang; Han, Zhenbo; Zhang, Lai; Huang, Qi; Ding, Fengzhi; Bi, Zhengang; Cai, Benzhi

2017-10-01

Bone marrow mesenchymal stem cells (BMSCs) are an expandable population of stem cells which can differentiate into osteoblasts, chondrocytes and adipocytes. Dysfunction of BMSCs in response to pathological stimuli contributes to bone diseases. Melatonin, a hormone secreted from pineal gland, has been proved to be an important mediator in bone formation and mineralization. The aim of this study was to investigate whether melatonin protected against iron overload-induced dysfunction of BMSCs and its underlying mechanisms. Here, we found that iron overload induced by ferric ammonium citrate (FAC) caused irregularly morphological changes and markedly reduced the viability in BMSCs. Consistently, osteogenic differentiation of BMSCs was significantly inhibited by iron overload, but melatonin treatment rescued osteogenic differentiation of BMSCs. Furthermore, exposure to FAC led to the senescence in BMSCs, which was attenuated by melatonin as well. Meanwhile, melatonin was able to counter the reduction in cell proliferation by iron overload in BMSCs. In addition, protective effects of melatonin on iron overload-induced dysfunction of BMSCs were abolished by its inhibitor luzindole. Also, melatonin protected BMSCs against iron overload-induced ROS accumulation and membrane potential depolarization. Further study uncovered that melatonin inhibited the upregulation of p53, ERK and p38 protein expressions in BMSCs with iron overload. Collectively, melatonin plays a protective role in iron overload-induced osteogenic differentiation dysfunction and senescence through blocking ROS accumulation and p53/ERK/p38 activation. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

An Overview of Long Noncoding RNAs Involved in Bone Regeneration from Mesenchymal Stem Cells

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Shuping Peng

2018-01-01

Full Text Available Bone regeneration is very important for the recovery of some diseases including osteoporosis and bone fracture trauma. It is a multiple-step- and multiple-gene-involved complex process, including the matrix secretion and calcium mineralization by osteoblasts differentiated from mesenchymal stem cells (MSCs and the absorption of calcium and phosphorus by osteoclasts differentiated from hematopoietic stem cells. Long noncoding RNAs (lncRNAs are a family of transcripts longer than 200 nt without or with very low protein-coding potential. Recent studies have demonstrated that lncRNAs are widely involved in the regulation of lineage commitment and differentiation of stem cells through multiple mechanisms. In this review, we will summarize the roles and molecular mechanism of lncRNAs including H19, MALAT1, MODR, HOTAIR, DANCR, MEG3, HoxA-AS3, and MIAT in osteogenesis ossification; lncRNA ZBED3-AS1 and CTA-941F9.9, DANCR, and HIT in chondrogenic differentiation; and lncRNA DANCR in osteoclast differentiation. These findings will facilitate the development and application of novel molecular drugs which regulate the balance of bone formation and absorption.

Gene expression patterns related to osteogenic differentiation of bone marrow-derived mesenchymal stem cells during ex vivo expansion.

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Granchi, Donatella; Ochoa, Gorka; Leonardi, Elisa; Devescovi, Valentina; Baglìo, Serena Rubina; Osaba, Lourdes; Baldini, Nicola; Ciapetti, Gabriela

2010-06-01

Bone marrow is commonly used as a source of adult multipotent mesenchymal stem cells (MSCs), defined for their ability to differentiate in vitro into multiple lineages. The ex vivo-expanded MSCs are currently being evaluated as a strategy for the restoration of function in damaged skeletal tissue, both in cell therapy and tissue engineering applications. The aim of this study was to define gene expression patterns underlying the differentiation of MSCs into mature osteoblasts during the expansion in vitro, and to explore a variety of cell functions that cannot be easily evaluated using morphological, cytochemical, and biochemical assays. Cell cultures were obtained from bone marrow samples of six individuals undergoing total hip replacement, and a large-scale transcriptome analysis, using Affymetrix HG-U133A Plus 2.0 array (Affymetrix((R)), Santa Clara, CA), was performed at the occurrence of specific events, including the appearance of MSC surface markers, formation of colonies, and deposition of mineral nodules. We focused our attention on 213 differentially upregulated genes, some belonging to well-known pathways and some having one or more Gene Ontology annotations related to bone cell biology, including angiogenesis, bone-related genes, cell communication, development and morphogenesis, transforming growth factor-beta signaling, and Wnt signaling. Twenty-nine genes, whose role in bone cell pathophysiology has not been described yet, were found. In conclusion, gene expression patterns that characterize the early, intermediate, and late phases of the osteogenic differentiation process of ex vivo-expanded MSCs were defined. These signatures represent a useful tool to monitor the osteogenic process, and to analyze a broad spectrum of functions of MSCs cultured on scaffolds, especially when the constructs are conceived for releasing growth factors or other signals to promote bone regeneration.

Spinal bone marrow necrosis with vertebral compression fracture: differentiation of BMN from AVN.

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Nix, J S; Fitzgerald, R T; Samant, R S; Harrison, M; Angtuaco, E J

2014-09-01

Bone marrow necrosis (BMN) is a rare malignancy-associated hematologic disorder characterized by necrosis of myeloid and stromal marrow elements with preservation of cortical bone. Overlap between the imaging appearances of BMN and avascular necrosis (AVN) raises the potential for diagnostic confusion. We report a case of BMN presenting with a traumatic multi-level vertebral body collapse, and finding that may potentially confound distinction between the two entities. We discuss important pathophysiologic, clinical, and radiologic differences between BMN and AVN with emphasis on features important in the differential diagnosis.

Differentiating benign from malignant bone tumors using fluid-fluid level features on magnetic resonance imaging

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Yu, Hong; Cui, Jian Ling; Cui, Sheng Jie; Sun, Ying Cal; Cui, Feng Zhen [Dept. of Radiology, The Third Hospital of Hebei Medical University, Hebei Province Biomechanical Key Laborary of Orthopedics, Shijiazhuang, Hebei (China)

2014-12-15

To analyze different fluid-fluid level features between benign and malignant bone tumors on magnetic resonance imaging (MRI). This study was approved by the hospital ethics committee. We retrospectively analyzed 47 patients diagnosed with benign (n = 29) or malignant (n = 18) bone tumors demonstrated by biopsy/surgical resection and who showed the intratumoral fluid-fluid level on pre-surgical MRI. The maximum length of the largest fluid-fluid level and the ratio of the maximum length of the largest fluid-fluid level to the maximum length of a bone tumor in the sagittal plane were investigated for use in distinguishing benign from malignant tumors using the Mann-Whitney U-test and a receiver operating characteristic (ROC) analysis. Fluid-fluid level was categorized by quantity (multiple vs. single fluid-fluid level) and by T1-weighted image signal pattern (high/low, low/high, and undifferentiated), and the findings were compared between the benign and malignant groups using the chi2 test. The ratio of the maximum length of the largest fluid-fluid level to the maximum length of bone tumors in the sagittal plane that allowed statistically significant differentiation between benign and malignant bone tumors had an area under the ROC curve of 0.758 (95% confidence interval, 0.616-0.899). A cutoff value of 41.5% (higher value suggests a benign tumor) had sensitivity of 73% and specificity of 83%. The ratio of the maximum length of the largest fluid-fluid level to the maximum length of a bone tumor in the sagittal plane may be useful to differentiate benign from malignant bone tumors.

Differentiating benign from malignant bone tumors using fluid-fluid level features on magnetic resonance imaging

International Nuclear Information System (INIS)

Yu, Hong; Cui, Jian Ling; Cui, Sheng Jie; Sun, Ying Cal; Cui, Feng Zhen

2014-01-01

To analyze different fluid-fluid level features between benign and malignant bone tumors on magnetic resonance imaging (MRI). This study was approved by the hospital ethics committee. We retrospectively analyzed 47 patients diagnosed with benign (n = 29) or malignant (n = 18) bone tumors demonstrated by biopsy/surgical resection and who showed the intratumoral fluid-fluid level on pre-surgical MRI. The maximum length of the largest fluid-fluid level and the ratio of the maximum length of the largest fluid-fluid level to the maximum length of a bone tumor in the sagittal plane were investigated for use in distinguishing benign from malignant tumors using the Mann-Whitney U-test and a receiver operating characteristic (ROC) analysis. Fluid-fluid level was categorized by quantity (multiple vs. single fluid-fluid level) and by T1-weighted image signal pattern (high/low, low/high, and undifferentiated), and the findings were compared between the benign and malignant groups using the chi2 test. The ratio of the maximum length of the largest fluid-fluid level to the maximum length of bone tumors in the sagittal plane that allowed statistically significant differentiation between benign and malignant bone tumors had an area under the ROC curve of 0.758 (95% confidence interval, 0.616-0.899). A cutoff value of 41.5% (higher value suggests a benign tumor) had sensitivity of 73% and specificity of 83%. The ratio of the maximum length of the largest fluid-fluid level to the maximum length of a bone tumor in the sagittal plane may be useful to differentiate benign from malignant bone tumors.

Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions

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Hongying, Ren; Huiguo, Cai; Zhongchao, Han; Renchi, Yang; Zhao, Qinjun [State Key Lab of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin (China); Ying, Cao; Jing, Li [Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Cixiang, Zhou [Health Science Center, Shanghai Institutes of Biological Sciences, Chinese Academy of Science-SSMU, Shanghai (China); Lianming, Liao; Mingyue, Jia [Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China); Qian, Zhao [Health Science Center, Shanghai Institutes of Biological Sciences, Chinese Academy of Science-SSMU, Shanghai (China); Guoqiang, Chen [Health Science Center, Shanghai Institutes of Biological Sciences, Chinese Academy of Science-SSMU, Shanghai (China); Zhao, R C [State Key Lab of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union of Medical College, Tianjin (China); [Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (China)]. E-mail: chunhuaz@public.tpt.tj.cn

2006-08-18

Low oxygen tension is a potent differentiation inducer of numerous cell types and an effective stimulus of many gene expressions. Here, we described that under 8% O{sub 2}, bone marrow stromal cells (MSCs) exhibited proliferative and morphologic changes. The level of differentiated antigen H-2Dd and the number of G{sub 2}/S/M phase cells increased evidently under 8% O{sub 2} condition. Also, the proportion of wide, flattened, and epithelial-like cells (which were alkaline phosphatase staining positive) in MSCs increased significantly. When cultured in adipogenic medium, there was a 5- to 6-fold increase in the number of lipid droplets under hypoxic conditions compared with that in normoxic culture. We also demonstrated the existence of MSC differentiation under hypoxic conditions by electron microscopy. Expression of Oct4 was inhibited under 8% O{sub 2} condition, but after adipocyte differentiation in normoxic culture and hypoxia-mimicking agents cobalt chloride (CoCl{sub 2}) and deferoxamine mesylate (DFX) treatments, Oct4 was still expressed in MSCs. These results indicate hypoxia accelerates MSC differentiation and hypoxia and hypoxia-mimicking agents exert different effects on MSC differentiation.

Surface topography of hydroxyapatite promotes osteogenic differentiation of human bone marrow mesenchymal stem cells.

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Yang, Wanlei; Han, Weiqi; He, Wei; Li, Jianlei; Wang, Jirong; Feng, Haotian; Qian, Yu

2016-03-01

Effective and safe induction of osteogenic differentiation is one of the key elements of bone tissue engineering. Surface topography of scaffold materials was recently found to promote osteogenic differentiation. Utilization of this topography may be a safer approach than traditional induction by growth factors or chemicals. The aim of this study is to investigate the enhancement of osteogenic differentiation by surface topography and its mechanism of action. Hydroxyapatite (HA) discs with average roughness (Ra) of surface topography ranging from 0.2 to 1.65 μm and mean distance between peaks (RSm) ranging from 89.7 to 18.6 μm were prepared, and human bone-marrow mesenchymal stem cells (hBMSCs) were cultured on these discs. Optimal osteogenic differentiation was observed on discs with surface topography characterized by Ra ranging from 0.77 to 1.09 μm and RSm ranging from 53.9 to 39.3 μm. On this surface configuration of HA, hBMSCs showed oriented attachment, F-actin arrangement, and a peak in the expression of Yes-associated protein (YAP) and PDZ binding motif (TAZ) (YAP/TAZ). These results indicated that the surface topography of HA promoted osteogenic differentiation of hBMSCs, possibly by increasing cell attachment and promoting the YAP/TAZ signaling pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

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Brady, Robert T.; O'Brien, Fergal J.; Hoey, David A.

2015-01-01

Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

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Brady, Robert T. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); O' Brien, Fergal J. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Hoey, David A., E-mail: david.hoey@ul.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); The Centre for Applied Biomedical Engineering Research, University of Limerick (Ireland); Materials & Surface Science Institute, University of Limerick (Ireland)

2015-03-27

Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

Investigation of bone and mineral metabolism in hyperthyroidism before and after treatment using calcitonin, /sup 47/Ca and balance studies

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Hendriks, J Th.A.M. [Department of Internal Medicine, St. Franciscus Hospital, 4708 AE Roosendaal, The Netherlands; Smeenk, D [Department of Endocrinology, University Hospital, 2333 AA Leiden, The Netherlands

1979-01-01

Seventeen normocalcaemic patients with severe hyperthyroidism were examined before therapy was initiated; 9 were re-examined about 1 year later. Studies with /sup 47/Ca under balance conditions and with calcitonin demonstrated a high rate of bone resorption in untreated patients. As a result of the increased bone turnover, the reaction to 6 MRC units of porcine calcitonin iv was more marked in the untreated than in the treated patients, or the control group. In contrast to the normal diurnal pattern for PO/sub 4/, it was found that during fasting the plasma PO/sub 4/ level increases in the morning in patients with hyperthyroidism. This increase which was not suppressed by the administered dose of calcitonin developed in spite of an elevated urinary PO/sub 4/ excretion. After treatment, the serum Ca concentration as well as the urinary and faecal Ca excretion was decreased. The Ca balance improved; the rapidly-exchangeable Ca pool returned to normal. The slowly-exchangeable and the total Ca pools, however, remained enlarged. The rate of bone resorption normalized. The accretion rate on the other hand remained elevated. This is attributed to continued enhancement of bone formation to compensate for the previous loss of bony tissue.

The effect of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow‑derived mesenchymal stem cells.

Science.gov (United States)

Javanmard, F; Azadbakht, M; Pourmoradi, M

2016-01-01

In this study, the role of hydrostatic pressure on staurosporine-induced neural differentiation in mouse bone marrow mesenchymal stem cells were investigated. The cells were cultured in treatment medium containing 100 nM of staurosporine for 4 hours; then the cells were affected by hydrostatic pressure (0, 25,50, 100 mmHg). The percentage of cell viability by trypan blue staining and the percentage of cell death by Hoechst/PI differential staining were assessed. We obtained the total neurite length. Expression of β-tubulin III and GFAP (Glial fibrillary acidic protein) proteins were also analyzed by immunocytochemistry. The percentage of cell viability in treatments decreased relative to the increase in hydrostatic pressure and time (p Keywords: bone marrow mesenchymal stem cell, hydrostatic pressure, immunocytochemistry, neural differentiation, neurite length, cell differentiation.

Bone and fat connection in aging bone.

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Duque, Gustavo

2008-07-01

The fat and bone connection plays an important role in the pathophysiology of age-related bone loss. This review will focus on the age-induced mechanisms regulating the predominant differentiation of mesenchymal stem cells into adipocytes. Additionally, bone marrow fat will be considered as a diagnostic and therapeutic approach to osteoporosis. There are two types of bone and fat connection. The 'systemic connection', usually seen in obese patients, is hormonally regulated and associated with high bone mass and strength. The 'local connection' happens inside the bone marrow. Increasing amounts of bone marrow fat affect bone turnover through the inhibition of osteoblast function and survival and the promotion of osteoclast differentiation and activation. This interaction is regulated by paracrine secretion of fatty acids and adipokines. Additionally, bone marrow fat could be quantified using noninvasive methods and could be used as a therapeutic approach due to its capacity to transdifferentiate into bone without affecting other types of fat in the body. The bone and fat connection within the bone marrow constitutes a typical example of lipotoxicity. Additionally, bone marrow fat could be used as a new diagnostic and therapeutic approach for osteoporosis in older persons.

T-Stability of the Heun Method and Balanced Method for Solving Stochastic Differential Delay Equations

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Xiaolin Zhu

2014-01-01

Full Text Available This paper studies the T-stability of the Heun method and balanced method for solving stochastic differential delay equations (SDDEs. Two T-stable conditions of the Heun method are obtained for two kinds of linear SDDEs. Moreover, two conditions under which the balanced method is T-stable are obtained for two kinds of linear SDDEs. Some numerical examples verify the theoretical results proposed.

Omega 3 fatty acids reduce myeloid progenitor cell frequency in the bone marrow of mice and promote progenitor cell differentiation

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Sollars Vincent E

2009-03-01

Full Text Available Abstract Background Omega 3 fatty acids have been found to inhibit proliferation, induce apoptosis, and promote differentiation in various cell types. The processes of cell survival, expansion, and differentiation are of key importance in the regulation of hematopoiesis. We investigated the role of omega 3 fatty acids in controlling the frequency of various myeloid progenitor cells in the bone marrow of mice. Increased progenitor cell frequency and blocked differentiation are characteristics of hematopoietic disorders of the myeloid lineage, such as myeloproliferative diseases and myeloid leukemias. Results We found that increasing the proportion of omega 3 fatty acids relative to the proportion of omega 6 fatty acids in the diet caused increased differentiation and reduced the frequency of myeloid progenitor cells in the bone marrow of mice. Furthermore, this had no adverse effect on peripheral white blood cell counts. Conclusion Our results indicate that omega 3 fatty acids impact hematopoietic differentiation by reducing myeloid progenitor cell frequency in the bone marrow and promoting progenitor cell differentiation. Further exploration of this discovery could lead to the use of omega 3 fatty acids as a therapeutic option for patients that have various disorders of hematopoiesis.

Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

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Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang; Li, Haowei; Ouyang, Zhengxiao; Wu, Chuanlong; Liu, Guangwang; Fan, Qiming; Tang, Tingting; Qin, An; Dai, Kerong

2014-01-01

Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases

Dioscin inhibits osteoclast differentiation and bone resorption though down-regulating the Akt signaling cascades

Energy Technology Data Exchange (ETDEWEB)

Qu, Xinhua; Zhai, Zanjing; Liu, Xuqiang; Li, Haowei [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Ouyang, Zhengxiao [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha (China); Wu, Chuanlong [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Liu, Guangwang [Department of Orthopaedic Surgery, The Central Hospital of Xuzhou, Affiliated Hospital of Medical Collage of Southeast University, Xuzhou (China); Fan, Qiming; Tang, Tingting [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Qin, An, E-mail: dr.qinan@gmail.com [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Dai, Kerong, E-mail: krdai@163.com [Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedics, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

2014-01-10

Highlights: •A natural-derived compound, dioscin, suppresses osteoclast formation and bone resorption. •Dioscin inhibits osteolytic bone loss in vivo. •Dioscin impairs the Akt signaling cascades pathways during osteoclastogenesis. •Dioscin have therapeutic value in treating osteoclast-related diseases. -- Abstract: Bone resorption is the unique function of osteoclasts (OCs) and is critical for both bone homeostasis and pathologic bone diseases including osteoporosis, rheumatoid arthritis and tumor bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. In this study, we for the first time demonstrated that dioscin suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro in a dose-dependent manner. The suppressive effect of dioscin is supported by the reduced expression of osteoclast-specific markers. Further molecular analysis revealed that dioscin abrogated AKT phosphorylation, which subsequently impaired RANKL-induced nuclear factor-kappaB (NF-κB) signaling pathway and inhibited NFATc1 transcriptional activity. Moreover, in vivo studies further verified the bone protection activity of dioscin in osteolytic animal model. Together our data demonstrate that dioscin suppressed RANKL-induced osteoclast formation and function through Akt signaling cascades. Therefore, dioscin is a potential natural agent for the treatment of osteoclast-related diseases.

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

Science.gov (United States)

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.

A pilot study of the feasibility of long-term human bone balance during perimenopause using a {sup 41}Ca tracer

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Hui, S.K. [Racah Institute of Physics, Hebrew University, Jerusalem 91904 (Israel) and Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 494, Minneapolis, MN 55455 (United States)]. E-mail: huixx019@umn.edu; Prior, J. [Deparment of Medicine/Endocrinology, University of British Columbia, Vancouver, B.C., V5Z 1C6 (Canada); Gelbart, Z. [TRIUMF, Vancouver, B.C., V6T2A3 (Canada); Johnson, R.R. [TRIUMF, Vancouver, B.C., V6T2A3 (Canada); Lentle, B.C. [Department of Radiology, University of British Columbia, British Columbia, V8M 1V4 (Canada); Paul, M. [Racah Institute of Physics, Hebrew University, Jerusalem 91904 (Israel)

2007-06-15

The mechanisms governing calcium fluxes during bone remodeling processes in perimenopausal women are poorly known. Despite higher, albeit erratic, estradiol levels in perimenopause, spine bone loss is greater than during the first five years past the final menstrual flow when estradiol becomes low. Understanding changes during this dynamic transition are important to prevent fragility fractures in midlife and older women. The exploration of long-lived {sup 41}Ca (T {sub 1/2} = 1.04 x 10{sup 5} yrs) tracer measurements using accelerator mass spectrometry (AMS) leads to the possibility of monitoring bone remodeling balance. With this new technology, we explored a pilot long-term feasibility study of bone health by measuring the {sup 41}Ca trace element in urine for six years from premenopausal to later perimenopausal phases in one midlife woman. We measured bone mineral density in parallel.

Mechanisms of Bone Resorption in Periodontitis

Directory of Open Access Journals (Sweden)

Stefan A. Hienz

2015-01-01

Full Text Available Alveolar bone loss is a hallmark of periodontitis progression and its prevention is a key clinical challenge in periodontal disease treatment. Bone destruction is mediated by the host immune and inflammatory response to the microbial challenge. However, the mechanisms by which the local immune response against periodontopathic bacteria disturbs the homeostatic balance of bone formation and resorption in favour of bone loss remain to be established. The osteoclast, the principal bone resorptive cell, differentiates from monocyte/macrophage precursors under the regulation of the critical cytokines macrophage colony-stimulating factor, RANK ligand, and osteoprotegerin. TNF-α, IL-1, and PGE2 also promote osteoclast activity, particularly in states of inflammatory osteolysis such as those found in periodontitis. The pathogenic processes of destructive inflammatory periodontal diseases are instigated by subgingival plaque microflora and factors such as lipopolysaccharides derived from specific pathogens. These are propagated by host inflammatory and immune cell influences, and the activation of T and B cells initiates the adaptive immune response via regulation of the Th1-Th2-Th17 regulatory axis. In summary, Th1-type T lymphocytes, B cell macrophages, and neutrophils promote bone loss through upregulated production of proinflammatory mediators and activation of the RANK-L expression pathways.

Development of a rapid culture method to induce adipocyte differentiation of human bone marrow-derived mesenchymal stem cells

International Nuclear Information System (INIS)

Ninomiya, Yuichi; Sugahara-Yamashita, Yzumi; Nakachi, Yutaka; Tokuzawa, Yoshimi; Okazaki, Yasushi; Nishiyama, Masahiko

2010-01-01

Human mesenchymal stem cells (hMSCs) derived from bone marrow are multipotent stem cells that can regenerate mesenchymal tissues such as adipose, bone or muscle. It is thought that hMSCs can be utilized as a cell resource for tissue engineering and as human models to study cell differentiation mechanisms, such as adipogenesis, osteoblastogenesis and so on. Since it takes 2-3 weeks for hMSCs to differentiate into adipocytes using conventional culture methods, the development of methods to induce faster differentiation into adipocytes is required. In this study we optimized the culture conditions for adipocyte induction to achieve a shorter cultivation time for the induction of adipocyte differentiation in bone marrow-derived hMSCs. Briefly, we used a cocktail of dexamethasone, insulin, methylisobutylxanthine (DIM) plus a peroxisome proliferator-activated receptor γ agonist, rosiglitazone (DIMRo) as a new adipogenic differentiation medium. We successfully shortened the period of cultivation to 7-8 days from 2-3 weeks. We also found that rosiglitazone alone was unable to induce adipocyte differentiation from hMSCs in vitro. However, rosiglitazone appears to enhance hMSC adipogenesis in the presence of other hormones and/or compounds, such as DIM. Furthermore, the inhibitory activity of TGF-β1 on adipogenesis could be investigated using DIMRo-treated hMSCs. We conclude that our rapid new culture method is very useful in measuring the effect of molecules that affect adipogenesis in hMSCs.

Biological effects of drinking-water mineral composition on calcium balance and bone remodeling markers.

Science.gov (United States)

Roux, S; Baudoin, C; Boute, D; Brazier, M; De La Guéronniere, V; De Vernejoul, M C

2004-01-01

To compare the effects of 2 drinking waters containing similar calcium (Ca) concentration in order to analyze the role of ions other than Ca on bone metabolism. These mineral drinking-waters differed by their mineral composition primarily concerning the concentration of bicarbonate (HCO3-), high in the HB, and sulfate, high in HS water. Of 60 included women, 39 completed the study. Patients were randomly assigned to an intake of 1 liter per day of mineral water HB or HS for 28 d, followed by cross-over to the alternative drinking-water for a further 28 d. At baseline and after each period of one month, Ca metabolism parameters, acid-base status, and bone remodeling markers were measured. Changes in Ca metabolism were significant in the HB group where the ionized Ca increased and the PTH decreased. Serum pH showed a similar increase whatever the used drinking water compared to baseline. In the HB group, significant increase in urine pH, and significant decrease in AT-HCO3- and NH4+ were observed. Bone resorption markers, urinary CTx/Cr, Pyr/Cr, and D-Pyr/Cr, significantly decreased in the HB group compared to baseline, and were not significantly modified in the HS group. These results showed a beneficial effect of the bicarbonaterich HB water on bone metabolism. This may account for a better bioavailability of the Ca, a greater alkalinization, and a larger decrease in PTH level secondary to a higher ionized Ca level. The higher content of silica in HB water may have also participated to the positive action on bone balance that was observed. In this short term study, these data underlined the potential role of the mineral drinking water composition on bone metabolism.

Myostatin inhibits osteoblastic differentiation by suppressing osteocyte-derived exosomal microRNA-218: A novel mechanism in muscle-bone communication.

Science.gov (United States)

Qin, Yiwen; Peng, Yuanzhen; Zhao, Wei; Pan, Jianping; Ksiezak-Reding, Hanna; Cardozo, Christopher; Wu, Yingjie; Divieti Pajevic, Paola; Bonewald, Lynda F; Bauman, William A; Qin, Weiping

2017-06-30

Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts

International Nuclear Information System (INIS)

Utting, J.C.; Robins, S.P.; Brandao-Burch, A.; Orriss, I.R.; Behar, J.; Arnett, T.R.

2006-01-01

We investigated the effect of hypoxia on rat osteoblast function in long-term primary cultures. Reduction of pO 2 from 20% to 5% and 2% decreased formation of mineralized bone nodules 1.7-fold and 11-fold, respectively. When pO 2 was reduced further to 0.2%, bone nodule formation was almost abolished. The inhibitory effect of hypoxia on bone formation was partly due to decreased osteoblast proliferation, as measured by 3 H-thymidine incorporation. Hypoxia also sharply reduced osteoblast alkaline phosphatase (ALP) activity and expression of mRNAs for ALP and osteocalcin, suggesting inhibition of differentiation to the osteogenic phenotype. Hypoxia did not increase the apoptosis of osteoblasts but induced a reversible state of quiescence. Transmission electron microscopy revealed that collagen fibrils deposited by osteoblasts cultured in 2% O 2 were less organized and much less abundant than in 20% O 2 cultures. Furthermore, collagen produced by hypoxic osteoblasts contained a lower percentage of hydroxylysine residues and exhibited an increased sensitivity to pepsin degradation. These data demonstrate the absolute oxygen requirement of osteoblasts for successful bone formation and emphasize the importance of the vasculature in maintaining bone health. We recently showed that hypoxia also acts in a reciprocal manner as a powerful stimulator of osteoclast formation. Considered together, our results help to explain the bone loss that occurs at the sites of fracture, tumors, inflammation and infection, and in individuals with vascular disease or anemia

Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo.

Science.gov (United States)

Xu, Song; De Veirman, Kim; Evans, Holly; Santini, Gaia Cecilia; Vande Broek, Isabelle; Leleu, Xavier; De Becker, Ann; Van Camp, Ben; Croucher, Peter; Vanderkerken, Karin; Van Riet, Ivan

2013-05-01

Vorinostat, a histone deacetylase (HDAC) inhibitor currently in a clinical phase III trial for multiple myeloma (MM) patients, has been reported to cause bone loss. The purpose of this study was to test whether, and to what extent, vorinostat influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and bone formation in vivo. Bone marrow-derived MSCs were prepared from both normal donors and MM patients. The MSCs were cultured in an osteogenic differentiation induction medium to induce osteogenic differentiation, which was evaluated by alkaline phosphatase (ALP) staining, Alizarin Red S staining and the mRNA expression of osteogenic markers. Naïve mice were administered vorinostat (100 mg/kg, ip) every other day for 3 weeks. After the mice were sacrificed, bone formation was assessed based on serum osteocalcin level and histomorphometric analysis. Vorinostat inhibited the viability of hMSCs in a concentration-dependent manner (the IC50 value was 15.57 μmol/L). The low concentration of vorinostat (1 μmol/L) did not significantly increase apoptosis in hMSCs, whereas pronounced apoptosis was observed following exposure to higher concentrations of vorinostat (10 and 50 μmol/L). In bone marrow-derived hMSCs from both normal donors and MM patients, vorinostat (1 μmol/L) significantly increased ALP activity, mRNA expression of osteogenic markers, and matrix mineralization. These effects were associated with upregulation of the bone-specifying transcription factor Runx2 and with the epigenetic alterations during normal hMSCs osteogenic differentiation. Importantly, the mice treated with vorinostat did not show any bone loss in response to the optimized treatment regimen. Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis in vitro. With the optimized treatment regimen, any decrease in bone formation was not observed in vivo.

Osteogenic medium is superior to growth factors in differentiation of human adipose stem cells towards bone-forming cells in 3D culture

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L Tirkkonen

2013-01-01

Full Text Available Human adipose stem cells (hASCs have been recently used to treat bone defects in clinical practice. Yet there is a need for more optimal scaffolds and cost-effective approaches to induce osteogenic differentiation of hASCs. Therefore, we compared the efficiency of bone morphogenetic proteins (BMP-2 and BMP-7, vascular endothelial growth factor (VEGF, and osteogenic medium (OM for the osteo-induction of hASCs in 3D culture. In addition, growth factors were tested in combination with OM. Commercially available bioactive glass scaffolds (BioRestore and biphasic calcium phosphate granules (BoneCeramic were evaluated as prospective carriers for hASCs. Both biomaterials supported hASC-viability, but BioRestore resulted in higher cell number than BoneCeramic, whereas BoneCeramic supported more significant collagen production. The most efficient osteo-induction was achieved with plain OM, promoting higher alkaline phosphatase activity and collagen production than growth factors. In fact, treatment with BMP-2 or VEGF did not increase osteogenic differentiation or cell number significantly more than maintenance medium with either biomaterial. Moreover, BMP-7 treatment consistently inhibited proliferation and osteogenic differentiation of hASCs. Interestingly, there was no benefit from growth factors added to OM. This is the first study to demonstrate that OM enhances hASC-differentiation towards bone-forming cells significantly more than growth factors in 3D culture.

Fisetin antagonizes cell fusion, cytoskeletal organization and bone resorption in RANKL-differentiated murine macrophages.

Science.gov (United States)

Kim, Yun-Ho; Kim, Jung-Lye; Lee, Eun-Jung; Park, Sin-Hye; Han, Seon-Young; Kang, Soon Ah; Kang, Young-Hee

2014-03-01

Osteoclastogenesis is comprised of several stage s including progenitor survival, differentiation to mononuclear preosteoclasts, cell fusion to multinuclear mature osteoclasts, and activation to osteoclasts with bone resorbing activity. Botanical antioxidants are now being increasingly investigated for their health-promoting effects on bone. This study investigated that fisetin, a flavonol found naturally in many fruits and vegetables, suppressed osteoclastogenesis by disturbing receptor activator of nuclear factor (NF)-κB ligand (RANKL)-mediated signaling pathway and demoting osteoclastogenic protein induction. Nontoxic fisetin at ≤10 μM inhibited the induction of RANK, tumor necrosis factor receptor associated factor 6 (TRAF6) and the activation of NF-κB in RANKL-stimulated RAW 264.7 macrophages. In RANKL-differentiated osteoclasts cell fusion protein of E-cadherin was induced, which was dampened by fisetin. The formation of tartrate-resistance acid phosphatase-positive multinucleated osteoclasts was suppressed by adding fisetin to RANKL-exposed macrophages. It was also found that fisetin reduced actin ring formation and gelsolin induction of osteclasts enhanced by RANKL through disturbing c-Src-proline-rich tyrosine kinase 2 signaling. Fisetin deterred preosteoclasts from the cell-cell fusion and the organization of the cytoskeleton to seal the resorbing area and to secret protons for bone resorption. Consistently, the 5 day-treatment of fisetin diminished RANKL-induced cellular expression of carbonic anhydrase II and integrin β3 concurrently with a reduction of osteoclast bone-resorbing activity. Therefore, fisetin was a natural therapeutic agent retarding osteoclast fusion and cytoskeletal organization such as actin rings and ruffled boarder, which is a property of mature osteoclasts and is required for osteoclasts to resorb bone. Copyright © 2014 Elsevier Inc. All rights reserved.

CT diagnosis and differential diagnosis of otodystrophic lesions of the temporal bone

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D' Archambeau, O.; Parizel, P.M.; Schepper, A.M. De (Antwerp University Hospital (Belgium). Department of Radiology); Koekelkoren, E.; Van De Heyning, P. (Antwerp University Hospital (Belgium). Department of E.N.T.)

The purpose of this study was to assess the diagnostic and differential diagnostic value of high-resolution computed tomography in the evaluation of temporal-bone dystrophies. The study group included 55 patients with osseous abnormalities of the temporal bone in general, and the labyrinthine capsule in particular. In 27 patients the CT scan revealed evidence of otodystrophic lesions. The CT findings in patients with otosclerosis (21 patients), osteogenesis imperfecta (two patients), fibrous dysplasia (one patient). Paget's disease (one patient) and osteoporosis (two patients) are described. The CT scans of 17 patients revealed secondary osseous lesions due to metastasis (five patients), post-inflammatory changes (10 patients) or labyrinthitis ossificans (two patients). Normal variants and congenital mineralization defects were diagnosed in nine patients, Down's syndrome in two. Our results indicate the importance of high-resolution computed tomography as the primary imaging modality in evaluating osseous lesions of the temporal bone and labyrinth. (author). 14 refs.; 13 figs; 2 tabs.

CT diagnosis and differential diagnosis of otodystrophic lesions of the temporal bone

International Nuclear Information System (INIS)

D'Archambeau, O.; Parizel, P.M.; Schepper, A.M. De; Koekelkoren, E.; Van De Heyning, P.

1990-01-01

The purpose of this study was to assess the diagnostic and differential diagnostic value of high-resolution computed tomography in the evaluation of temporal-bone dystrophies. The study group included 55 patients with osseous abnormalities of the temporal bone in general, and the labyrinthine capsule in particular. In 27 patients the CT scan revealed evidence of otodystrophic lesions. The CT findings in patients with otosclerosis (21 patients), osteogenesis imperfecta (two patients), fibrous dysplasia (one patient). Paget's disease (one patient) and osteoporosis (two patients) are described. The CT scans of 17 patients revealed secondary osseous lesions due to metastasis (five patients), post-inflammatory changes (10 patients) or labyrinthitis ossificans (two patients). Normal variants and congenital mineralization defects were diagnosed in nine patients, Down's syndrome in two. Our results indicate the importance of high-resolution computed tomography as the primary imaging modality in evaluating osseous lesions of the temporal bone and labyrinth. (author). 14 refs.; 13 figs; 2 tabs

Differential Intracochlear Sound Pressure Measurements in Normal Human Temporal Bones

Science.gov (United States)

Nakajima, Hideko Heidi; Dong, Wei; Olson, Elizabeth S.; Merchant, Saumil N.; Ravicz, Michael E.; Rosowski, John J.

2009-02-01

We present the first simultaneous sound pressure measurements in scala vestibuli and scala tympani of the cochlea in human cadaveric temporal bones. Micro-scale fiberoptic pressure sensors enabled the study of differential sound pressure at the cochlear base. This differential pressure is the input to the cochlear partition, driving cochlear waves and auditory transduction. Results showed that: pressure of scala vestibuli was much greater than scala tympani except at low and high frequencies where scala tympani pressure affects the input to the cochlea; the differential pressure proved to be an excellent measure of normal ossicular transduction of sound (shown to decrease 30-50 dB with ossicular disarticulation, whereas the individual scala pressures were significantly affected by non-ossicular conduction of sound at high frequencies); the middle-ear gain and differential pressure were generally bandpass in frequency dependence; and the middle-ear delay in the human was over twice that of the gerbil. Concurrent stapes velocity measurements allowed determination of the differential impedance across the partition and round-window impedance. The differential impedance was generally resistive, while the round-window impedance was consistent with a compliance in conjunction with distributed inertia and damping. Our techniques can be used to study inner-ear conductive pathologies (e.g., semicircular dehiscence), as well as non-ossicular cochlear stimulation (e.g., round-window stimulation) - situations that cannot be completely quantified by measurements of stapes velocity or scala-vestibuli pressure by themselves.

White blood cell differential count of maturation stages in bone marrow smear using dual-stage convolutional neural networks.

Directory of Open Access Journals (Sweden)

Jin Woo Choi

Full Text Available The white blood cell differential count of the bone marrow provides information concerning the distribution of immature and mature cells within maturation stages. The results of such examinations are important for the diagnosis of various diseases and for follow-up care after chemotherapy. However, manual, labor-intensive methods to determine the differential count lead to inter- and intra-variations among the results obtained by hematologists. Therefore, an automated system to conduct the white blood cell differential count is highly desirable, but several difficulties hinder progress. There are variations in the white blood cells of each maturation stage, small inter-class differences within each stage, and variations in images because of the different acquisition and staining processes. Moreover, a large number of classes need to be classified for bone marrow smear analysis, and the high density of touching cells in bone marrow smears renders difficult the segmentation of single cells, which is crucial to traditional image processing and machine learning. Few studies have attempted to discriminate bone marrow cells, and even these have either discriminated only a few classes or yielded insufficient performance. In this study, we propose an automated white blood cell differential counting system from bone marrow smear images using a dual-stage convolutional neural network (CNN. A total of 2,174 patch images were collected for training and testing. The dual-stage CNN classified images into 10 classes of the myeloid and erythroid maturation series, and achieved an accuracy of 97.06%, a precision of 97.13%, a recall of 97.06%, and an F-1 score of 97.1%. The proposed method not only showed high classification performance, but also successfully classified raw images without single cell segmentation and manual feature extraction by implementing CNN. Moreover, it demonstrated rotation and location invariance. These results highlight the promise of

White blood cell differential count of maturation stages in bone marrow smear using dual-stage convolutional neural networks.

Science.gov (United States)

Choi, Jin Woo; Ku, Yunseo; Yoo, Byeong Wook; Kim, Jung-Ah; Lee, Dong Soon; Chai, Young Jun; Kong, Hyoun-Joong; Kim, Hee Chan

2017-01-01

The white blood cell differential count of the bone marrow provides information concerning the distribution of immature and mature cells within maturation stages. The results of such examinations are important for the diagnosis of various diseases and for follow-up care after chemotherapy. However, manual, labor-intensive methods to determine the differential count lead to inter- and intra-variations among the results obtained by hematologists. Therefore, an automated system to conduct the white blood cell differential count is highly desirable, but several difficulties hinder progress. There are variations in the white blood cells of each maturation stage, small inter-class differences within each stage, and variations in images because of the different acquisition and staining processes. Moreover, a large number of classes need to be classified for bone marrow smear analysis, and the high density of touching cells in bone marrow smears renders difficult the segmentation of single cells, which is crucial to traditional image processing and machine learning. Few studies have attempted to discriminate bone marrow cells, and even these have either discriminated only a few classes or yielded insufficient performance. In this study, we propose an automated white blood cell differential counting system from bone marrow smear images using a dual-stage convolutional neural network (CNN). A total of 2,174 patch images were collected for training and testing. The dual-stage CNN classified images into 10 classes of the myeloid and erythroid maturation series, and achieved an accuracy of 97.06%, a precision of 97.13%, a recall of 97.06%, and an F-1 score of 97.1%. The proposed method not only showed high classification performance, but also successfully classified raw images without single cell segmentation and manual feature extraction by implementing CNN. Moreover, it demonstrated rotation and location invariance. These results highlight the promise of the proposed method

White blood cell differential count of maturation stages in bone marrow smear using dual-stage convolutional neural networks

Science.gov (United States)

Choi, Jin Woo; Ku, Yunseo; Yoo, Byeong Wook; Kim, Jung-Ah; Lee, Dong Soon; Chai, Young Jun; Kong, Hyoun-Joong

2017-01-01

The white blood cell differential count of the bone marrow provides information concerning the distribution of immature and mature cells within maturation stages. The results of such examinations are important for the diagnosis of various diseases and for follow-up care after chemotherapy. However, manual, labor-intensive methods to determine the differential count lead to inter- and intra-variations among the results obtained by hematologists. Therefore, an automated system to conduct the white blood cell differential count is highly desirable, but several difficulties hinder progress. There are variations in the white blood cells of each maturation stage, small inter-class differences within each stage, and variations in images because of the different acquisition and staining processes. Moreover, a large number of classes need to be classified for bone marrow smear analysis, and the high density of touching cells in bone marrow smears renders difficult the segmentation of single cells, which is crucial to traditional image processing and machine learning. Few studies have attempted to discriminate bone marrow cells, and even these have either discriminated only a few classes or yielded insufficient performance. In this study, we propose an automated white blood cell differential counting system from bone marrow smear images using a dual-stage convolutional neural network (CNN). A total of 2,174 patch images were collected for training and testing. The dual-stage CNN classified images into 10 classes of the myeloid and erythroid maturation series, and achieved an accuracy of 97.06%, a precision of 97.13%, a recall of 97.06%, and an F-1 score of 97.1%. The proposed method not only showed high classification performance, but also successfully classified raw images without single cell segmentation and manual feature extraction by implementing CNN. Moreover, it demonstrated rotation and location invariance. These results highlight the promise of the proposed method

Differentiation of malignant and degenerative benign bone disease using 99mTc-citrate scintigraphy

International Nuclear Information System (INIS)

Guo Rui; Jin Jianhua; Li Sijin; Li Xianfeng; Zhang Xiaojuan; Ren Yuan

2008-01-01

Objective: To differentiate malignant and degenerative benign bone disease using 99m Tc- citrate scintigraphy. Methods: Thirty-nine patients (92 lesions) with confirmed malignant bone disease or degenerative benign bone disease were studied, for which the results of 99m Te-methylene diphosphonate( 99m Tc- MDP) scintigraphy were positive. 99m Tc-citrate scintigraphy was performed within a time interval of 2-7 days after 99m Tc-MDP scintigraphy. Visual analysis and semiquantitative analysis were applied. Each lesion was scored as malignant or benign, which was independently verified, using conventional techniques (histopathology, X-ray, CT, MRI and clinical follow up). Results: In visual analysis of 99m Tc-citrate imaging, most malignant lesions (35/48, 72.92%) clearly showed high radioactivity accumulation, while most benign lesions (39/44, 88.64%) had not obviously visible uptake of 99m Tc-citrate. In semiquantitative analysis of 99m Tc- citrate image, malignant lesions demonstrated a higher lesion-to-background radioisotope uptake ratio (RUR) than that of benign degenerative lesions (1.47 ± 0.42 vs. 1.09 ± 0.38, t=2.887, P 99m Tc-MDP in the two groups is of the same (1.96 ± 0.25 vs. 1.87 ± 0.21, t=1.178, P>0.20). Conclusion: 99m Tc- citrate scintigraphy is a promising method to differentiate malignant from benign degenerative lesions seen as areas of increased activity on 99m Tc-MDP bone scintigraphy. (authors)

Endothelial Progenitor Cell Fraction Contained in Bone Marrow-Derived Mesenchymal Stem Cell Populations Impairs Osteogenic Differentiation

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Fabian Duttenhoefer

2015-01-01

Full Text Available In bone tissue engineering (TE endothelial cell-osteoblast cocultures are known to induce synergies of cell differentiation and activity. Bone marrow mononucleated cells (BMCs are a rich source of mesenchymal stem cells (MSCs able to develop an osteogenic phenotype. Endothelial progenitor cells (EPCs are also present within BMC. In this study we investigate the effect of EPCs present in the BMC population on MSCs osteogenic differentiation. Human BMCs were isolated and separated into two populations. The MSC population was selected through plastic adhesion capacity. EPCs (CD34+ and CD133+ were removed from the BMC population and the resulting population was named depleted MSCs. Both populations were cultured over 28 days in osteogenic medium (Dex+ or medium containing platelet lysate (PL. MSC population grew faster than depleted MSCs in both media, and PL containing medium accelerated the proliferation for both populations. Cell differentiation was much higher in Dex+ medium in both cases. Real-time RT-PCR revealed upregulation of osteogenic marker genes in depleted MSCs. Higher values of ALP activity and matrix mineralization analyses confirmed these results. Our study advocates that absence of EPCs in the MSC population enables higher osteogenic gene expression and matrix mineralization and therefore may lead to advanced bone neoformation necessary for TE constructs.

MicroRNA-4739 regulates osteogenic and adipocytic differentiation of immortalized human bone marrow stromal cells via targeting LRP3

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Mona Elsafadi

2017-04-01

Full Text Available Understanding the regulatory networks underlying lineage differentiation and fate determination of human bone marrow stromal cells (hBMSC is a prerequisite for their therapeutic use. The goal of the current study was to unravel the novel role of the low-density lipoprotein receptor-related protein 3 (LRP3 in regulating the osteogenic and adipogenic differentiation of immortalized hBMSCs. Gene expression profiling revealed significantly higher LRP3 levels in the highly osteogenic hBMSC clone imCL1 than in the less osteogenic clone imCL2, as well as a significant upregulation of LRP3 during the osteogenic induction of the imCL1 clone. Data from functional and gene expression assays demonstrated the role of LRP3 as a molecular switch promoting hBMSC lineage differentiation into osteoblasts and inhibiting differentiation into adipocytes. Interestingly, microRNA (miRNA expression profiling identified miR-4739 as the most under-represented miRNA (−36.11 fold in imCL1 compared to imCL2. The TargetScan prediction algorithm, combined with functional and biochemical assays, identified LRP3 mRNA as a novel target of miR-4739, with a single potential binding site for miR-4739 located in the LRP3 3′ UTR. Regulation of LRP3 expression by miR-4739 was subsequently confirmed by qRT-PCR, western blotting, and luciferase assays. Over-expression of miR-4739 mimicked the effects of LRP3 knockdown on promoting adipogenic and suppressing osteogenic differentiation of hBMSCs. Hence, we report for the first time a novel biological role for the LRP3/hsa-miR-4739 axis in balancing osteogenic and adipocytic differentiation of hBMSCs. Our data support the potential utilization of miRNA-based therapies in regenerative medicine.

Cancer Metastases to Bone: Concepts, Mechanisms, and Interactions with Bone Osteoblasts

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Alison B. Shupp

2018-06-01

Full Text Available The skeleton is a unique structure capable of providing support for the body. Bone resorption and deposition are controlled in a tightly regulated balance between osteoblasts and osteoclasts with no net bone gain or loss. However, under conditions of disease, the balance between bone resorption and deposition is upset. Osteoblasts play an important role in bone homeostasis by depositing new bone osteoid into resorption pits. It is becoming increasingly evident that osteoblasts additionally play key roles in cancer cell dissemination to bone and subsequent metastasis. Our laboratory has evidence that when osteoblasts come into contact with disseminated breast cancer cells, the osteoblasts produce factors that initially reduce breast cancer cell proliferation, yet promote cancer cell survival in bone. Other laboratories have demonstrated that osteoblasts both directly and indirectly contribute to dormant cancer cell reactivation in bone. Moreover, we have demonstrated that osteoblasts undergo an inflammatory stress response in late stages of breast cancer, and produce inflammatory cytokines that are maintenance and survival factors for breast cancer cells and osteoclasts. Advances in understanding interactions between osteoblasts, osteoclasts, and bone metastatic cancer cells will aid in controlling and ultimately preventing cancer cell metastasis to bone.

Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

DEFF Research Database (Denmark)

Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

2018-01-01

during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor......Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling...... signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand...

Insecurity of Employment and Work-Life Balance: From the viewpoint of compensating wage differentials

OpenAIRE

MORIKAWA Masayuki

2010-01-01

This paper presents survey-based evidence on the "fair" compensating wage differentials for insecurity of employment and lack of work-life balance (WLB). We present facts about individual perceptions of the desirable compensating differentials and then estimate the effects of working hours and wages on job satisfaction. The fair wage premiums for insecurity of employment and lack of WLB are both around 10% to 20%. The actual relative wages of nonstandard workers seem to be lower than those in...

Metabolic, endocrine, and related bone diseases

International Nuclear Information System (INIS)

Rogers, L.F.

1987-01-01

Bone is living tissue, and old bone is constantly removed and replaced with new bone. Normally this exchange is in balance, and the mineral content remains relatively constant. This balance may be disturbed as a result of certain metabolic and endocrinologic disorders. The term dystrophy, referring to a disturbance of nutrition, is applied to metabolic and endocrine bone diseases and should be distinguished from the term dysplasia, referring to a disturbance of bone growth. The two terms are easily confused but are not interchangeable. Metabolic bone disease is caused by endocrine imbalance, vitamin deficiency or excess, and other disturbances in bone metabolism leading to osteoporosis and osteomalacia

A genomic characterization of the influence of silver nanoparticles on bone differentiation in MC3T3-E1 cells.

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Qing, Tao; Mahmood, Meena; Zheng, Yuanting; Biris, Alexandru S; Shi, Leming; Casciano, Daniel A

2018-02-01

Silver nanoparticles (AgNPs) have been widely used in a variety of biomedical applications. Previous studies demonstrated that AgNPs significantly enhanced bone cell mineralization and differentiation in MC3T3-1 cells, a model in vitro system, when compared to several other NPs. This increased bone deposition was evaluated by phenotypic measurements and assessment of the expression of miRNAs associated with regulation of bone morphogenic proteins. In the present study, we used RNA-seq technology, a more direct measurement of gene expression, to investigate further the mechanisms of bone differentiation induced by AgNP treatment. Key factors associated with the osteoclast pathway were significantly increased in response to AgNP exposure including Bmp4, Bmp6 and Fosl1. In addition, genes of metabolism and toxicity pathways were significantly regulated as well. Although this study suggests the potential for AgNPs to influence bone morphogenesis in injury or disease applications, further investigation into the efficacy and safety of AgNPs in bone regeneration is warranted. Copyright © 2017 John Wiley & Sons, Ltd.

On the role of subtype selective adenosine receptor agonists during proliferation and osteogenic differentiation of human primary bone marrow stromal cells.

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Costa, M Adelina; Barbosa, A; Neto, E; Sá-e-Sousa, A; Freitas, R; Neves, J M; Magalhães-Cardoso, T; Ferreirinha, F; Correia-de-Sá, P

2011-05-01

Purines are important modulators of bone cell biology. ATP is metabolized into adenosine by human primary osteoblast cells (HPOC); due to very low activity of adenosine deaminase, the nucleoside is the end product of the ecto-nucleotidase cascade. We, therefore, investigated the expression and function of adenosine receptor subtypes (A(1) , A(2A) , A(2B) , and A(3) ) during proliferation and osteogenic differentiation of HPOC. Adenosine A(1) (CPA), A(2A) (CGS21680C), A(2B) (NECA), and A(3) (2-Cl-IB-MECA) receptor agonists concentration-dependently increased HPOC proliferation. Agonist-induced HPOC proliferation was prevented by their selective antagonists, DPCPX, SCH442416, PSB603, and MRS1191. CPA and NECA facilitated osteogenic differentiation measured by increases in alkaline phosphatase (ALP) activity. This contrasts with the effect of CGS21680C which delayed HPOC differentiation; 2-Cl-IB-MECA was devoid of effect. Blockade of the A(2B) receptor with PSB603 prevented osteogenic differentiation by NECA. In the presence of the A(1) antagonist, DPCPX, CPA reduced ALP activity at 21 and 28 days in culture. At the same time points, blockade of A(2A) receptors with SCH442416 transformed the inhibitory effect of CGS21680C into facilitation. Inhibition of adenosine uptake with dipyridamole caused a net increase in osteogenic differentiation. The presence of all subtypes of adenosine receptors on HPOC was confirmed by immunocytochemistry. Data show that adenosine is an important regulator of osteogenic cell differentiation through the activation of subtype-specific receptors. The most abundant A(2B) receptor seems to have a consistent role in cell differentiation, which may be balanced through the relative strengths of A(1) or A(2A) receptors determining whether osteoblasts are driven into proliferation or differentiation. Copyright © 2010 Wiley-Liss, Inc.

Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells.

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Delk, Nikki A; Farach-Carson, Mary C

2012-04-01

Autophagy reallocates nutrients and clears normal cells of damaged proteins and organelles. In the context of metastatic disease, invading cancer cells hijack autophagic processes to survive and adapt in the host microenvironment. We sought to understand how autophagy is regulated in the metastatic niche for prostate cancer (PCa) cells where bone marrow stromal cell (BMSC) paracrine signaling induces PCa neuroendocrine differentiation (NED). In PCa, this transdifferentiation of metastatic PCa cells to neuronal-like cells correlates with advanced disease. Because autophagy provides a survival advantage for cancer cells and promotes cell differentiation, we hypothesized that autophagy mediates PCa NED in the bone. Thus, we determined the ability of paracrine factors in conditioned media (CM) from two separate BMSC subtypes, HS5 and HS27a, to induce autophagy in C4-2 and C4-2B bone metastatic PCa cells by characterizing the autophagy marker, LC3. Unlike HS27a CM, HS5 CM induced LC3 accumulation in PCa cells, suggesting autophagy was induced and indicating that HS5 and HS27a secrete a different milieu of paracrine factors that influence PCa autophagy. We identified interleukin-6 (IL-6), a cytokine more highly expressed in HS5 cells than in HS27a cells, as a paracrine factor that regulates PCa autophagy. Pharmacological inhibition of STAT3 activity did not attenuate LC3 accumulation, implying that IL-6 regulates NED and autophagy through different pathways. Finally, chloroquine inhibition of autophagic flux blocked PCa NED; hence autophagic flux maintains NED. Our studies imply that autophagy is cytoprotective for PCa cells in the bone, thus targeting autophagy is a potential therapeutic strategy.

Isolation, Culture, and Differentiation of Bone Marrow Stromal Cells and Osteoclast Progenitors from Mice.

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Maridas, David E; Rendina-Ruedy, Elizabeth; Le, Phuong T; Rosen, Clifford J

2018-01-06

Bone marrow stromal cells (BMSCs) constitute a cell population routinely used as a representation of mesenchymal stem cells in vitro. They reside within the bone marrow cavity alongside hematopoietic stem cells (HSCs), which can give rise to red blood cells, immune progenitors, and osteoclasts. Thus, extractions of cell populations from the bone marrow results in a very heterogeneous mix of various cell populations, which can present challenges in experimental design and confound data interpretation. Several isolation and culture techniques have been developed in laboratories in order to obtain more or less homogeneous populations of BMSCs and HSCs invitro. Here, we present two methods for isolation of BMSCs and HSCs from mouse long bones: one method that yields a mixed population of BMSCs and HSCs and one method that attempts to separate the two cell populations based on adherence. Both methods provide cells suitable for osteogenic and adipogenic differentiation experiments as well as functional assays.

Menopause and Bone Loss

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Fact Sheet & Menopause Bone Loss How are bone loss and menopause related? Throughout life your body keeps a balance between the ... lose bone faster than it can be replaced. Menopause—the time when menstrual periods end, which usually ...

Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation

Energy Technology Data Exchange (ETDEWEB)

Chu, Tianqing; Teng, Jiajun; Jiang, Liyan; Zhong, Hua; Han, Baohui, E-mail: baohuihan1@163.com

2014-01-17

Highlights: •DKK1 level was associated with NSCLC bone metastases. •Lung tumor cells derived DKK1 inhibited osteoblast differentiation. •Lung tumor cells derived DKK1 modulates β-catenin and RUNX2. -- Abstract: Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC.

Lung cancer-derived Dickkopf1 is associated with bone metastasis and the mechanism involves the inhibition of osteoblast differentiation

International Nuclear Information System (INIS)

Chu, Tianqing; Teng, Jiajun; Jiang, Liyan; Zhong, Hua; Han, Baohui

2014-01-01

Highlights: •DKK1 level was associated with NSCLC bone metastases. •Lung tumor cells derived DKK1 inhibited osteoblast differentiation. •Lung tumor cells derived DKK1 modulates β-catenin and RUNX2. -- Abstract: Wnt/β-catenin signaling and Dickkopf1 (DKK1) play important roles in the progression of lung cancer, which preferably metastasizes to skeleton. But the role of them in bone dissemination is poorly understood. This study aims to define the role of DKK1 in lung cancer bone metastases and investigate the underlying mechanism. Our results demonstrated that DKK1 over-expression was a frequent event in non-small-cell lung cancer (NSCLC) blood samples, and serous DKK1 level was much higher in bone metastatic NSCLC compared to non-bone metastatic NSCLC. We also found that conditioned medium from DKK1 over-expressing lung cancer cells inhibited the differentiation of osteoblast, determined by alkaline phosphatase activity and osteocalcin secretion, whereas the conditioned medium from DKK1 silencing lung cancer cells exhibited the opposite effects. Mechanistically, DKK1 reduced the level of β-catenin and RUNX2, as well as inhibiting the nuclear translocation of β-catenin. Taken together, these results suggested that lung cancer-produced DKK1 may be an important mechanistic link between NSCLC and bone metastases, and targeting DKK1 may be an effective method to treat bone metastase of NSCLC

Role of apparent diffusion coefficients with diffusion-weighted magnetic resonance imaging in differentiating between benign and malignant bone tumors.

Science.gov (United States)

Wang, Tingting; Wu, Xiangru; Cui, Yanfen; Chu, Caiting; Ren, Gang; Li, Wenhua

2014-11-29

Benign and malignant bone tumors can present similar imaging features. This study aims to evaluate the significance of apparent diffusion coefficients (ADC) in differentiating between benign and malignant bone tumors. A total of 187 patients with 198 bone masses underwent diffusion-weighted (DW) magnetic resonance (MR) imaging. The ADC values in the solid components of the bone masses were assessed. Statistical differences between the mean ADC values in the different tumor types were determined by Student's t-test. Histological analysis showed that 84/198 (42.4%) of the bone masses were benign and 114/198 (57.6%) were malignant. There was a significant difference between the mean ADC values in the benign and malignant bone lesions (Pbenign and malignant bone tumors.

Induction of DNA-strand breaks after X- irradiation in murine bone cells of various differentiation capacities

Science.gov (United States)

Lau, P.; Hellweg, C. E.; Kirchner, S.; Arenz, A.; Baumstark-Khan, C.; Horneck, G.

Bone loss resulting from long-duration space flight is a well known medical risk for space travellers, as a weakened skeleton is more susceptible to bone fractures. In addition to weightlessness the astronaut is also exposed to cosmic ionizing radiation. In order to elucidate changes in bone cell metabolism by ionizing radiation, a ground-based bone cell model has been developed. This model consists of a bunch of immortalized murine osteocyte, osteoblast and pre-osteoblast cell lines representing discrete stages of differentiation: The osteocyte cell line MLO-Y4 (obtained from L. Bonewald, Kansas City, USA), the osteoblast cell line OCT-1 (obtained from D. Chen, San Antonio, USA), and the subclones 4 and 24 of the osteoblast cell line MC3T3-E1 (obtained from ATCC, Manassas, Virginia, USA). Regarding their growth properties, MLO-Y4 cells show the highest growth velocity with a doubling time of 15.8 h. The osteoblast cell line OCT-1 has a doubling time of 27.3 h. The respective values for MC3T3-E1 subclone 24 and S4 are 90.5 h and 51.6 h. To investigate the stage of differentiation, the expression of alkaline phosphatase, of osteocalcin and of E11 was examined. Survival after X-ray exposure was determined using the colony forming ability test. The resulting dose-effect relationships revealed significant differences. The parameter D0 of the survival curves ranges between 1.8 Gy for OCT-1, 1.9 Gy for MLO-Y4, 2.0 Gy for subclone 24 and 2,3 Gy for subclone 4. The quantitative acquisition of DNA-strand breaks was performed by Fluorescent Analysis of DNA-Unwinding (FADU). The results can be correlated with the corresponding survival curve. In conclusion, the cell lines with higher differentiation levels are less sensitive to radiation when compared to the lower differentiated osteoblast cell lines.

The Him gene reveals a balance of inputs controlling muscle differentiation in Drosophila.

Science.gov (United States)

Liotta, David; Han, Jun; Elgar, Stuart; Garvey, Clare; Han, Zhe; Taylor, Michael V

2007-08-21

Tissue development requires the controlled regulation of cell-differentiation programs. In muscle, the Mef2 transcription factor binds to and activates the expression of many genes and has a major positive role in the orchestration of differentiation. However, little is known about how Mef2 activity is regulated in vivo during development. Here, we characterize a gene, Holes in muscle (Him), which our results indicate is part of this control in Drosophila. Him expression rapidly declines as embryonic muscle differentiates, and consistent with this, Him overexpression inhibits muscle differentiation. This inhibitory effect is suppressed by mef2, implicating Him in the mef2 pathway. We then found that Him downregulates the transcriptional activity of Mef2 in both cell culture and in vivo. Furthermore, Him protein binds Groucho, a conserved, transcriptional corepressor, through a WRPW motif and requires this motif and groucho function to inhibit both muscle differentiation and Mef2 activity during development. Together, our results identify a mechanism that can inhibit muscle differentiation in vivo. We conclude that a balance of positive and negative inputs, including Mef2, Him, and Groucho, controls muscle differentiation during Drosophila development and suggest that one outcome is to hold developing muscle cells in a state with differentiation genes poised to be expressed.

Receptor tyrosine kinase inhibition causes simultaneous bone loss and excess bone formation within growing bone in rats

International Nuclear Information System (INIS)

Nurmio, Mirja; Joki, Henna; Kallio, Jenny; Maeaettae, Jorma A.; Vaeaenaenen, H. Kalervo; Toppari, Jorma; Jahnukainen, Kirsi; Laitala-Leinonen, Tiina

2011-01-01

During postnatal skeletal growth, adaptation to mechanical loading leads to cellular activities at the growth plate. It has recently become evident that bone forming and bone resorbing cells are affected by the receptor tyrosine kinase (RTK) inhibitor imatinib mesylate (STI571, Gleevec (registered) ). Imatinib targets PDGF, ABL-related gene, c-Abl, c-Kit and c-Fms receptors, many of which have multiple functions in the bone microenvironment. We therefore studied the effects of imatinib in growing bone. Young rats were exposed to imatinib (150 mg/kg on postnatal days 5-7, or 100 mg/kg on postnatal days 5-13), and the effects of RTK inhibition on bone physiology were studied after 8 and 70 days (3-day treatment), or after 14 days (9-day treatment). X-ray imaging, computer tomography, histomorphometry, RNA analysis and immunohistochemistry were used to evaluate bone modeling and remodeling in vivo. Imatinib treatment eliminated osteoclasts from the metaphyseal osteochondral junction at 8 and 14 days. This led to a resorption arrest at the growth plate, but also increased bone apposition by osteoblasts, thus resulting in local osteopetrosis at the osteochondral junction. The impaired bone remodelation observed on day 8 remained significant until adulthood. Within the same bone, increased osteoclast activity, leading to bone loss, was observed at distal bone trabeculae on days 8 and 14. Peripheral quantitative computer tomography (pQCT) and micro-CT analysis confirmed that, at the osteochondral junction, imatinib shifted the balance from bone resorption towards bone formation, thereby altering bone modeling. At distal trabecular bone, in turn, the balance was turned towards bone resorption, leading to bone loss. - Research highlights: → 3-Day imatinib treatment. → Causes growth plate anomalies in young rats. → Causes biomechanical changes and significant bone loss at distal trabecular bone. → Results in loss of osteoclasts at osteochondral junction.

Differential effects of calorie restriction and involuntary wheel running on body composition and bone structure in diet-induced obese rats

Science.gov (United States)

Weight reduction is recommended to reduce obesity-related health disorders. This study investigated the differential effects of weight reduction through caloric restriction and/or physical activity on bone structure and molecular characteristics of bone metabolism in an obese rat model. We tested th...

Inhibiting actin depolymerization enhances osteoblast differentiation and bone formation in human stromal stem cells

DEFF Research Database (Denmark)

Chen, Li; Shi, Kaikai; Frary, Charles

2015-01-01

Remodeling of the actin cytoskeleton through actin dynamics is involved in a number of biological processes, but its role in human stromal (skeletal) stem cells (hMSCs) differentiation is poorly understood. In the present study, we demonstrated that stabilizing actin filaments by inhibiting gene...... expression of the two main actin depolymerizing factors (ADFs): Cofilin 1 (CFL1) and Destrin (DSTN) in hMSCs, enhanced cell viability and differentiation into osteoblastic cells (OB) in vitro, as well as heterotopic bone formation in vivo. Similarly, treating hMSC with Phalloidin, which is known to stabilize...... polymerized actin filaments, increased hMSCs viability and OB differentiation. Conversely, Cytocholasin D, an inhibitor of actin polymerization, reduced cell viability and inhibited OB differentiation of hMSC. At a molecular level, preventing Cofilin phosphorylation through inhibition of LIM domain kinase 1...

Role of RHEB in Regulating Differentiation Fate of Mesenchymal Stem Cells for Cartilage and Bone Regeneration

Directory of Open Access Journals (Sweden)

Sajjad Ashraf

2017-04-01

Full Text Available Advances in mesenchymal stem cells (MSCs and cell replacement therapies are promising approaches to treat cartilage and bone defects since substantial differentiation capacities of MSCs match the demands of tissue regeneration. Our understanding of the dynamic process requiring indispensable differentiation of MSCs remains limited. Herein, we describe the role of RHEB (Ras homolog enriched in brain regulating gene signature for differentiation of human adipose derived mesenchymal stem cells (ASCs into chondrogenic, osteogenic, and adipogenic lineages. RHEB-overexpression increases the proliferation of the ASCs. RHEB enhances the chondrogenic differentiation of ASCs in 3D culture via upregulation of SOX9 with concomitant increase in glycosaminoglycans (GAGs, and type II collagen (COL2. RHEB increases the osteogenesis via upregulation of runt related transcription factor 2 (RUNX2 with an increase in the calcium and phosphate contents. RHEB also increases the expression of osteogenic markers, osteonectin and osteopontin. RHEB knockdown ASCs were incapable of expressing sufficient SRY (Sex determining region Y-box 9 (SOX9 and RUNX2, and therefore had decreased chondrogenic and osteogenic differentiation. RHEB-overexpression impaired ASCs differentiation into adipogenic lineage, through downregulation of CCAAT/enhancer binding protein beta (C/EBPβ. Conversely, RHEB knockdown abolished the negative regulation of adipogenesis. We demonstrate that RHEB is a novel regulator, with a critical role in ASCs lineage determination, and RHEB-modulated ASCs may be useful as a cell therapy for cartilage and bone defect treatments.

Effects of low-doses of Bacillus spp. from permafrost on differentiation of bone marrow cells.

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Kalyonova, L F; Novikova, M A; Kostolomova, E G

2015-01-01

The effects of a new microorganism species (Bacillus spp., strain M3) isolated from permafrost specimens from Central Yakutia (Mamontova Mountain) on the bone marrow hemopoiesis were studied on laboratory mice. Analysis of the count and immunophenotype of bone marrow cells indicated that even in low doses (1000-5000 microbial cells) these microorganisms modulated hemopoiesis and lymphopoiesis activity. The percentage of early hemopoietic precursors (CD117(+)CD34(-)) increased, intensity of lymphocyte precursor proliferation and differentiation (CD25(+)CD44(-)) decreased, and the percentage of lymphocytes released from the bone marrow (CD25(+)CD44(+)) increased on day 21 after injection of the bacteria. These changes in activity of hemopoiesis were associated with changes in the level of regulatory T lymphocytes (reduced expression of TCRαβ) and were most likely compensatory. The possibility of modulating hemopoiesis activity in the bone marrow by low doses of one microorganism strain isolated from the permafrost could be useful for evaluating the effects of other low dose bacteria on the bone marrow hemopoiesis.

Theoretical analysis of the spatio-temporal structure of bone multicellular units

International Nuclear Information System (INIS)

Buenzli, P R; Pivonka, P; Gardiner, B S; Smith, D W; Dunstan, C R; Mundy, G R

2010-01-01

Bone multicellular units (BMUs) maintain the viability of the skeletal tissue by coordinating locally the sequence of bone resorption and bone formation performed by cells of the osteoclastic and osteoblastic lineage. Understanding the emergence and the net bone balance of such structured microsystems out of the complex network of biochemical interactions between bone cells is fundamental for many bone-related diseases and the evaluation of fracture risk. Based on current experimental knowledge, we propose a spatio-temporal continuum model describing the interactions of osteoblastic and osteoclastic cells. We show that this model admits travelling-wave-like solutions with well-confined cell profiles upon specifying external conditions mimicking the environment encountered in cortical bone remodelling. The shapes of the various cell concentration profiles within this travelling structure are intrinsically linked to the parameters of the model such as differentiation, proliferation, and apoptosis rates of bone cells. The internal structure of BMUs is reproduced, allowing for experimental calibration. The spatial distribution of the key regulatory factors can also be exhibited, which in diseased states could give hints as to the biochemical agent most accountable for the disorder.

Bone marrow oedema associated with benign and malignant bone tumours

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James, S.L.J. [Department of Radiology, Royal Orthopaedic Hospital, Birmingham, B31 2AP (United Kingdom)], E-mail: steven.james@roh.nhs.uk; Panicek, D.M. [Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 (United States); Davies, A.M. [Department of Radiology, Royal Orthopaedic Hospital, Birmingham, B31 2AP (United Kingdom)

2008-07-15

Bone marrow oedema is associated with a wide variety of pathological processes including both benign and malignant bone tumours. This imaging finding in relation to intraosseous tumours can aid in providing a more focused differential diagnosis. In this review, we will discuss the MR imaging of bone marrow oedema surrounding intraosseous neoplasms. The different pulse sequences used in differentiating underlying tumour from surrounding oedema are discussed along with the role of dynamic contrast enhanced MRI. Benign lesions commonly associated with bone marrow oedema include osteoid osteoma, osteoblastoma, chondroblastoma and Langerhan's cell histiocytosis. Metastases and malignant primary bone tumours such as osteosarcoma, Ewing's sarcoma and chondrosarcoma may also be surrounded by bone marrow oedema. The imaging findings of these conditions are reviewed and illustrated. Finally, the importance of bone marrow oedema in assessment of post chemotherapeutic response is addressed.

The transcription factor Jdp2 controls bone homeostasis and antibacterial immunity by regulating osteoclast and neutrophil differentiation.

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Maruyama, Kenta; Fukasaka, Masahiro; Vandenbon, Alexis; Saitoh, Tatsuya; Kawasaki, Takumi; Kondo, Takeshi; Yokoyama, Kazunari K; Kidoya, Hiroyasu; Takakura, Nobuyuki; Standley, Daron; Takeuchi, Osamu; Akira, Shizuo

2012-12-14

Jdp2 is an AP-1 family transcription factor that regulates the epigenetic status of histones. Previous in vitro studies revealed that Jdp2 is involved in osteoclastogenesis. However, the roles of Jdp2 in vivo and its pleiotropic functions are largely unknown. Here we generated Jdp2(-/-) mice and discovered its crucial roles not only in bone metabolism but also in differentiation of neutrophils. Jdp2(-/-) mice exhibited osteopetrosis resulting from impaired osteoclastogenesis. Jdp2(-/-) neutrophils were morphologically normal but had impaired surface expression of Ly6G, bactericidal function, and apoptosis. We also found that ATF3 was an inhibitor of neutrophil differentiation and that Jdp2 directly suppresses its expression via inhibition of histone acetylation. Strikingly, Jdp2(-/-) mice were highly susceptible to Staphylococcus aureus and Candida albicans infection. Thus, Jdp2 plays pivotal roles in in vivo bone homeostasis and host defense by regulating osteoclast and neutrophil differentiation. Copyright © 2012 Elsevier Inc. All rights reserved.

Differentiation of malignant and degenerative benign bone disease using Tc-99m Citrate and Tc-99m MDP scintigraphy

International Nuclear Information System (INIS)

Jin, J.; Guo, R.; Li, S.-J.; Ren, Y.; Zhang, C.; Zhang, X.

2007-01-01

Full text: For the evaluation of bone metastases in patients (pts) with cancer, 99mTcMDP bone scintigraphy is an important tool, but some limitations exist. One of these is the differential diagnosis of malignant and degenerative benign bone disease. The aim of this study was to differentiate them using 99mTcCitrate and 99mTcMDP scintigraphy. Methods: 39 pts (92 lesions) with known malignant or degenerative benign bone disease were studied. 23 pts had malignant bone disease (48 lesions, group 1), the other 16 pts had degenerative benign bone disease (44 lesions, group2), for which the results of 99mTcMDP scintigraphy were positive. In both groups, 99mTcCitrate scintigraphy was performed within a time interval of 2-7 days after 99mTcMDP scintigraphy (555∼740MBq. static, 3hr, planar or SPECT i m a g e s w h e n r e q u i r e d ) . The 99mTccitrate/99mTcMDP lesion-to-background radioisotope uptake ratio (RUR) was calculated for each lesion. Conventional techniques (histopathology, X-ray, CT, MRI and clinical follow up) were considered to be proof of the presence of bone metastases and degenerative benign bone disease. Results: Uptake of 99mTcMDP in the two groups is the same (1.96±0.25 vs. 1.87±0.21; t=1.178, P>0.20), while in 99mTcCitrate image, malignant lesions demonstrated a higher uptake of lesion activity than that of benign degenerative lesions (1.47±0.42 vs. 1.09±0.38; t=2.887, P<0.01). The mean 99mTccitrate/99mTcMDP RUR in the malignant group was significantly higher than the mean in the benign group (0.78±0.21 vs. 0.54±0.19; t=3.646, P<0.001). Conclusions: The preliminary results of the study confirm the usefulness and feasibility of 99mTcCitrate scintigraphy for differentiating malignant from benign degenerative lesions seen as areas of increased activity on 99mTcMDP bone scintigraphy. (author)

Secreted Clusterin protein inhibits osteoblast differentiation of bone marrow mesenchymal stem cells by suppressing ERK1/2 signaling pathway.

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Abdallah, Basem M; Alzahrani, Abdullah M; Kassem, Moustapha

2018-05-01

Secreted Clusterin (sCLU, also known as Apolipoprotein J) is an anti-apoptotic glycoprotein involved in the regulation of cell proliferation, lipid transport, extracellular tissue remodeling and apoptosis. sCLU is expressed and secreted by mouse bone marrow-derived skeletal (stromal or mesenchymal) stem cells (mBMSCs), but its functional role in MSC biology is not known. In this study, we demonstrated that Clusterin mRNA expression and protein secretion in conditioned medium increased during adipocyte differentiation and decreased during osteoblast differentiation of mBMSCs. Treatment of mBMSC cultures with recombinant sCLU protein increased cell proliferation and exerted an inhibitory effect on the osteoblast differentiation while stimulated adipocyte differentiation in a dose-dependent manner. siRNA-mediated silencing of Clu expression in mBMSCs reduced adipocyte differentiation and stimulated osteoblast differentiation of mBMSCs. Furthermore, the inhibitory effect of sCLU on the osteoblast differentiation of mBMSCs was mediated by the suppression of extracellular signal-regulated kinase (ERK1/2) phosphorylation. In conclusion, we identified sCLU as a regulator of mBMSCs lineage commitment to osteoblasts versus adipocytes through a mechanism mediated by ERK1/2 signaling. Inhibiting sCLU is a possible therapeutic approach for enhancing osteoblast differentiation and consequently bone formation. Copyright © 2018 Elsevier Inc. All rights reserved.

Hepcidin promotes osteogenic differentiation through the bone morphogenetic protein 2/small mothers against decapentaplegic and mitogen-activated protein kinase/P38 signaling pathways in mesenchymal stem cells

OpenAIRE

LU, HUADING; LIAN, LIYI; SHI, DEHAI; ZHAO, HUIQING; DAI, YUHU

2014-01-01

The ability of mesenchymal stem cells (MSCs) to differentiate into osteogenic lineages requires management for their future use in treating bone destruction and osteoporosis. Hepcidin is closely associated with bone metabolism, however, it remains to be elucidated whether hepcidin affects osteogenic differentiation in MSCs. The present study demonstrated that hepcidin enhanced osteoblastic differentiation and mineralization, which was manifested by an upregulation in the differentiation marke...

Patterns of proliferation and differentiation of irradiated haemopoietic stem cells cultured on normal 'stromal' cell colonies in vitro

International Nuclear Information System (INIS)

Mori, K.J.

1981-01-01

Experiments were designed to elucidate whether or not the irradiated bone marrow cells receive any stimulation for the self-replication and differentiation from normal 'stromal' cell colonies in the bone marrow cell culture in vitro. When irradiated or unirradiated bone marrow cells were overlaid on the normal adherent cell colonies, the proliferation of haemopoietic stem cells was supported, the degree of the stimulation depending on the starting cellular concentration. There was, however, no significant changes in the concentration of either CFUs or CFUc regardless of the dose of irradiation on the bone marrow cells overlaid. This was a great contrast to the dose-dependent decrease of CFUs or CFUc within the culture in which both the stem cells and stromal cells were simultaneously irradiated. These results suggest that the balance of self-replication and differentiation of the haemopoietic stem cells is affected only when haemopoietic microenvironment is perturbed. (author)

Bone morphogenetic protein-2 functions as a negative regulator in the differentiation of myoblasts, but not as an inducer for the formations of cartilage and bone in mouse embryonic tongue

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Suzuki Erika

2011-07-01

Full Text Available Abstract Background In vitro studies using the myogenic cell line C2C12 demonstrate that bone morphogenetic protein-2 (BMP-2 converts the developmental pathway of C2C12 from a myogenic cell lineage to an osteoblastic cell lineage. Further, in vivo studies using null mutation mice demonstrate that BMPs inhibit the specification of the developmental fate of myogenic progenitor cells. However, the roles of BMPs in the phases of differentiation and maturation in skeletal muscles have yet to be determined. The present study attempts to define the function of BMP-2 in the final stage of differentiation of mouse tongue myoblast. Results Recombinant BMP-2 inhibited the expressions of markers for the differentiation of skeletal muscle cells, such as myogenin, muscle creatine kinase (MCK, and fast myosin heavy chain (fMyHC, whereas BMP-2 siRNA stimulated such markers. Neither the recombinant BMP-2 nor BMP-2 siRNA altered the expressions of markers for the formation of cartilage and bone, such as osteocalcin, alkaline phosphatase (ALP, collagen II, and collagen X. Further, no formation of cartilage and bone was observed in the recombinant BMP-2-treated tongues based on Alizarin red and Alcian blue stainings. Neither recombinant BMP-2 nor BMP-2 siRNA affected the expression of inhibitor of DNA binding/differentiation 1 (Id1. The ratios of chondrogenic and osteogenic markers relative to glyceraldehyde-3-phosphate dehydrogenase (GAPDH, a house keeping gene were approximately 1000-fold lower than those of myogenic markers in the cultured tongue. Conclusions BMP-2 functions as a negative regulator for the final differentiation of tongue myoblasts, but not as an inducer for the formation of cartilage and bone in cultured tongue, probably because the genes related to myogenesis are in an activation mode, while the genes related to chondrogenesis and osteogenesis are in a silencing mode.

Fall-related self-efficacy, not balance and mobility performance, is related to accidental falls in chronic stroke survivors with low bone mineral density.

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Pang, M Y C; Eng, J J

2008-07-01

Chronic stroke survivors with low hip bone density are particularly prone to fractures. This study shows that fear of falling is independently associated with falls in this population. Thus, fear of falling should not be overlooked in the prevention of fragility fractures in these patients. Chronic stroke survivors with low bone mineral density (BMD) are particularly prone to fragility fractures. The purpose of this study was to identify the determinants of balance, mobility and falls in this sub-group of stroke patients. Thirty-nine chronic stroke survivors with low hip BMD (T-score fall-related self-efficacy. Any falls in the past 12 months were also recorded. Multiple regression analysis was used to identify the determinants of balance and mobility performance, whereas logistic regression was used to identify the determinants of falls. Multiple regression analysis revealed that after adjusting for basic demographics, fall-related self-efficacy remained independently associated with balance/mobility performance (R2 = 0.494, P fall-related self-efficacy, but not balance and mobility performance, was a significant determinant of falls (odds ratio: 0.18, P = 0.04). Fall-related self-efficacy, but not mobility and balance performance, was the most important determinant of accidental falls. This psychological factor should not be overlooked in the prevention of fragility fractures among chronic stroke survivors with low hip BMD.

Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

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Aaron W. James

2013-01-01

Full Text Available Mesenchymal stem cells (MSC are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ (PPARγ and Runt-related transcription factor 2 (Runx2. These two transcription factors, PPARγ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP signaling and insulin growth factor (IGF signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

Acute bone crises in sickle cell disease: the T1 fat-saturated sequence in differentiation of acute bone infarcts from acute osteomyelitis

International Nuclear Information System (INIS)

Jain, R.; Sawhney, S.; Rizvi, S.G.

2008-01-01

Aim: To prove the hypothesis that acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells (RBCs) in bone marrow, and to evaluate the unenhanced T1 fat-saturated (fs) sequence in the differentiation of acute bone infarction from acute osteomyelitis in patients with sickle-cell disease. Materials and methods: Two studies were undertaken: an experimental study using in-vitro packed red blood cells and normal volunteers, and a retrospective clinical study of 86 magnetic resonance imaging (MRI) studies. For the experimental study containers of packed RBCs were placed between the knees of four healthy volunteers with a saline bag under the containers as an additional control, and were scanned with the pre-contrast T1-fs sequence. Signal intensity (SI) ratios were obtained for packed RBCs:skeletal muscle and packed RBCs:saline. For the clinical study, the SIs of normal bone marrow, packed RBCs, bone and/or soft-tissue lesions, and normal skeletal muscle of 74 patients (86 MRI studies) were measured using unenhanced, T1 fat-saturated MRI. The ratios of the above SIs to normal skeletal muscle were calculated and subjected to statistical analysis. Results: Fifty-one of 86 MRI studies were included in the final analysis. The ratios of SIs for normal bone marrow, packed red cells, bone infarction, acute osteomyelitis, and soft-tissue lesions associated with bone infarct, compared with normal skeletal muscle were (mean ± SD) 0.9 ± 0.2, 2.1 ± 0.7, 1.7 ± 0.5, 1.0 ± 0.3, and 2.2 ± 0.7, respectively. The difference in the ratio of SIs of bone infarcts and osteomyelitis was significant (p = 0.003). The final diagnoses were bone infarction (n = 50), acute osteomyelitis (n = 1), and co-existent bone infarction and osteomyelitis (n = 2). Seven patients who had suspected osteomyelitis underwent image-guided aspiration. Conclusion: Acute bone infarcts in sickle cell disease are caused by sequestration of red blood cells in the bone marrow. The

[Frontier in bone biology].

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Takeda, Shu

2015-10-01

Bone is an active organ in which bone mass is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption, i.e., coupling of bone formation and bone resorption. Recent advances in molecular bone biology uncovered the molecular mechanism of the coupling. A fundamental role of osteocyte in the maintenance of bone mass and whole body metabolism has also been revealed recently. Moreover, neurons and neuropeptides have been shown to be intimately involved in bone homeostasis though inter-organ network, in addition to "traditional" regulators of bone metabolism such as soluble factors and cytokines

Ciclosporin Does Not Influence Bone Marrow-Derived Cell Differentiation to Myofibroblasts Early after Renal Ischemia/Reperfusion

NARCIS (Netherlands)

Broekema, Martine; Harmsen, Martin C.; Koerts, Jasper A.; van Kooten, Theo G.; Uges, Donald R. A.; Petersen, Arjen H.; van Luyn, Marja J. A.; Navis, Gerjan; Popa, Eliane R.

2009-01-01

Background: Ischemia/reperfusion injury (IRI) is a risk factor for the development of interstitial fibrosis. Previously we had shown that after renal IRI, bone marrow-derived cells (BMDC) can differentiate to interstitial myofibroblasts. Here we hypothesized that the immunosuppressant ciclosporin A

Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation

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Moustafa Sayed

2014-07-01

Full Text Available Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells differentiation capacity. BMSCs were isolated from male Sprague–Dawley rats and cultured in minimal essential medium alpha (MEM-α supplemented with 15% Fetal Bovine serum (FBS. The results showed that marinobufagenin (MBG, a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα protein expression through activation of an extracellular regulated kinase (ERK signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2 expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.

Protein Malnutrition Induces Bone Marrow Mesenchymal Stem Cells Commitment to Adipogenic Differentiation Leading to Hematopoietic Failure

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Cunha, Mayara Caldas Ramos; Lima, Fabiana da Silva; Vinolo, Marco Aurélio Ramirez; Hastreiter, Araceli; Curi, Rui; Borelli, Primavera; Fock, Ricardo Ambrósio

2013-01-01

Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states. PMID:23516566

Protein malnutrition induces bone marrow mesenchymal stem cells commitment to adipogenic differentiation leading to hematopoietic failure.

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Cunha, Mayara Caldas Ramos; Lima, Fabiana da Silva; Vinolo, Marco Aurélio Ramirez; Hastreiter, Araceli; Curi, Rui; Borelli, Primavera; Fock, Ricardo Ambrósio

2013-01-01

Protein malnutrition (PM) results in pathological changes that are associated with peripheral leukopenia, bone marrow (BM) hypoplasia and alterations in the BM microenvironment leading to hematopoietic failure; however, the mechanisms involved are poorly understood. In this context, the BM mesenchymal stem cells (MSCs) are cells intimately related to the formation of the BM microenvironment, and their differentiation into adipocytes is important because adipocytes are cells that have the capability to negatively modulate hematopoiesis. Two-month-old male Balb/c mice were subjected to protein-energy malnutrition with a low-protein diet containing 2% protein, whereas control animals were fed a diet containing 12% protein. The hematopoietic parameters and the expression of CD45 and CD117 positive cells in the BM were evaluated. MSCs were isolated from BM, and their capability to produce SCF, IL-3, G-CSF and GM-CSF were analyzed. The expression of PPAR-γ and C/EBP-α as well as the expression of PPAR-γ and SREBP mRNAs were evaluated in MSCs together with their capability to differentiate into adipocytes in vitro. The malnourished animals had anemia and leukopenia as well as spleen and bone marrow hypoplasia and a reduction in the expression of CD45 and CD117 positive cells from BM. The MSCs of the malnourished mice presented an increased capability to produce SCF and reduced production of G-CSF and GM-CSF. The MSCs from the malnourished animals showed increased expression of PPAR-γ protein and PPAR-γ mRNA associated with an increased capability to differentiate into adipocytes. The alterations found in the malnourished animals allowed us to conclude that malnutrition committed MSC differentiation leading to adipocyte decision and compromised their capacity for cytokine production, contributing to an impaired hematopoietic microenvironment and inducing the bone marrow failure commonly observed in protein malnutrition states.

Evaluation of bone diseases using dynamic bone scintigraphy

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Kumano, Machiko; Tamura, Kenji; Hamada, Tatsumi; Ishida, Osamu [Kinki Univ., Higashi-Osaka, Osaka (Japan); Kajita, Akiyoshi

1983-12-01

Dynamic bone scintigraphy with sup(99m)Tc-EHDP was performed on 96 patients with various bone diseases. The dynamic scintigrams obtained were then used to aid in the differential diagnosis of malignant (49 cases) and benign (8 cases) diseases. Short-term local deposition of the tracer in all cases of malignant bone diseases was observed in vascular (10-40 sec. after injection), and blood pool (1-3 min. after injection) phases. In the cases of malignant bone tumors where osteosclerotic lesions were present, tracer accumulation appeared in the blood pool phase. If osteolytic lesions were present, accumulation appeared in the vascular phase, and when the lesion was larger than 2 cm, accumulation was frequently found in the arterial phase. Scintigraphic differentiation of early primary and metastatic bone tumors from other lesions was facilitated by performing the dynamic scintigraphy with sup(99m)Tc-EHDP. Dynamic bone scintigraphy also allowed early diagnosis of avascular necrosis (14 cases) prior to the appearance of minimally abnormal X-ray findings, especially in cases of corticosteroid-induced necrosis.

Modeling real-time balancing power demands in wind power systems using stochastic differential equations

International Nuclear Information System (INIS)

Olsson, Magnus; Perninge, Magnus; Soeder, Lennart

2010-01-01

The inclusion of wind power into power systems has a significant impact on the demand for real-time balancing power due to the stochastic nature of wind power production. The overall aim of this paper is to present probabilistic models of the impact of large-scale integration of wind power on the continuous demand in MW for real-time balancing power. This is important not only for system operators, but also for producers and consumers since they in most systems through various market solutions provide balancing power. Since there can occur situations where the wind power variations cancel out other types of deviations in the system, models on an hourly basis are not sufficient. Therefore the developed model is in continuous time and is based on stochastic differential equations (SDE). The model can be used within an analytical framework or in Monte Carlo simulations. (author)

Stem cells in bone tissue engineering

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Seong, Jeong Min [Department of Preventive and Social Dentistry and Institute of Oral Biology, College of Dentistry, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Kim, Byung-Chul; Park, Jae-Hong; Kwon, Il Keun; Hwang, Yu-Shik [Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, College of Dentistry, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Mantalaris, Anathathios, E-mail: yshwang@khu.ac.k [Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ (United Kingdom)

2010-12-15

Bone tissue engineering has been one of the most promising areas of research, providing a potential clinical application to cure bone defects. Recently, various stem cells including embryonic stem cells (ESCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), adipose tissue-derived stem cells (ADSCs), muscle-derived stem cells (MDSCs) and dental pulp stem cells (DPSCs) have received extensive attention in the field of bone tissue engineering due to their distinct biological capability to differentiate into osteogenic lineages. The application of these stem cells to bone tissue engineering requires inducing in vitro differentiation of these cells into bone forming cells, osteoblasts. For this purpose, efficient in vitro differentiation towards osteogenic lineage requires the development of well-defined and proficient protocols. This would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source for application to bone tissue engineering therapies. This review provides a critical examination of the various experimental strategies that could be used to direct the differentiation of ESC, BM-MSC, UCB-MSC, ADSC, MDSC and DPSC towards osteogenic lineages and their potential applications in tissue engineering, particularly in the regeneration of bone. (topical review)

Stem cells in bone tissue engineering

International Nuclear Information System (INIS)

Seong, Jeong Min; Kim, Byung-Chul; Park, Jae-Hong; Kwon, Il Keun; Hwang, Yu-Shik; Mantalaris, Anathathios

2010-01-01

Bone tissue engineering has been one of the most promising areas of research, providing a potential clinical application to cure bone defects. Recently, various stem cells including embryonic stem cells (ESCs), bone marrow-derived mesenchymal stem cells (BM-MSCs), umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs), adipose tissue-derived stem cells (ADSCs), muscle-derived stem cells (MDSCs) and dental pulp stem cells (DPSCs) have received extensive attention in the field of bone tissue engineering due to their distinct biological capability to differentiate into osteogenic lineages. The application of these stem cells to bone tissue engineering requires inducing in vitro differentiation of these cells into bone forming cells, osteoblasts. For this purpose, efficient in vitro differentiation towards osteogenic lineage requires the development of well-defined and proficient protocols. This would reduce the likelihood of spontaneous differentiation into divergent lineages and increase the available cell source for application to bone tissue engineering therapies. This review provides a critical examination of the various experimental strategies that could be used to direct the differentiation of ESC, BM-MSC, UCB-MSC, ADSC, MDSC and DPSC towards osteogenic lineages and their potential applications in tissue engineering, particularly in the regeneration of bone. (topical review)

Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells

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Jin Jiali

2011-07-01

Full Text Available Abstract Background Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present. Results In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM for six days, BM-MSCs were differentiated into neuron-like cells by the observation of optical microscopy. Immunofluorescence demonstrated that the differentiated BM-MSCs expressed neural specific markers including MAP-2, Nestin, NeuN and GFAP. In addition, NeuN positive cells could co-localize with TH or ChAT by double-labled immunofluorescence and Nissl bodies were found in several differentiated cells by Nissl stain. Furthermore, BDNF and NGF were increased by CART using RT-PCR. Conclusion This study demonstrated that CART could promote the differentiation of BM-MSCs into neural cells through increasing neurofactors, including BNDF and NGF. Combined application of CART and BM-MSCs may be a promising cell-based therapy for neurological diseases.

Study of mesanchymal stem cells derived from human umbilical cord vein wall and determining the Process of differentiation to cartilage and bone

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MohammadAli Zare

2015-01-01

Full Text Available Background: Mesenchymal stem cells (MSCs comprise a rare population of multipotent progenitors capable of supporting hematopoiesis and differentiating into three (osteogenic, adipogenic, and chondrogenic or more (myogenic, cardiomyogenic, etc. lineages. Due to this ability, MSCs appear to be an attractive tool in the context of tissue engineering and cell-based therapy. Currently, bone marrow represents the main source of MSCs for both experimental and clinical studies. The purpose of this study was isolation and quantitative comparison of mesenchymal stem cells derived from umbilical vein. Materials and Methods: In this study, 35 samples of umbilical cord of healthy full- term newborn were studied. Results: The cells had fibroblastoid like appearance and had revealed the potential to differentiate into three linage of bone, Adipose and cartilage. Surface markers for mesenchymal nature were their demonstratives. Conclusion: Based on our findings the mesenchymal stem cells, from umbilical vein wall can be isolated, cultured and differentiated into three categories of bone, cartilage and adipose.

Sodium and bone health

DEFF Research Database (Denmark)

Teucher, B.; Dainty, J. R.; Spinks, C. A.

2008-01-01

High salt intake is a well-recognized risk factor for osteoporosis because it induces calciuria, but the effects of salt on calcium metabolism and the potential impact on bone health in postmenopausal women have not been fully characterized. This study investigated adaptive mechanisms in response.......9 Versus 11.2 g) diets, reflecting lower and upper intakes in post men opausal women consuming a Western-style diet, were provided. Stable isotope labeling techniques were used to measure calcium absorption and excretion, compartmental modeling was undertaken to estimate bone calcium balance......, and biomarkers of bone formation and resorption were measured in blood and urine. Moderately high salt intake (11.2 g/d) elicited a significant increase in urinary calcium excretion (p = 0.0008) and significantly affected bone calcium balance with the high calcium diet 0.024). Efficiency of calcium absorption...

Osteogenic differentiation of mesenchymal stem cells is regulated by osteocyte and osteoblast cells in a simplified bone niche

Directory of Open Access Journals (Sweden)

LM McNamara

2012-01-01

Full Text Available Mesenchymal stem cells (MSCs within their native environment of the stem cell niche in bone receive biochemical stimuli from surrounding cells. These stimuli likely influence how MSCs differentiate to become bone precursors. The ability of MSCs to undergo osteogenic differentiation is well established in vitro;however, the role of the natural cues from bone’s regulatory cells, osteocytes and osteoblasts in regulating the osteogenic differentiation of MSCs in vivo are unclear. In this study we delineate the role of biochemical signalling from osteocytes and osteoblasts, using conditioned media and co-culture experiments, to understand how they direct osteogenic differentiation of MSCs. Furthermore, the synergistic relationship between osteocytes and osteoblasts is examined by transwell co-culturing of MSCs with both simultaneously. Osteogenic differentiation of MSCs was quantified by monitoring alkaline phosphatase (ALP activity, calcium deposition and cell number. Intracellular ALP was found to peak earlier and there was greater calcium deposition when MSCs were co-cultured with osteocytes rather than osteoblasts, suggesting that osteocytes are more influential than osteoblasts in stimulating osteogenesis in MSCs. Osteoblasts initially stimulated an increase in the number of MSCs, but ultimately regulated MSC differentiation down the same pathway. Our novel co-culture system confirmed a synergistic relationship between osteocytes and osteoblasts in producing biochemical signals to stimulate the osteogenic differentiation of MSCs. This study provides important insights into the mechanisms at work within the native stem cell niche to stimulate osteogenic differentiation and outlines a possible role for the use of co-culture or conditioned media methodologies for tissue engineering applications.

Nicotine-induced chondrogenic differentiation of human bone marrow stromal cells in vitro.

Science.gov (United States)

Ying, Xiaozhou; Zhang, Wei; Cheng, Shaowen; Nie, Pengfei; Cheng, Xiaojie; Shen, Yue; Wang, Wei; Xue, Enxing; Chen, Qingyu; Kou, Dongquan; Peng, Lei; Zhang, Yu; Lu, Chuanzhu

2012-11-01

Nicotine has been reported that it has a dose-dependent effect on matrix mineralization by human bone marrow cells. However, there is no relevant research concerning on chondrogenic differentiation potential of bone marrow stromal stem cells (BMSCs) treated with nicotine in vitro. The aims of the study were to examine the effects of nicotine (0, 10(-7), 10(-6) and 10(-5) M) on the proliferation and chondrogenic differentiation of BMSCs from three healthy donors in vitro. BMSCs proliferation was analyzed by CCK8 assay and real-time polymerase chain reaction was used to assay the expression of type II collagen, aggrecan, type I collagen and type X collagen. The proteoglycan content was stained by Alcian blue, and the sulfated glycosaminoglycan (sGAG) content of BMSCs was quantified spectrofluorometrically using dimethylmethylene blue. The cell viability was not significantly impaired until up to a concentration of 10(-5) M nicotine. Nicotine promoted the proliferation and enhanced the expression of type II collagen at the level up to 10(-6) M (P < 0.05). The expression of aggrecan was reduced at the concentration of 10(-5) M nicotine at day 14 (P < 0.05), and there was no significant difference in aggrecan gene expression at 10(-7) and 10(-6) M nicotine levels compared to control group (n.s.). Also the fibroblastic and hypertrophic gene expressions were down-regulated in the chondrogenic medium with 10(-7)-10(-5) M nicotine (P < 0.05). It was implied that local application of nicotine at an appropriate concentration may be a promising approach for enhancing chondrogenic differentiation capacity of BMSCs in cell-based cartilage tissue engineering. Also these results indicate that nicotine maybe a potentially useful drug for the treatment of Osteoarthritis.

Differential radioprotection of bone marrow and tumour cells by zinc aspartate

International Nuclear Information System (INIS)

Floersheim, G.L.; Chiodetti, N.; Bieri, A.

1988-01-01

The radioprotector zinc aspartate did not inhibit the radiotherapeutic effect of γ rays on human tumours grown as xenografts in immunosuppressed mice, while aminothiol radioprotectors afforded a slight inhibition. On the other hand, zinc aspartate significantly reduced the fall in the haematocrit and numbers of thrombocytes, erythrocytes and leucocytes caused by irradiation, indicating a sparing effect on bone marrow precursors of peripheral blood cells. This differential protection of neoplastic and normal cells may be of considerable benefit in clinical cancer radiotherapy, provided that zinc aspartate is better tolerated and has a more favourable therapeutic index in humans than aminothiol radioprotectors. (author)

Bone marrow mesenchymal stem cells differentiation and proliferation on the surface of coral implant

International Nuclear Information System (INIS)

Al-Salihi, K.A.; Samsudin, A.R.

2004-01-01

This study was designed to evaluate the ability of natural coral implant to provide an environment for marrow cells to differentiate into osteoblasts and function suitable for mineralized tissue formation. DNA content, alkaline phosptatase (ALP) activity, calcium (Ca) content and mineralized nodules, were measured at day 3, day 7 and day 14, in rat bone marrow stromal cells cultured with coral discs glass discs, while cells alone and coral disc alone cultured as control. DNA content, ALP activity, Ca content measurements showed no difference between coral, glass and cells groups at 3 day which were higher than control (coral disc alone), but there were higher asurement at day 7 and 14 in the cell cultured on coral than on glass discs, control cells and control coral discs. Mineralized nodules formation (both in area and number) was more predominant on the coral surface than in control groups. These results showed that natural coral implant provided excellent and favorable situation for marrow cell to differentiate to osteoblasts, lead to large amount of mineralized tissue formation on coral surface. This in vitro result could explain the rapid bone bonding of coral in vivo. (Author)

Benign versus malignant osseous lesions in spine: differentiation by means of bone SPECT/CT fused image

International Nuclear Information System (INIS)

Yao Zhiming; Qu Wanying

2004-01-01

This study compared the efficiency of SPECT-CT fused image with planar bone scan, bone SPECT and CT in differentiating malignant from benign lesions and detecting metastases to the spine. Methods. Total 144 patients with spinal lesions underwent planar bone scan (WB), single photon tomography (SPECT), CT and SPECT-CT fused image by a SPECT/CT system. The malignant or benign nature of lesions was proved by radiological Methods, histological findings, 6-24 month follow-up, or all of these. The diagnostic results was divided into 4 types, i.e., normal, benign, doubtful malignant and malignant. Results. There were 137 malignant and 252 benign lesions in 144 patients, respectively. The percentages of doubtful malignant diagnosed by WB, SPECT, CT and fused image are 22.6%, 5.1%, 9.5% and 0%, respectively, p < 0.01-0.001, except for the comparison between the percentages of SPECT and CT. Sensitivities in detection of malignant lesions by WB, SPECT, CT and fused image are 75.2%, 94.2%, 96.6% and 99.3%, respectively, P < 0.001, excepting for the comparisons between those of SPECT and CT, and between those of CT and fused image. The sensitivities m detection of benign lesions by WB, SPECT, CT and fused image are, 56.7%, 86.5%, 90.1% and 96.8%, respectively, P < 0.005 - 0.001, excepting for the comparison between those of SPECT and CT. The specificities in detection of maliganant lesions by WB, SPECT, CT and fused image are 70.6%, 88.9%, 97.2% and 97.6%, respectively, P < 0.001, excepting for the comparison between those of CT and fused image. Conclusion. Bone SPECT-CT fused image has highest diagnostic and differentiating diagnostic values in detection of spinal abnormalities over the planar bone scanning and SPECT. The CT by present SPECT/CT system can complement planar bone scanning and SPECT and is clinically valuable in detection of spinal abnormalities. (authors)

The role of the BH3-only protein Noxa in bone homeostasis.

Science.gov (United States)

Idrus, Erik; Nakashima, Tomoki; Wang, Ling; Hayashi, Mikihito; Okamoto, Kazuo; Kodama, Tatsuhiko; Tanaka, Nobuyuki; Taniguchi, Tadatsugu; Takayanagi, Hiroshi

2011-07-08

Bone homeostasis is maintained by a dynamic balance between bone resorption by osteoclasts and bone formation by osteoblasts. Since excessive osteoclast activity is implicated in pathological bone resorption, understanding the mechanism underlying osteoclast differentiation, function and survival is of both scientific and clinical importance. Osteoclasts are monocyte/macrophage lineage cells with a short life span that undergo rapid apoptosis, the rate of which critically determines the level of bone resorption in vivo. However, the molecular basis of rapid osteoclast apoptosis remains obscure. Here we report the role of a BH3-only protein, Noxa (encoded by the Pmaip1 gene), in bone homeostasis using Noxa-deficient mice. Among the Bcl-2 family members, Noxa was selectively induced during osteoclastogenesis. Mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts. Noxa deficiency did not have any effect on the number of osteoclast precursor cells or the expression of osteoclast-specific genes, but led to a prolonged survival of osteoclasts. Furthermore, adenovirus-mediated Noxa overexpression remarkably reduced bone loss in a model of inflammation-induced bone destruction. This study reveals Noxa to be a crucial regulator of osteoclast apoptosis, and may provide a molecular basis for a new therapeutic approach to bone diseases. Copyright © 2011 Elsevier Inc. All rights reserved.

Associations of dietary patterns with bone mass, muscle strength and balance in a cohort of Australian middle-aged women.

Science.gov (United States)

Wu, Feitong; Wills, Karen; Laslett, Laura L; Oldenburg, Brian; Jones, Graeme; Winzenberg, Tania

2017-10-01

Influences of dietary patterns on musculoskeletal health are poorly understood in middle-aged women. This cross-sectional analysis from a cohort of 347 women (aged 36-57 years) aimed to examine associations between dietary patterns and musculoskeletal health outcomes in middle-aged women. Diet was measured by the Cancer Council of Victoria FFQ. Total body bone mineral content (TB BMC), femoral neck and lumbar spine bone density (dual-energy X-ray absorptiometry), lower limbs muscle strength (LMS) and balance tests (timed up and go test, step test, functional reach test (FRT) and lateral reach test) were also measured. Exploratory factor analysis was used to identify dietary patterns and scores for each pattern generated using factor loadings with absolute values ≥0·20. Associations between food pattern scores and musculoskeletal outcomes were assessed using multivariable linear regression. Three dietary patterns were identified: 'Healthy' (high consumption of a plant-based diet - vegetables, legumes, fruit, tomatoes, nuts, snacks, garlic, whole grains and low intake of high-fat dairy products), 'high protein, high fat' (red meats, poultry, processed meats, potatoes, cruciferous and dark-yellow vegetables, fish, chips, spirits and high-fat dairy products) and 'Processed foods' (high intakes of meat pies, hamburgers, beer, sweets, fruit juice, processed meats, snacks, spirits, pizza and low intake of cruciferous vegetables). After adjustment for confounders, Healthy pattern was positively associated with LMS, whereas Processed foods pattern was inversely associated with TB BMC and FRT. The associations were not significant after accounting for multiple comparisons. There were no associations with any other outcomes. These results suggest that maintaining a healthy diet could contribute to bone acquisition, muscle strength and balance in adult life. However, while they provide some support for further investigating dietary strategies for prevention of age

In vitro differentiation of bone marrow stromal cells into neurons and glial cells and differential protein expression in a two-compartment bone marrow stromal cell/neuron co-culture system.

Science.gov (United States)

Qi, Xu; Shao, Ming; Peng, Haisheng; Bi, Zhenggang; Su, Zhiqiang; Li, Hulun

2010-07-01

This study was performed to establish a bone marrow stromal cell (BMSC)/neuron two-compartment co-culture model in which differentiation of BMSCs into neurons could occur without direct contact between the two cell types, and to investigate protein expression changes during differentiation of this entirely BMSC-derived population. Cultured BMSCs isolated from Wistar rats were divided into three groups: BMSC culture, BMSC/neuron co-culture and BMSC/neuron two-compartment co-culture. Cells were examined for neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) expression. The electrophysiological behavior of the BMSCs was examined using patch clamping. Proteins that had significantly different expression levels in BMSCs cultured alone and co-cultured with neurons were studied using a protein chip-mass spectroscopy technique. Expression of NSE and GFAP were significantly higher in co-culture cells than in two-compartment co-culture cells, and significantly higher in both co-culture groups than in BMSCs cultured alone. Five proteins showed significant changes in expression during differentiation: TIP39_RAT and CALC_RAT underwent increases, and INSL6_RAT, PNOC_RAT and PCSK1_RAT underwent decreases in expression. We conclude that BMSCs can differentiate into neurons during both contact co-culture with neurons and two-compartment co-culture with neurons. The rate at which BMSCs differentiated into neurons was higher in contact co-culture than in non-contact co-culture.

Bone-marrow-derived mesenchymal stem cells as a target for cytomegalovirus infection: Implications for hematopoiesis, self-renewal and differentiation potential

International Nuclear Information System (INIS)

Smirnov, Sergey V.; Harbacheuski, Ryhor; Lewis-Antes, Anita; Zhu Hua; Rameshwar, Pranela; Kotenko, Sergei V.

2007-01-01

Mesenchymal stem cells (MSCs) in bone marrow (BM) regulate the differentiation and proliferation of adjacent hematopoietic precursor cells and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, fat and connective tissue. BM is an important site for the pathogenesis of human cytomegalovirus (HCMV) where the virus establishes latency in hematopoietic progenitors and can transmit after reactivation to neighboring cells. Here we demonstrate that BM-MSCs are permissive to productive HCMV infection, and that HCMV alters the function of MSCs: (i) by changing the repertoire of cell surface molecules in BM-MSCs, HCMV modifies the pattern of interaction between BM-MSCs and hematopoietic cells; (ii) HCMV infection of BM-MSCs undergoing adipogenic or osteogenic differentiation impaired the process of differentiation. Our results suggest that by altering BM-MSC biology, HCMV may contribute to the development of various diseases

Force-balance and differential equation for the ground-state electron density in atoms and molecules

International Nuclear Information System (INIS)

Amovilli, C.; March, N.H.; Gal, T.; Nagy, A.

2000-01-01

Holas and March (1995) established a force-balance equation from the many-electron Schroedinger equation. Here, the authors propose this as a basis for the construction of a (usually approximate) differential equation for the ground-state electron density. By way of example they present the simple case of two-electron systems with different external potentials but with weak electron-electron Coulomb repulsion λe 2 /r 12 . In this case first-order Rayleigh-Schroedinger (RS) perturbation theory of the ground-state wave function is known to lead to a compact expression for the first-order density matrix γ(r,rprime) in terms of its diagonal density ρ(r) and the density corresponding to λ = 0. This result allows the force-balance equation to be written as a third-order linear, differential homogeneous equation for the ground-state electron density ρ(r). The example of the two-electron Hookean atom is treated: For this case one can also transcend the first-order RS perturbation theory and get exact results for discrete choices of force constants (external potential)

[Effects of nicotine on bone marrow stromal cells proliferation and differentiation of chondrocyte in vitro].

Science.gov (United States)

Ying, Xiao-zhou; Peng, Lei; Cheng, Shao-wen; Chen, Qing-yu; Zhang, Wei; Kou, Dong-quan; Shen, Yue

2011-11-01

To examine the effects of various concentration of nicotine on bone marrow stromal cells (BMSCs) proliferation and differentiation of cartilaginous in vitro. BMSCs was obtained from femoral bone and tibia of New-Zealand albino rabbit. The cells of the 3rd generation were used in study. Different concentration of nicotine (0, 1 x 10(-7), 1 x 10(-6), 1 x 10(-5) M) were added into BMSCs. BMSCs proliferation was analyzed by MTT assay at the 1, 4, 7, 14 days. The expression of collagen type II and aggrecan as the marker genes of cartilaginous differentiation from BMSCs were detected by reverse transcriptase-polymerase chain reaction (RT-PCR). Microscope showed that BMSCs transformed from round to fusiform shape. The concentration of nicotine in 1 x 10(-7), 1 x 10(-6) M had a significant positive effect on cell proliferation and the expression of type II collagen in a time-dependent manner when supplemented in commonly used induction media (P<0.05). Concentrations of nicotine in 1 x 10(-7) can promote the expression of aggrecan at the 7th day after induction,and in 1 x 10(-5) M may inhibit the expression of type II collagen and aggrecan. It was implied that local application of nicotine at an appropriate concentration may be a promising approach for enhancing cartilaginous differentiation capacity of BMSCs in cartilage tissue engineering.

A Comparison between the Effects of Aerobic Dance Training on Mini-Trampoline and Hard Wooden Surface on Bone Resorption, Health-Related Physical Fitness, Balance, and Foot Plantar Pressure in Thai Working Women.

Science.gov (United States)

Sukkeaw, Wittawat; Kritpet, Thanomwong; Bunyaratavej, Narong

2015-09-01

To compare the effects of aerobic dance training on mini-trampoline and hard wooden surface on bone resorption, health-related physical fitness, balance, and foot plantar pressure in Thai working women. Sixty-three volunteered females aged 35-45 years old participated in the study and were divided into 3 groups: A) aerobic dance on mini-trampoline (21 females), B) aerobic dance on hard wooden surface (21 females), and C) control group (21 females). All subjects in the aerobic dance groups wore heart rate monitors during exercise. Aerobic dance worked out 3 times a week, 40 minutes a day for 12 weeks. The intensity was set at 60-80% of the maximum heart rate. The control group engaged in routine physical activity. The collected data were bone formation (N-terminal propeptine of procollagen type I: P1NP) bone resorption (Telopeptide cross linked: β-CrossLaps) health-related physical fitness, balance, and foot plantar pressure. The obtained data from pre- and post trainings were compared and analyzed by paired samples t-test and one way analysis of covariance. The significant difference was at 0.05 level. After the 12-week training, the biochemical bone markers of both mini-trampoline and hard wooden surface aerobic dance training subjects decreased in bone resorption (β-CrossLaps) but increased in boneformation (P1NP). Health-related physical fitness, balance, and foot plantar pressure were not only better when comparing to the pre-test result but also significantly different when comparing to the control group (p trampoline showed that leg muscular strength, balance and foot plantar pressure were significantly better than the aerobic dance on hard wooden surface (p trampoline and hard wooden surface had positive effects on biochemical bone markers. However, the aerobic dance on mini-trampoline had more leg muscular strength and balance including less foot plantar pressure. It is considered to be an appropriate exercise programs in working women.

Evaluating differential nuclear DNA yield rates and osteocyte numbers among human bone tissue types: A synchrotron radiation micro-CT approach.

Science.gov (United States)

Andronowski, Janna M; Mundorff, Amy Z; Pratt, Isaac V; Davoren, Jon M; Cooper, David M L

2017-05-01

Molecular human identification has conventionally focused on DNA sampling from dense, weight-bearing cortical bone tissue, typically from femora or tibiae. A comparison of skeletal elements from three contemporary individuals demonstrated that elements with high quantities of cancellous bone yielded nuclear DNA at the highest rates, suggesting that preferentially sampling cortical bone may be suboptimal (Mundorff & Davoren, 2014). Despite these findings, the reason for the differential DNA yields between cortical and cancellous bone tissues remains unknown. The primary goal of this work is to ascertain whether differences in bone microstructure can be used to explain differential nuclear DNA yield among bone tissue types observed by Mundorff and Davoren (2014), with a focus on osteocytes and the three-dimensional (3D) quantification of their associated lacunae. Osteocytes and other bone cells are recognized to house DNA in bone tissue, thus examining the density of their lacunae may explain why nuclear DNA yield rates differ among bone tissue types. Lacunae were visualized and quantified using synchrotron radiation-based micro-Computed Tomographic imaging (SR micro-CT). Volumes of interest (VOIs) from cortical and cancellous bone tissues (n=129) were comparatively analyzed from the three skeletons sampled for Mundorff and Davoren's (2014) study. Analyses tested the primary hypothesis that the abundance and density of osteocytes (inferred from their lacunar spaces) vary between cortical and cancellous bone tissue types. Results demonstrated that osteocyte lacunar abundance and density vary between cortical and cancellous bone tissue types, with cortical bone VOIs containing a higher lacunar abundance and density. We found that the osteocyte lacunar density values are independent of nuclear DNA yield, suggesting an alternative explanation for the higher nuclear DNA yields from bones with greater quantities of cancellous bone tissue. The use of SR micro-CT allowed for

OP9 bone marrow stroma cells differentiate into megakaryocytes and platelets.

Directory of Open Access Journals (Sweden)

Yumiko Matsubara

Full Text Available Platelets are essential for hemostatic plug formation and thrombosis. The mechanisms of megakaryocyte (MK differentiation and subsequent platelet production from stem cells remain only partially understood. The manufacture of megakaryocytes (MKs and platelets from cell sources including hematopoietic stem cells and pluripotent stem cells have been highlighted for studying the platelet production mechanisms as well as for the development of new strategies for platelet transfusion. The mouse bone marrow stroma cell line OP9 has been widely used as feeder cells for the differentiation of stem cells into MK lineages. OP9 cells are reported to be pre-adipocytes. We previously reported that 3T3-L1 pre-adipocytes differentiated into MKs and platelets. In the present study, we examined whether OP9 cells differentiate into MKs and platelets using MK lineage induction (MKLI medium previously established to generate MKs and platelets from hematopoietic stem cells, embryonic stem cells, and pre-adipocytes. OP9 cells cultured in MKLI medium had megakaryocytic features, i.e., positivity for surface markers CD41 and CD42b, polyploidy, and distinct morphology. The OP9-derived platelets had functional characteristics, providing the first evidence for the differentiation of OP9 cells into MKs and platelets. We then analyzed gene expressions of critical factors that regulate megakaryopoiesis and thrombopoiesis. The gene expressions of p45NF-E2, FOG, Fli1, GATA2, RUNX1, thrombopoietin, and c-mpl were observed during the MK differentiation. Among the observed transcription factors of MK lineages, p45NF-E2 expression was increased during differentiation. We further studied MK and platelet generation using p45NF-E2-overexpressing OP9 cells. OP9 cells transfected with p45NF-E2 had enhanced production of MKs and platelets. Our findings revealed that OP9 cells differentiated into MKs and platelets in vitro. OP9 cells have critical factors for megakaryopoiesis and

Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo.

Science.gov (United States)

He, Shengwei; Zhao, Wenzhi; Zhang, Lu; Mi, Lidong; Du, Guangyu; Sun, Chuanxiu; Sun, Xuegang

2017-01-01

To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo . Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz) were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligan, and pre-collagen type 1 α were measured. Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor κ-B ligand, and pre-collagen type 1 α were also markedly higher following 25 and 50 Hz treatment. Low frequency (25-50 Hz) vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury.

Effect of calcium phosphate coating crystallinity and implant surface roughness on differentiation of rat bone marrow cells.

NARCIS (Netherlands)

Brugge, P.J. ter; Wolke, J.G.C.; Jansen, J.A.

2002-01-01

In this study, we examined the effect of calcium phosphate (Ca-P) coating crystallinity and of surface roughness on growth and differentiation of osteogenic cells. Grit-blasted titanium substrates were provided with Ca-P coatings of different crystallinities. Rat bone marrow (RBM) cells were

Osteoblastic cells: differentiation and trans-differentiation

DEFF Research Database (Denmark)

Kassem, Moustapha; Abdallah, Basem; Saeed, Hamid

2008-01-01

The osteoblast is the bone forming cell and is derived from mesenchymal stem cells (MSC) present among the bone marrow stroma. MSC are capable of multi-lineage differentiation into mesoderm-type cells such as osteoblasts and adipocytes. Understanding the mechanisms underlying osteoblast different...

Differential gene expression profile associated with the abnormality of bone marrow mesenchymal stem cells in aplastic anemia.

Directory of Open Access Journals (Sweden)

Jianping Li

Full Text Available Aplastic anemia (AA is generally considered as an immune-mediated bone marrow failure syndrome with defective hematopoietic stem cells (HSCs and marrow microenvironment. Previous studies have demonstrated the defective HSCs and aberrant T cellular-immunity in AA using a microarray approach. However, little is known about the overall specialty of bone marrow mesenchymal stem cells (BM-MSCs. In the present study, we comprehensively compared the biological features and gene expression profile of BM-MSCs between AA patients and healthy volunteers. In comparison with healthy controls, BM-MSCs from AA patients showed aberrant morphology, decreased proliferation and clonogenic potential and increased apoptosis. BM-MSCs from AA patients were susceptible to be induced to differentiate into adipocytes but more difficult to differentiate into osteoblasts. Consistent with abnormal biological features, a large number of genes implicated in cell cycle, cell division, proliferation, chemotaxis and hematopoietic cell lineage showed markedly decreased expression in BM-MSCs from AA patients. Conversely, more related genes with apoptosis, adipogenesis and immune response showed increased expression in BM-MSCs from AA patients. The gene expression profile of BM-MSCs further confirmed the abnormal biological properties and provided significant evidence for the possible mechanism of the destruction of the bone marrow microenvironment in AA.

In vitro evaluation of cardiomyogenic differentiation of bone marrow derived mesenchymal stem cells (MSCs)

Energy Technology Data Exchange (ETDEWEB)

Kim, Min Hwan; Lee, Yong Jin; Kang, Joo Hyun [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

2010-10-15

Bone marrow derived mesenchymal stem cells (MSCs) are excellent candidate as therapeutic agent for cell therapy. MSCs can be expanded in vitro rapidly (more than 3-5 fold in a weeks), and maintained their stem cell properties for a long culture period. Recently, many investigators have suggested that MSCs have ability to differentiate into cardiomyocytes by given appropriate condition in vitro or in vivo. Although, MSCs may be useful cell therapeutic agents in heart disease, there are still exist major barriers to track their capacity to differentiate into functional cardiomyocytes. In our previous study, the transgenic mouse model expressing sodium iodide symporter (NIS) driven by {alpha}-myosin heavy chain ({alpha}-MHC) promoter was developed to image cardiomyocyte with {gamma}-camera and microPET in vivo. In this study, we investigate the monitoring availability of {alpha}-MHC driven NIS gene of MSCs from the transgenic mouse during cardiomyogenic differentiation in vitro

Manganese Supplementation in Deer under Balanced Diet Increases Impact Energy and Contents in Minerals of Antler Bone Tissue.

Directory of Open Access Journals (Sweden)

Jamil Cappelli

Full Text Available Bone ash, collagen, Ca and P composition, are considered the main factors affecting mechanical properties in bones. However, a series of studies in bone and antler have shown that some trace minerals, such as manganese, may play a role whose importance exceeds what may be expected considering their low content. A previous study showed that a reduction in manganese in antlers during a year of late winter frosts led to generalized antler breakage in Spain, which included a reduction of 30% of cortical thickness, 27% reduction in impact energy, and 10% reduction in work to peak force. Starting for this observation, we experimentally studied the effects of manganese supplementation in adults and yearling (yearlings red deer under a balanced diet. Subjects were 29 deer of different age classes (adult n = 19, yearlings n = 10 that were divided in a manganese injected group (n = 14 and a control group (n = 15. Antler content in ashes and minerals, intrinsic mechanical properties and cross section structure were examined at 4 points along the antler beam. A one way ANOVA (mean per antler showed that in yearlings, manganese supplementation only increased its content and that of Fe. However, in adults, Mn supplementation increased the mean content per antler of Ca, Na, P, B, Co, Cu, K, Mn, Ni, Se (while Si content was reduced, and impact work but not Young's modulus of elasticity, bending strength or work to peak force. A GLM series on characteristics in the uppermost part examined in the antler, often showing physiological exhaustion and depletion of body stores, showed also a 16% increase in work to peak force in the antlers of the treated group. Thus, manganese supplementation altered mineral composition of antler and improved structure and some mechanical properties despite animals having a balanced diet.

Manganese Supplementation in Deer under Balanced Diet Increases Impact Energy and Contents in Minerals of Antler Bone Tissue.

Science.gov (United States)

Cappelli, Jamil; Garcia, Andrés; Ceacero, Francisco; Gomez, Santiago; Luna, Salvador; Gallego, Laureano; Gambin, Pablo; Landete-Castillejos, Tomás

2015-01-01

Bone ash, collagen, Ca and P composition, are considered the main factors affecting mechanical properties in bones. However, a series of studies in bone and antler have shown that some trace minerals, such as manganese, may play a role whose importance exceeds what may be expected considering their low content. A previous study showed that a reduction in manganese in antlers during a year of late winter frosts led to generalized antler breakage in Spain, which included a reduction of 30% of cortical thickness, 27% reduction in impact energy, and 10% reduction in work to peak force. Starting for this observation, we experimentally studied the effects of manganese supplementation in adults and yearling (yearlings) red deer under a balanced diet. Subjects were 29 deer of different age classes (adult n = 19, yearlings n = 10) that were divided in a manganese injected group (n = 14) and a control group (n = 15). Antler content in ashes and minerals, intrinsic mechanical properties and cross section structure were examined at 4 points along the antler beam. A one way ANOVA (mean per antler) showed that in yearlings, manganese supplementation only increased its content and that of Fe. However, in adults, Mn supplementation increased the mean content per antler of Ca, Na, P, B, Co, Cu, K, Mn, Ni, Se (while Si content was reduced), and impact work but not Young's modulus of elasticity, bending strength or work to peak force. A GLM series on characteristics in the uppermost part examined in the antler, often showing physiological exhaustion and depletion of body stores, showed also a 16% increase in work to peak force in the antlers of the treated group. Thus, manganese supplementation altered mineral composition of antler and improved structure and some mechanical properties despite animals having a balanced diet.

Pro-oxidant/antioxidant balance controls pancreatic β-cell differentiation through the ERK1/2 pathway.

Science.gov (United States)

Hoarau, E; Chandra, V; Rustin, P; Scharfmann, R; Duvillie, B

2014-10-23

During embryogenesis, the intrauterine milieu affects cell proliferation, differentiation, and function by modifying gene expression in susceptible cells, such as the pancreatic β-cells. In this limited energy environment, mitochondrial dysfunction can lead to overproduction of reactive oxygen species (ROS) and to a decline in β-cell function. In opposition to this toxicity, ROS are also required for insulin secretion. Here we investigated the role of ROS in β-cell development. Surprisingly, decreasing ROS production in vivo reduced β-cell differentiation. Moreover, in cultures of pancreatic explants, progenitors were highly sensitive to ROS stimulation and responded by generating β-cells. ROS enhanced β-cell differentiation through modulation of ERK1/2 signaling. Gene transfer and pharmacological manipulations, which diminish cellular ROS levels, also interfered with normal β-cell differentiation. This study highlights the role of the redox balance on β-cell development and provides information that will be useful for improving β-cell production from embryonic stem cells, a step in cell therapy for diabetes.

Novel Vanadium-Loaded Ordered Collagen Scaffold Promotes Osteochondral Differentiation of Bone Marrow Progenitor Cells

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Ana M. Cortizo

2016-01-01

Full Text Available Bone and cartilage regeneration can be improved by designing a functionalized biomaterial that includes bioactive drugs in a biocompatible and biodegradable scaffold. Based on our previous studies, we designed a vanadium-loaded collagen scaffold for osteochondral tissue engineering. Collagen-vanadium loaded scaffolds were characterized by SEM, FTIR, and permeability studies. Rat bone marrow progenitor cells were plated on collagen or vanadium-loaded membranes to evaluate differences in cell attachment, growth and osteogenic or chondrocytic differentiation. The potential cytotoxicity of the scaffolds was assessed by the MTT assay and by evaluation of morphological changes in cultured RAW 264.7 macrophages. Our results show that loading of VOAsc did not alter the grooved ordered structure of the collagen membrane although it increased membrane permeability, suggesting a more open structure. The VOAsc was released to the media, suggesting diffusion-controlled drug release. Vanadium-loaded membranes proved to be a better substratum than C0 for all evaluated aspects of BMPC biocompatibility (adhesion, growth, and osteoblastic and chondrocytic differentiation. In addition, there was no detectable effect of collagen or vanadium-loaded scaffolds on macrophage viability or cytotoxicity. Based on these findings, we have developed a new ordered collagen scaffold loaded with VOAsc that shows potential for osteochondral tissue engineering.

Porous surface modified bioactive bone cement for enhanced bone bonding.

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Qiang He

Full Text Available Polymethylmethacrylate bone cement cannot provide an adhesive chemical bonding to form a stable cement-bone interface. Bioactive bone cements show bone bonding ability, but their clinical application is limited because bone resorption is observed after implantation. Porous polymethylmethacrylate can be achieved with the addition of carboxymethylcellulose, alginate and gelatin microparticles to promote bone ingrowth, but the mechanical properties are too low to be used in orthopedic applications. Bone ingrowth into cement could decrease the possibility of bone resorption and promote the formation of a stable interface. However, scarce literature is reported on bioactive bone cements that allow bone ingrowth. In this paper, we reported a porous surface modified bioactive bone cement with desired mechanical properties, which could allow for bone ingrowth.The porous surface modified bioactive bone cement was evaluated to determine its handling characteristics, mechanical properties and behavior in a simulated body fluid. The in vitro cellular responses of the samples were also investigated in terms of cell attachment, proliferation, and osteoblastic differentiation. Furthermore, bone ingrowth was examined in a rabbit femoral condyle defect model by using micro-CT imaging and histological analysis. The strength of the implant-bone interface was also investigated by push-out tests.The modified bone cement with a low content of bioactive fillers resulted in proper handling characteristics and adequate mechanical properties, but slightly affected its bioactivity. Moreover, the degree of attachment, proliferation and osteogenic differentiation of preosteoblast cells was also increased. The results of the push-out test revealed that higher interfacial bonding strength was achieved with the modified bone cement because of the formation of the apatite layer and the osseointegration after implantation in the bony defect.Our findings suggested a new bioactive

Adhesive and mechanical regulation of mesenchymal stem cell differentiation in human bone marrow and periosteum-derived progenitor cells

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Jeroen Eyckmans

2012-08-01

It has previously been demonstrated that cell shape can influence commitment of human bone marrow-derived mesenchymal stem cells (hBMCs to adipogenic, osteogenic, chondrogenic, and other lineages. Human periosteum-derived cells (hPDCs exhibit multipotency similar to hBMCs, but hPDCs may offer enhanced potential for osteogenesis and chondrogenesis given their apparent endogenous role in bone and cartilage repair in vivo. Here, we examined whether hPDC differentiation is regulated by adhesive and mechanical cues comparable to that reported for hBMC differentiation. When cultured in the appropriate induction media, hPDCs at high cell seeding density demonstrated enhanced levels of adipogenic or chondrogenic markers as compared with hPDCs at low cell seeding density. Cell seeding density correlated inversely with projected area of cell spreading, and directly limiting cell spreading with micropatterned substrates promoted adipogenesis or chondrogenesis while substrates promoting cell spreading supported osteogenesis. Interestingly, cell seeding density influenced differentiation through both changes in cell shape and non-shape-mediated effects: density-dependent adipogenesis and chondrogenesis were regulated primarily by cell shape whereas non-shape effects strongly influenced osteogenic potential. Inhibition of cytoskeletal contractility by adding the Rho kinase inhibitor Y27632 further enhanced adipogenic differentiation and discouraged osteogenic differentiation of hPDCs. Together, our results suggest that multipotent lineage decisions of hPDCs are impacted by cell adhesive and mechanical cues, though to different extents than hBMCs. Thus, future studies of hPDCs and other primary stem cell populations with clinical potential should consider varying biophysical metrics for more thorough optimization of stem cell differentiation.

Human decellularized bone scaffolds from aged donors show improved osteoinductive capacity compared to young donor bone.

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Christopher A Smith

Full Text Available To improve the safe use of allograft bone, decellularization techniques may be utilized to produce acellular scaffolds. Such scaffolds should retain their innate biological and biomechanical capacity and support mesenchymal stem cell (MSC osteogenic differentiation. However, as allograft bone is derived from a wide age-range, this study aimed to determine whether donor age impacts on the ability an osteoinductive, acellular scaffold produced from human bone to promote the osteogenic differentiation of bone marrow MSCs (BM-MSC. BM-MSCs from young and old donors were seeded on acellular bone cubes from young and old donors undergoing osteoarthritis related hip surgery. All combinations resulted in increased osteogenic gene expression, and alkaline phosphatase (ALP enzyme activity, however BM-MSCs cultured on old donor bone displayed the largest increases. BM-MSCs cultured in old donor bone conditioned media also displayed higher osteogenic gene expression and ALP activity than those exposed to young donor bone conditioned media. ELISA and Luminex analysis of conditioned media demonstrated similar levels of bioactive factors between age groups; however, IGF binding protein 1 (IGFBP1 concentration was significantly higher in young donor samples. Additionally, structural analysis of old donor bone indicated an increased porosity compared to young donor bone. These results demonstrate the ability of a decellularized scaffold produced from young and old donors to support osteogenic differentiation of cells from young and old donors. Significantly, the older donor bone produced greater osteogenic differentiation which may be related to reduced IGFBP1 bioavailability and increased porosity, potentially explaining the excellent clinical results seen with the use of allograft from aged donors.

Low-frequency vibration treatment of bone marrow stromal cells induces bone repair in vivo

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Shengwei He

2017-01-01

Full Text Available Objective(s:To study the effect of low-frequency vibration on bone marrow stromal cell differentiation and potential bone repair in vivo. Materials and Methods:Forty New Zealand rabbits were randomly divided into five groups with eight rabbits in each group. For each group, bone defects were generated in the left humerus of four rabbits, and in the right humerus of the other four rabbits. To test differentiation, bones were isolated and demineralized, supplemented with bone marrow stromal cells, and implanted into humerus bone defects. Varying frequencies of vibration (0, 12.5, 25, 50, and 100 Hz were applied to each group for 30 min each day for four weeks. When the bone defects integrated, they were then removed for histological examination. mRNA transcript levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor k-B ligan, and pre-collagen type 1 a were measured. Results:Humeri implanted with bone marrow stromal cells displayed elevated callus levels and wider, more prevalent, and denser trabeculae following treatment at 25 and 50 Hz. The mRNA levels of runt-related transcription factor 2, osteoprotegerin, receptor activator of nuclear factor k-B ligand, and pre-collagen type 1 a were also markedly higher following 25 and 50 Hz treatment. Conclusion:Low frequency (25–50 Hz vibration in vivo can promote bone marrow stromal cell differentiation and repair bone injury.

Oxidative stress in bone remodeling: role of antioxidants.

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Domazetovic, Vladana; Marcucci, Gemma; Iantomasi, Teresa; Brandi, Maria Luisa; Vincenzini, Maria Teresa

2017-01-01

ROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss.

Cocaine- and amphetamine-regulated transcript promotes the differentiation of mouse bone marrow-derived mesenchymal stem cells into neural cells

OpenAIRE

Jin Jiali; Chen Zhibin; Zhang Meijuan; Huang Danqing; Liu Zhuo; Huang Siyuan; Zhang Zhuo; Wang Zhongyuan; Chen Lei; Chen Ling; Xu Yun

2011-01-01

Abstract Background Neural tissue has limited potential to self-renew after neurological damage. Cell therapy using BM-MSCs (bone marrow mesenchymal stromal cells) seems like a promising approach for the treatment of neurological diseases. However, the neural differentiation of stem cells influenced by massive factors and interactions is not well studied at present. Results In this work, we isolated and identified MSCs from mouse bone marrow. Co-cultured with CART (0.4 nM) for six days, BM-MS...

Clinical research of bone scan characteristics for metabolic bone diseases

International Nuclear Information System (INIS)

Zhu Ruisen; Luo Qiong; Lu Haikui; Chen Libo; Luo Quanyong

2009-01-01

Characteristic images of 99m Tc-MDP bone scintigraphy in patients with metabolic bone diseases (MBD) were analyzed and compared, in an attempt to improve the capability of differential diagnosis in this aspect. A total of 142 cases, clinically confirmed as (MBD), were categorized into six groups: hyperparathyroidism (117), renal osteodystrophy (4), Paget's disease (16), hypophosphatemic osteomalacia (2), Albers-Schonberg disease (2), and Brittle bone disease (1). They were diagnosed clinically or pathologically, and scanned with 99m Tc-MDP bone scintegraphy, from which the 142 MBD cases were classified into 4 types. The cases of Type I had increased amount of 99m Tc-MDP uptake in whole body bones, including hyperparathyroidism, Albers-Schonberg disease, brittle bone disease and renal osteodystrophy. The cases of Type II had high uptake of 99m Tc-MDP in local region of bones, including paget's disease, hypophosphatemic osteomalacia and hyperparathyroidism. A Type I case with pathological fracture or secondary osteopathy was classified as Type III. Type IV cases were in early stage of hyperparathyroidism, with normal bone scan image. Analysis of the characteristics of 99m Tc-MDP bone scintigraphic findings (locations, morphology and intensities) in patients with MBD may be helpful in the differential diagnosis of MBD, in association with the patient's history and X-ray data altogether. (authors)

Reconstitution of bone-like matrix in osteogenically differentiated mesenchymal stem cell–collagen constructs: A three-dimensional in vitro model to study hematopoietic stem cell niche

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WY Lai

2013-10-01

Full Text Available Mesenchymal stem/stromal cells (MSCs and osteoblasts are important niche cells for hematopoietic stem cells (HSCs in bone marrow osteoblastic niche. Here, we aim to partially reconstitute the bone marrow HSC niche in vitro using collagen microencapsulation for investigation of the interactions between HSCs and MSCs. Mouse MSCs (mMSCs microencapsulated in collagen were osteogenically differentiated to derive a bone-like matrix consisting of osteocalcin, osteopontin, and calcium deposits and secreted bone morphogenic protein 2 (BMP2. Decellularized bone-like matrix was seeded with fluorescence-labeled human MSCs and HSCs. Comparing with pure collagen scaffold, significantly more HSCs and HSC–MSC pairs per unit area were found in the decellularized bone-like matrix. Moreover, incubation with excess neutralizing antibody of BMP2 resulted in a significantly higher number of HSC per unit area than that without in the decellularized matrix. This work suggests that the osteogenic differentiated MSC–collagen microsphere is a valuable three-dimensional in vitro model to elucidate cell–cell and cell–matrix interactions in HSC niche.

The role of bone marrow-derived cells during the bone healing process in the GFP mouse bone marrow transplantation model.

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Tsujigiwa, Hidetsugu; Hirata, Yasuhisa; Katase, Naoki; Buery, Rosario Rivera; Tamamura, Ryo; Ito, Satoshi; Takagi, Shin; Iida, Seiji; Nagatsuka, Hitoshi

2013-03-01

Bone healing is a complex and multistep process in which the origin of the cells participating in bone repair is still unknown. The involvement of bone marrow-derived cells in tissue repair has been the subject of recent studies. In the present study, bone marrow-derived cells in bone healing were traced using the GFP bone marrow transplantation model. Bone marrow cells from C57BL/6-Tg (CAG-EGFP) were transplanted into C57BL/6 J wild mice. After transplantation, bone injury was created using a 1.0-mm drill. Bone healing was histologically assessed at 3, 7, 14, and 28 postoperative days. Immunohistochemistry for GFP; double-fluorescent immunohistochemistry for GFP-F4/80, GFP-CD34, and GFP-osteocalcin; and double-staining for GFP and tartrate-resistant acid phosphatase were performed. Bone marrow transplantation successfully replaced the hematopoietic cells into GFP-positive donor cells. Immunohistochemical analyses revealed that osteoblasts or osteocytes in the repair stage were GFP-negative, whereas osteoclasts in the repair and remodeling stages and hematopoietic cells were GFP-positive. The results indicated that bone marrow-derived cells might not differentiate into osteoblasts. The role of bone marrow-derived cells might be limited to adjustment of the microenvironment by differentiating into inflammatory cells, osteoclasts, or endothelial cells in immature blood vessels.

Onset of apoprotein E secretion during differentiation of mouse bone marrow-derived mononuclear phagocytes

International Nuclear Information System (INIS)

Werb, Z.; Chin, J.R.

1983-01-01

A number of macrophage functions were sequentially expressed when the bone marrow precursors of mononuclear phagocytes differentiated in culture in the presence of a specific growth factor, colony-stimulating factor-1. The authors defined the expression of apoprotein E (ApoE), a major secreted protein of resident peritoneal macrophages, during maturation of adherent bone marrow-derived mononuclear phagocytes into macrophages. By 5 d the bone marrow macrophages were active secretory cells, but few cells contained intracellular immunoreactive ApoE, and little, if any, ApoE was secreted. ApoE secretion was initiated at 9 d, and this correlated with an increase in the percentage of macrophages containing intracellular ApoE. The onset of ApoE secretion was selective, and little change occurred in the other major secreted proteins detected by [ 35 S]methionine incorporation. In parallel, the high rate of plasminogen activator secretion, which peaked at 7 d, decreased markedly. ApoE secretion was not associated with altered expression of the macrophage surface antigen, la, or with secretion of fibronectin. Virtually all cells in independent colonies of bone marrow-derived macrophages eventually expressed ApoE. The proliferating monocyte/macrophage-like cell lines P388D1, J774.2, WHEI-3, RAW 264.1, and MGI.D + secreted little or no ApoE. These data establish that ApoE secretion is developmentally regulated

The Bone Marrow-Derived Stromal Cells

DEFF Research Database (Denmark)

Tencerova, Michaela; Kassem, Moustapha

2016-01-01

Bone marrow (BM) microenvironment represents an important compartment of bone that regulates bone homeostasis and the balance between bone formation and bone resorption depending on the physiological needs of the organism. Abnormalities of BM microenvironmental dynamics can lead to metabolic bone...... diseases. BM stromal cells (also known as skeletal or mesenchymal stem cells) [bone marrow stromal stem cell (BMSC)] are multipotent stem cells located within BM stroma and give rise to osteoblasts and adipocytes. However, cellular and molecular mechanisms of BMSC lineage commitment to adipocytic lineage...

[Bone homeostasis and Mechano biology.

Science.gov (United States)

Nakashima, Tomoki

The weight-bearing exercises help to build bones and to maintain them strength. Bone is constantly renewed by the balanced action of osteoblastic bone formation and osteoclastic bone resorption both of which mainly occur at the bone surface. This restructuring process called "bone remodeling" is important not only for normal bone mass and strength, but also for mineral homeostasis. Bone remodeling is stringently regulated by communication between bone component cells such as osteoclasts, osteoblasts and osteocytes. An imbalance of this process is often linked to various bone diseases. During bone remodeling, resorption by osteoclasts precedes bone formation by osteoblasts. Based on the osteocyte location within the bone matrix and the cellular morphology, it is proposed that osteocytes potentially contribute to the regulation of bone remodeling in response to mechanical and endocrine stimuli.

Human Stromal (Mesenchymal) Stem Cells from Bone Marrow, Adipose Tissue and Skin Exhibit Differences in Molecular Phenotype and Differentiation Potential

DEFF Research Database (Denmark)

Al-Nbaheen, May; Vishnubalaji, Radhakrishnan; Ali, Dalia

2013-01-01

Human stromal (mesenchymal) stem cells (hMSCs) are multipotent stem cells with ability to differentiate into mesoderm-type cells e.g. osteoblasts and adipocytes and thus they are being introduced into clinical trials for tissue regeneration. Traditionally, hMSCs have been isolated from bone marrow......, but the number of cells obtained is limited. Here, we compared the MSC-like cell populations, obtained from alternative sources for MSC: adipose tissue and skin, with the standard phenotype of human bone marrow MSC (BM-MSCs). MSC from human adipose tissue (human adipose stromal cells (hATSCs)) and human skin......, MSC populations obtained from different tissues exhibit significant differences in their proliferation, differentiation and molecular phenotype, which should be taken into consideration when planning their use in clinical protocols....

Astrocytes from the contused spinal cord inhibit oligodendrocyte differentiation of adult oligodendrocyte precursor cells by increasing the expression of bone morphogenetic proteins.

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Wang, Yaping; Cheng, Xiaoxin; He, Qian; Zheng, Yiyan; Kim, Dong H; Whittemore, Scott R; Cao, Qilin L

2011-04-20

Promotion of remyelination is an important therapeutic strategy to facilitate functional recovery after traumatic spinal cord injury (SCI). Transplantation of neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) has been used to enhance remyelination after SCI. However, the microenvironment in the injured spinal cord is inhibitory for oligodendrocyte (OL) differentiation of NSCs or OPCs. Identifying the signaling pathways that inhibit OL differentiation in the injured spinal cord could lead to new therapeutic strategies to enhance remyelination and functional recovery after SCI. In the present study, we show that reactive astrocytes from the injured rat spinal cord or their conditioned media inhibit OL differentiation of adult OPCs with concurrent promotion of astrocyte differentiation. The expression of bone morphogenetic proteins (BMP) is dramatically increased in the reactive astrocytes and their conditioned media. Importantly, blocking BMP activity by BMP receptor antagonist, noggin, reverse the effects of active astrocytes on OPC differentiation by increasing the differentiation of OL from OPCs while decreasing the generation of astrocytes. These data indicate that the upregulated bone morphogenetic proteins in the reactive astrocytes are major factors to inhibit OL differentiation of OPCs and to promote its astrocyte differentiation. These data suggest that manipulation of BMP signaling in the endogenous or grafted NSCs or OPCs may be a useful therapeutic strategy to increase their OL differentiation and remyelination and enhance functional recovery after SCI.

Restoration of Respiratory Gases and Acid-base Balance of Blood of Gamma Irradiated Rats Through Bone Marrow Transplantation

International Nuclear Information System (INIS)

Eissa, S.M.; Roushdy, H.M.; Khamis, F. I.; Abu-Zeid, N.M.

2000-01-01

The present investigation aimed at elucidating the role played by bone marrow transplantation as a biological treatment against the deleterious effect of ionizing radiation. The parameters tested were PO2; PCO2; TCO2 and acid base balance encountering pH and (HCO3) in blood. Investigations were conducted 1,3,7,14 and 21 days post whole body gamma exposure at the dose levels 2 and 6 Gy. The data obtained showed highly significant changes in all tested parameters after whole body gamma irradiation. A higher depressant effect was more pronounced after exposure to higher radiation dose. Bone marrow transplantation to irradiated rats resulted in partial restoration or the radiation induced changes in both PO2 and PCO2 as recorded on the first week post treatment and succeeded to ameliorate the radiation induced changes in pH values and (HCO3) in blood

TBTC induces adipocyte differentiation in human bone marrow long term culture

International Nuclear Information System (INIS)

Carfi, M.; Croera, C.; Ferrario, D.; Campi, V.; Bowe, G.; Pieters, R.; Gribaldo, L.

2008-01-01

Organotins are widely used in agriculture and the chemical industry, causing persistent and widespread pollution. Organotins may affect the brain, liver and immune system and eventually human health. Recently, it has been shown that tri-butyltin (TBT) interacts with nuclear receptors PPARγ (peroxisome proliferator-activated receptor γ) and RXR (retinoid x receptor) leading to adipocyte differentiation in the 3T3 cell line. Since adipocytes are known to influence haematopoiesis, for instance through the expression of cytokines and adhesion molecules, it was considered of interest to further study the adipocyte-stimulating effect of TBTC in human bone marrow cultures. Nile Red spectrofluorimetric analysis showed a significant increase of adipocytes in TBTC-treated cultures after 14 days of long term culture. Real-time PCR and Western blot analysis confirmed the high expression of the specific adipocyte differentiation marker aP2 (adipocyte-specific fatty acid binding protein). PPARγ, but not RXR, mRNA was increased after 24 h and 48 h exposure. TBTC also induced a decrease in a number of chemokines, interleukins, and growth factors. Also the expression of leptin, a hormone involved in haematopoiesis, was down regulated by TBTC treatment. It therefore appears that TBTC induced adipocyte differentiation, whilst reducing a number of haematopoietic factors. This study indicates that TBTC may interfere in the haematopoietic process through an alteration of the stromal layer and cytokine homeostasis

Patients With High Bone Mass Phenotype Exhibit Enhanced Osteoblast Differentiation and Inhibition of Adipogenesis of Human Mesenchymal Stem Cells

DEFF Research Database (Denmark)

Qiu, Weimin; Andersen, Tom; Bollerslev, Jens

2007-01-01

in iliac crest bone biopsies from patients with the HBM phenotype and controls. We also used retrovirus-mediated gene transduction to establish three different human mesenchymal stem cell (hMSC) strains stably expressing wildtype LRP5 (hMSC-LRP5WT), LRP5T244 (hMSC-LRP5T244, inactivation mutation leading...... to osteoporosis), or LRP5T253 (hMSC-LRP5T253, activation mutation leading to high bone mass). We characterized Wnt signaling activation using a dual luciferase assay, cell proliferation, lineage biomarkers using real-time PCR, and in vivo bone formation. Results: In bone biopsies, we found increased trabecular...... mineralized bone when implanted subcutaneously with hydroxyapatite/tricalcium phosphate in SCID/NOD mice. Conclusions: LRP5 mutations and the level of Wnt signaling determine differentiation fate of hMSCs into osteoblasts or adipocytes. Activation of Wnt signaling can thus provide a novel approach to increase...

Differential responses of production and respiration to temperature and moisture drive the carbon balance across a climatic gradient in New Mexico

Science.gov (United States)

Kristina J. Anderson-Teixeira; John P. Delong; Andrew M. Fox; Daniel A. Brese; Marcy E. Litvak

2011-01-01

Southwestern North America faces an imminent transition to a warmer, more arid climate, and it is critical to understand how these changes will affect the carbon balance of southwest ecosystems. In order to test our hypothesis that differential responses of production and respiration to temperature and moisture shape the carbon balance across a range of spatio-temporal...

Different culture media affect growth characteristics, surface marker distribution and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells.

Science.gov (United States)

Hagmann, Sebastien; Moradi, Babak; Frank, Sebastian; Dreher, Thomas; Kämmerer, Peer Wolfgang; Richter, Wiltrud; Gotterbarm, Tobias

2013-07-30

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) play an important role in modern tissue engineering, while distinct variations of culture media compositions and supplements have been reported. Because MSCs are heterogeneous regarding their regenerative potential and their surface markers, these parameters were compared in four widely used culture media compositions. MSCs were isolated from bone marrow and expanded in four established cell culture media. MSC yield/1000 MNCs, passage time and growth index were observed. In P4, typical MSC surface markers were analysed by fluorescence cytometry. Additionally, chondrogenic, adipogenic and osteogenic differentiation potential were evaluated. Growth index and P0 cell yield varied importantly between the media. The different expansion media had a significant influence on the expression of CD10, CD90, CD105, CD140b CD146 and STRO-1. While no significant differences were observed regarding osteogenic and adipogenic differentiation, chondrogenic differentiation was superior in medium A as reflected by GAG/DNA content. The choice of expansion medium can have a significant influence on growth, differentiation potential and surface marker expression of mesenchymal stromal cells, which is of fundamental importance for tissue engineering procedures.

Human DPSCs fabricate vascularized woven bone tissue: A new tool in bone tissue engineering

Czech Academy of Sciences Publication Activity Database

Paino, F.; Noce, M.L.; Giuliani, A.; de Rosa, A.; Mazzoni, F.; Laino, L.; Amler, Evžen; Papaccio, G.; Desiderio, V.; Tirino, V.

2017-01-01

Roč. 131, č. 8 (2017), s. 699-713 ISSN 0143-5221 Institutional support: RVO:68378041 Keywords : bone differentiation * bone regeneration * bone tissue engineering Subject RIV: FP - Other Medical Disciplines OBOR OECD: Orthopaedics Impact factor: 4.936, year: 2016

Bone Marrow Mesenchymal Stem Cells Enhance the Differentiation of Human Switched Memory B Lymphocytes into Plasma Cells in Serum-Free Medium

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Guillaume Bonnaure

2016-01-01

Full Text Available The differentiation of human B lymphocytes into plasma cells is one of the most stirring questions with regard to adaptive immunity. However, the terminal differentiation and survival of plasma cells are still topics with much to be discovered, especially when targeting switched memory B lymphocytes. Plasma cells can migrate to the bone marrow in response to a CXCL12 gradient and survive for several years while secreting antibodies. In this study, we aimed to get closer to niches favoring plasma cell survival. We tested low oxygen concentrations and coculture with mesenchymal stem cells (MSC from human bone marrow. Besides, all cultures were performed using an animal protein-free medium. Overall, our model enables the generation of high proportions of CD38+CD138+CD31+ plasma cells (≥50% when CD40-activated switched memory B lymphocytes were cultured in direct contact with mesenchymal stem cells. In these cultures, the secretion of CXCL12 and TGF-β, usually found in the bone marrow, was linked to the presence of MSC. The level of oxygen appeared less impactful than the contact with MSC. This study shows for the first time that expanded switched memory B lymphocytes can be differentiated into plasma cells using exclusively a serum-free medium.

Micro/Nano Structural Tantalum Coating for Enhanced Osteogenic Differentiation of Human Bone Marrow Stem Cells

OpenAIRE

Ding Ding; Youtao Xie; Kai Li; Liping Huang; Xuebin Zheng

2018-01-01

Recently, tantalum has been attracting much attention for its anticorrosion resistance and biocompatibility, and it has been widely used in surface modification for implant applications. To improve its osteogenic differentiation of human bone marrow stem cells (hBMSCs), a micro/nano structure has been fabricated on the tantalum coating surface through the combination of anodic oxidation and plasma spraying method. The morphology, composition, and microstructure of the modified coating were co...

Differential radiodiagnosis of cranial lesions in hyperparathyroid and deforming asteodystrophy, fibrous osteoplasia, multiple myeloma and tumor metastases to the cranial bones

International Nuclear Information System (INIS)

Spuzyak, M.I.

1986-01-01

The results of an analysis of craniographic findings were provided for 58 patients with primary hyperparathyrosis, 12 with fibrous osteodysplasia, 6 with deforming osteodystrophy, 14 with multiple myeloma and 16 with tumor metastases to the cranial bones. A study was made of some features of roentgenological semiotics (changes in the structure thickness and shapes of the cranial bones) of cranial bone lesions in the above diseases. Differential radiodiagnosis of cranial lesions in hypeparathyroid and deforming osteodystrophy, fibrous osteodysplasia, multiple myeloma and metastatic lesions of the cranial bones should be based not on single signs but on the symptom-complex (x-ray syndrome). For each of the analysed diseases x-ray syndromes were described

Impaired osteoblast function in osteoporosis: comparison between calcium balance and dynamic histomorphometry.

Science.gov (United States)

Arlot, M; Edouard, C; Meunier, P J; Neer, R M; Reeve, J

1984-09-01

Osteoblast function was investigated in 27 patients with idiopathic osteoporosis. Transiliac bone biopsy specimens were taken after double labelling with tetracycline, and metabolic calcium balance was studied almost simultaneously. Many of the patients showed poor double labelling of their otherwise unremarkable trabecular osteoid, suggesting impaired formation of bone at many of these surfaces. This phenomenon was not accompanied by increased width of osteoid seams (as seen in osteomalacia), indicating that formation of the matrix and its mineralisation were in equilibrium. For the first time, highly significant positive correlations (p less than 0.01) were found between indices of bone formation, determined by labelling with tetracycline, and calcium balance. Thus some patients with osteoporosis who are rapidly losing bone have low rates of formation of trabecular bone both by individual osteoblasts and in relation to available bone surfaces. As histological indices of bone resorption also independently correlated strongly and inversely (p less than 0.01) with calcium balance the rate of initiation of new basic multicellular units by osteoclastic resorption of trabecular surfaces (or the depth of resorption at these surfaces) also appears to be an important determinant of mineral balance. The mechanisms that regulate the effective life span of mature osteoblasts require further investigation, particularly as some promising treatments that can increase trabecular bone volume in osteoporosis, such as parathyroid peptide hPTH (1-34) and sodium fluoride, must work through a reversal of osteoblastic depression.

The effect of long-term acidifying feeding on digesta organic acids, mineral balance, and bone mineralization in growing pigs

DEFF Research Database (Denmark)

Nørgaard, Jan Værum; Højberg, Ole; Sørensen, Kristina Ulrich

2014-01-01

Acidification of slurry through dietary manipulation of urinary pH is a means of mitigating nitrogen emission from pig production, but long-term effects of diet acidification on bone mineralization and mineral balance is less investigated. The objective was therefore to study the long-term effects...... of feeding benzoic acid (BA) and calcium chloride (CaCl2) on the mineral balance and microbial activity in the gastrointestinal tract of pigs. Four diets containing the combinations of 0 or 10 g/kg BA and 0 or 20 g/kg CaCl2 were fed to 24 pigs in a factorial design. For the diets without CaCl2, calcium...... carbonate (CaCO3) was added to provide equimolar levels of Ca. The pigs were fed the diets from 36 kg until slaughter at 113 kg BW, and they were housed in balance cages for 12 d from 60 to 66 kg BW. Supplementation of BA and/or CaCl2 had only minor effect on accumulation of digesta organic acids (acetate...

Polycomb Cbx family members mediate the balance between haematopoietic stem cell self-renewal and differentiation

DEFF Research Database (Denmark)

Klauke, Karin; Radulović, Višnja; Broekhuis, Mathilde

2013-01-01

The balance between self-renewal and differentiation of adult stem cells is essential for tissue homeostasis. Here we show that in the haematopoietic system this process is governed by polycomb chromobox (Cbx) proteins. Cbx7 is specifically expressed in haematopoietic stem cells (HSCs), and its...... overexpression enhances self-renewal and induces leukaemia. This effect is dependent on integration into polycomb repressive complex-1 (PRC1) and requires H3K27me3 binding. In contrast, overexpression of Cbx2, Cbx4 or Cbx8 results in differentiation and exhaustion of HSCs. ChIP-sequencing analysis shows that Cbx......7 and Cbx8 share most of their targets; we identified approximately 200 differential targets. Whereas genes targeted by Cbx8 are highly expressed in HSCs and become repressed in progenitors, Cbx7 targets show the opposite expression pattern. Thus, Cbx7 preserves HSC self-renewal by repressing...

Effects of Dendrobium officinale polysaccharide on adipogenic differentiation of rat bone marrow mesenchymal stem cells

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Yinjuan ZHAO

Full Text Available Abstract This study investigated the effect of Dendrobium officinale polysaccharide (DOP on the adipogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs. DOP was extracted fresh Dendrobium officinale. Rat BMSCs were prepared, and then were treated with 0 (control, 50, 100, 200, 400, 800 μg/mL DOP, respectively. The cell viability was determined by MTT assay. The adipogenic differentiation was quantitatively analyzed by oil red O staining assay. The mRNA expressions of adipogenic differentiation related gene peroxisome proliferator-activated receptor gamma (PPARG, lipoprotein lipase (LPL and fatty acid binding protein 4 (FABP4 were detected by RT-PCR. Results showed that, DOP with 0-800 μg/mL concentration had no significant toxicity to BMSCs. 200-800 μg/mL DOP could obviously inhibit the adipogenic differentiation of BMSCs. Compared with control group, the expression levels of PPARG, LPL and FABP4 mRNA 200, 400 and 800 μg/mL DOP groups were significantly decreased (P < 0.05 or P < 0.01. DOP can inhibit the adipogenic differentiation of BMSCs, which may be related with its down-regulation of PPARG, LPL and FABP4 expressions in BMSCs.

Effect of growth factors (BMP-4/7 & bFGF on proliferation & osteogenic differentiation of bone marrow stromal cells

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Shaohui Yuan

2013-01-01

Full Text Available Background & objectives: BMP (bone morphogenetic protein-4/7 and bFGF (basic fibroblast growth factor significantly promote the osteogenic activity and the proliferation of rabbit BMSCs (bone marrow stromal cells, respectively. However, their synergistic effects on the proliferation and the differentiation of BMSCs remain unclear. In the present study, the effects of bFGF and BMP-4/7 were investigated on the proliferation and the differentiation of rat BMSCs in vitro. Methods: BMSCs were isolated from New Zealand white rabbits and cultured to the third passage. The samples were divided into five groups according to the material implanted: (A 80 ng/ml BMP-4/7; (B 80 ng/ml bFGF; (C 30 ng/ml BMP-4/7 and 30 ng/ml bFGF; (D 50 ng/ml BMP-4/7 and 50 ng/ml bFGF; and (E 80 ng/ml BMP-4/7 and 80 ng/ml bFGF. Cell proliferation was analyzed using methyl thiazolyl tetrazolium (MTT assay. Alkaline phosphatase activity and osteocalcin (OC dynamics were also measured. Results: BMP-4/7 alone significantly (P<0.05 promoted the proliferation of BMSCs. At the same time, it also promoted or inhibited the osteogenic differentiation of BMSCs. The synergistic effects of BMP-4/7 and bFGF significantly promoted both the proliferation and the osteogenic differentiation of BMSCs. The treatment of the synergistic effects was dose and time dependent. Interpretation & conclusions: A rational combination of BMP-4/7 and bFGF can promote the proliferation and the osteogenic differentiation of BMSCs. In addition, the synergistic functions are effective.

New Insights into Osteogenic and Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells and Their Potential Clinical Applications for Bone Regeneration in Pediatric Orthopaedics

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Nicola Giuliani

2013-01-01

Full Text Available Human mesenchymal stem cells (hMSCs are pluripotent adult stem cells capable of being differentiated into osteoblasts, adipocytes, and chondrocytes. The osteogenic differentiation of hMSCs is regulated either by systemic hormones or by local growth factors able to induce specific intracellular signal pathways that modify the expression and activity of several transcription factors. Runt-related transcription factor 2 (Runx2 and Wnt signaling-related molecules are the major factors critically involved in the osteogenic differentiation process by hMSCs, and SRY-related high-mobility-group (HMG box transcription factor 9 (SOX9 is involved in the chondrogenic one. hMSCs have generated a great interest in the field of regenerative medicine, particularly in bone regeneration. In this paper, we focused our attention on the molecular mechanisms involved in osteogenic and chondrogenic differentiation of hMSC, and the potential clinical use of hMSCs in osteoarticular pediatric disease characterized by fracture nonunion and pseudarthrosis.

Micro/Nano Structural Tantalum Coating for Enhanced Osteogenic Differentiation of Human Bone Marrow Stem Cells.

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Ding, Ding; Xie, Youtao; Li, Kai; Huang, Liping; Zheng, Xuebin

2018-04-03

Recently, tantalum has been attracting much attention for its anticorrosion resistance and biocompatibility, and it has been widely used in surface modification for implant applications. To improve its osteogenic differentiation of human bone marrow stem cells (hBMSCs), a micro/nano structure has been fabricated on the tantalum coating surface through the combination of anodic oxidation and plasma spraying method. The morphology, composition, and microstructure of the modified coating were comprehensively studied by employing scanning electron microscopy (SEM), X-ray diffraction (XRD) as well as transmission electron microscopy (TEM). The effects of hierarchical structures as well as micro-porous structure of tantalum coating on the behavior for human bone marrow stem cells (hBMSCs) were evaluated and compared at both cellular and molecular levels in vitro. The experimental results show that a hierarchical micro/nano structure with Ta₂O₅ nanotubes spread onto a micro-scale tantalum coating has been fabricated successfully, which is confirmed to promote cell adhesion and spreading. Besides, the hierarchical micro/nano tantalum coating can provide 1.5~2.1 times improvement in gene expression, compared with the micro-porous tantalum coating. It demonstrates that it can effectively enhance the proliferation and differentiation of hBMSCs in vitro.

Nano-scaled hydroxyapatite/silk fibroin sheets support osteogenic differentiation of rat bone marrow mesenchymal cells

International Nuclear Information System (INIS)

Tanaka, Toshimitsu; Hirose, Motohiro; Kotobuki, Noriko; Ohgushi, Hajime; Furuzono, Tsutomu; Sato, Junichi

2007-01-01

A novel biomaterial that was composed of nano-scaled sintered hydroxyapatite (HAp) and silk fibroin (SF) was fabricated. We cultured rat marrow mesenchymal cells (MMCs) on this biomaterial (nano-HAp/SF sheet), on bare SF sheets, and on tissue culture polystyrene (TCPS) dishes as controls, then evaluated cell adhesion, proliferation, and differentiation of the MMCs. After 1 h of culture, a large number of viable cells were observed on the nano-HAp/SF sheets in comparison to the controls. In addition, after 3 h of culture, the morphology of the cells on the nano-HAp/SF sheets was quite different from that on the SF sheets. MMCs extrude their cytoplasmic processes to nano-HAp particles and are well attached to the sheets. After 14 days of culture, under osteogenic conditions, the alkaline phosphatase (ALP) activity and bone-specific osteocalcin secretion of the cells on nano-HAp/SF sheets were higher than were those on the controls. These results indicated that the surface of the nano-HAp/SF sheets is covered with appropriate HAp crystal for MMC adhesion/proliferation and that the sheets effectively support the osteogenic differentiation of MMCs. Therefore, the nano-HAp/SF sheet is an effective biomaterial that is applicable in bone reconstruction surgery

Micro/Nano Structural Tantalum Coating for Enhanced Osteogenic Differentiation of Human Bone Marrow Stem Cells

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Ding Ding

2018-04-01

Full Text Available Recently, tantalum has been attracting much attention for its anticorrosion resistance and biocompatibility, and it has been widely used in surface modification for implant applications. To improve its osteogenic differentiation of human bone marrow stem cells (hBMSCs, a micro/nano structure has been fabricated on the tantalum coating surface through the combination of anodic oxidation and plasma spraying method. The morphology, composition, and microstructure of the modified coating were comprehensively studied by employing scanning electron microscopy (SEM, X-ray diffraction (XRD as well as transmission electron microscopy (TEM. The effects of hierarchical structures as well as micro-porous structure of tantalum coating on the behavior for human bone marrow stem cells (hBMSCs were evaluated and compared at both cellular and molecular levels in vitro. The experimental results show that a hierarchical micro/nano structure with Ta2O5 nanotubes spread onto a micro-scale tantalum coating has been fabricated successfully, which is confirmed to promote cell adhesion and spreading. Besides, the hierarchical micro/nano tantalum coating can provide 1.5~2.1 times improvement in gene expression, compared with the micro-porous tantalum coating. It demonstrates that it can effectively enhance the proliferation and differentiation of hBMSCs in vitro.

Monitoring Bone Tissue Engineered (BTE) Constructs Based on the Shifting Metabolism of Differentiating Stem Cells.

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Simmons, Aaron D; Sikavitsas, Vassilios I

2018-01-01

Ever-increasing demand for bone grafts necessitates the realization of clinical implementation of bone tissue engineered constructs. The predominant hurdle to implementation remains to be securing FDA approval, based on the lack of viable methods for the rigorous monitoring of said constructs. The study presented herein details a method for such monitoring based on the shifting metabolism of mesenchymal stem cells (MSCs) as they differentiate into osteoblasts. To that end, rat MSCs seeded on 85% porous spunbonded poly(L-lactic acid) scaffolds were cultured in flow perfusion bioreactors with baseline or osteoinductive media, and levels of key physio-metabolic markers (oxygen, glucose, osteoprotegerin, and osteocalcin) were monitored throughout culture. Comparison of these non-destructively obtained values and current standard destructive analyses demonstrated key trends useful for the concurrent real-time monitoring of construct cellularity and maturation. Principle among these is the elucidation of the ratio of the rates of oxygen uptake to glucose consumption as a powerful quality marker. This ratio, supported on a physiological basis, has been shown herein to be reliable in the determination of both construct maturation (defined as osteoblastic differentiation and accompanying mineralization) and construct cellularity. Supplementary monitoring of OPG and OCN are shown to provide further validation of such metrics.

Low magnitude high frequency vibration promotes adipogenic differentiation of bone marrow stem cells via P38 MAPK signal.

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Qian Zhao

Full Text Available Low magnitude high frequency vibration (LMHFV has been mainly reported for its influence on the musculoskeletal system, particularly the bone tissue. In the bone structure, osteogenic activity is the main focus of study with regards to LMHFV. However, adipogenesis, another important mode of differentiation in the bone marrow cavity that might be affected by LMHFV, is much less researched. Furthermore, the molecular mechanism of how LMHFV influences adipogenesis still needs to be understood. Here, we tested the effect of LMHFV (0.3g, 40 Hz, amplitude: 50μm, 15min/d, on multipotent stem cells (MSCs, which are the common progenitors of osteogenic, chondrogenic, adipogenic and myogenic cells. It is previously shown that LMHFV promotes osteogenesis of MSCs. In this study, we further revealed its effect on adipo-differentiation of bone marrow stem cells (BMSCs and studied the underlying signaling pathway. We found that when treated with LMHFV, the cells showed a higher expression of PPARγ, C/EBPα, adiponectin and showed more oil droplets. After vibration, the protein expression of PPARγ increased, and the phosphorylation of p38 MAPK was enhanced. After treating cells with SB203580, a specific p38 inhibitor, both the protein level of PPARγ illustrated by immunofluorescent staining and the oil droplets number, were decreased. Altogether, this indicates that p38 MAPK is activated during adipogenesis of BMSCs, and this is promoted by LMHFV. Our results demonstrating that specific parameters of LMHFV promotes adipogenesis of MSCs and enhances osteogenesis, highlights an unbeneficial side effect of vibration therapy used for preventing obesity and osteoporosis.

Acellular dermal matrix loading with bFGF achieves similar acceleration of bone regeneration to BMP-2 via differential effects on recruitment, proliferation and sustained osteodifferentiation of mesenchymal stem cells

International Nuclear Information System (INIS)

Du, Mi; Zhu, Ting; Duan, Xiaoqi; Ge, Shaohua; Li, Ning; Sun, Qinfeng; Yang, Pishan

2017-01-01

New generation of barrier membranes has been developed, which not only act as barriers but also as delivery devices to release specific growth factors. This study observed biological behaviors of bone morrow mesenchymal stem cells (BMMSCs) pretreated by bFGF or BMP-2 in vitro and evaluated differential bone regeneration process induced by bFGF and BMP-2 loaded acellular dermal matrix (ADM) membrane using critical-size rat calvarial defect model in vivo. The results showed that the proliferation capability of BMMSCs pretreated by bFGF was stronger than that by BMP-2, while there was temporally differential effect of bFGF and BMP-2 pretreatment on MSC osteogenic differentiation potentials. During healing process of rat calvarial defects, 2-fold more CD34 −/CD90 + MSCs in group of bFGF-ADM was observed than in any other treatment group at 2 weeks. However, there were similar amount of new bone formation and expression of osteopotin in newly-formed bone tissue in groups of bFGF- and BMP-2-ADM at 8 weeks, which were more than those in ADM alone and blank control. Taken together, bFGF-ADM guided similar bone regeneration to BMP-2 through more efficient recruitment of MSCs, and moreover, BMMSCs pretreated by bFGF showed stronger proliferation at 1–5 days and osteogenic differentiation potentials at 14 days compared with BMP-2 pretreatment. - Highlights: • An improved barrier membrane used in the field of bone tissue engineering was proposed, which is acellular dermal matrix (ADM) loaded with growth factors. • It is generally agreed that BMP-2 and -7 provide the greatest bone regeneration potentials, however, we found that ADM loading with bFGF could guide similar bone regeneration to BMP-2. • Compared with BMP-2, bFGF could more effectively recruit MSCs and moreover, BMMSCs pretreated by bFGF showed out stronger proliferation at 1-5 days and osteogenic differentiation potentials at 14 days.

Culture conditions for equine bone marrow mesenchymal stem cells and expression of key transcription factors during their differentiation into osteoblasts

Science.gov (United States)

2013-01-01

Background The use of equine bone marrow mesenchymal stem cells (BMSC) is a novel method to improve fracture healing in horses. However, additional research is needed to identify optimal culture conditions and to determine the mechanisms involved in regulating BMSC differentiation into osteoblasts. The objectives of the experiments were to determine: 1) if autologous or commercial serum is better for proliferation and differentiation of equine BMSC into osteoblasts, and 2) the expression of key transcription factors during the differentiation of equine BMSC into osteoblasts. Equine BMSC were isolated from the sterna of 3 horses, treated with purchased fetal bovine serum (FBS) or autologous horse serum (HS), and cell proliferation determined. To induce osteoblast differentiation, cells were incubated with L-ascorbic acid-2-phosphate and glycerol-2-phosphate in the presence or absence of human bone morphogenetic protein2 (BMP2), dexamethasone (DEX), or combination of the two. Alkaline phosphatase (ALP) activity, a marker of osteoblast differentiation, was determined by ELISA. Total RNA was isolated from differentiating BMSC between d 0 to 18 to determine expression of runt-related transcription factor2 (Runx2), osterix (Osx), and T-box3 (Tbx3). Data were analyzed by ANOVA. Results Relative to control, FBS and HS increased cell number (133 ± 5 and 116 ± 5%, respectively; P  0.8). Runt-related transcription factor2 expression increased 3-fold (P equine BMSC into osteoblasts. In addition, expression of Runx2 and osterix increased and expression of Tbx3 is reduced during differentiation. PMID:24169030

Intravoxel incoherent motion diffusion-weighted magnetic resonance imaging of focal vertebral bone marrow lesions: initial experience of the differentiation of nodular hyperplastic hematopoietic bone marrow from malignant lesions

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Park, Sunghoon; Kwack, Kyu-Sung; Kim, Jae Ho [Ajou University School of Medicine, Division of Musculoskeletal Radiology, Department of Radiology, Suwon, Gyeonggi-do (Korea, Republic of); Ajou University Medical Center, Musculoskeletal Imaging Laboratory, Suwon (Korea, Republic of); Chung, Nam-Su [Ajou University School of Medicine, Department of Orthopaedic Surgery, Suwon (Korea, Republic of); Hwang, Jinwoo [Philips Healthcare, Department of Clinical Science, Seoul (Korea, Republic of); Lee, Hyun Young [Ajou University Medical Center, Regional Clinical Trial Center, Suwon (Korea, Republic of); Yonsei University College of Medicine, Department of Biostatistics, Seoul (Korea, Republic of)

2017-05-15

To evaluate the ability of intravoxel incoherent motion (IVIM) diffusion-weighted magnetic resonance imaging (MRI) parameters to differentiate nodular hyperplastic hematopoietic bone marrow (HHBM) from malignant vertebral bone marrow lesions (VBMLs). A total of 33 patients with 58 VBMLs, including 9 nodular HHBM lesions, 39 bone metastases, and 10 myelomas, were retrospectively assessed. All diagnoses were confirmed either pathologically or via image assessment. IVIM diffusion-weighted MRI with 11 b values (from 0 to 800 s/mm{sup 2}) were obtained using a 3.0-T MR imager. The apparent diffusion coefficient (ADC), pure diffusion coefficient (D), perfusion fraction (f), and pseudodiffusion coefficient (D*) were calculated. ADC and IVIM parameters were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic performances of ADC, D, f, and D* in terms of VBML characterization. The diagnostic performance of morphological MR sequences was also assessed for comparison. The ADC and D values of nodular HHBM were significantly lower than those of malignant VBML (both p values < 0.001), whereas the f value was significantly higher (p < 0.001). However, there were no significant differences in D* between the two groups (p = 0.688). On ROC analysis, the area under the curve (AUC) for D was 1.000, which was significantly larger than that for ADC (AUC = 0.902). Intravoxel incoherent motion diffusion-weighted MRI can be used to differentiate between nodular HHBM and malignant VBML. The D value was significantly lower for nodular HHBM, and afforded a better diagnostic performance than the ADC, f, and D* values in terms of such differentiation. (orig.)

Effect of the gamma radiation and common antioxidants on some aspects of osteoblast differentiation during the formation of bone tissue in an in-vivo model

International Nuclear Information System (INIS)

Quinones O, M. G.

2015-01-01

Gamma radiation is the emission of energy through short electromagnetic waves to a higher level of frequency with respect to ultraviolet light. This type of energy in the medical application is used as a tool to kill cancer cells in humans, however, adverse damages to its exposure can produce secondary effects in the short and long term depending on the damage in cells and tissues nearby to the irradiation zone, the human body will present various injuries and conditions. In bone tissue, secondary effects that have been observed, is an alteration of the architecture and integrity of bone extracellular matrix of cortical and trabecular tissue, which causes loss of bone density. However, the reason that the bone tissue is affected is not clear, but is believed to be related to the formation of free radicals, which generate oxidative damage in biomolecules of the cells, damaging the tissue structure, organs and systems of the human body. The studies to identify the main reasons that will affect bone tissue as a result of radiotherapy have been carried out by models In-vitro and some In-vivo. In most studies in-vitro with cells with osteoblast phenotype, the results suggest alterations in proliferation and differentiation of these cells. However, the etiology and the role of these changes in disorders and bone injuries as adverse secondary effects of the radiotherapy are very poorly understood to date. In the present study an In-vivo model was used, that are ectopic bone plates which are developed by endochondral ossification, after having implanted demineralized bone particles at 16 days of development, at which time they are constituted by bone tissue. Ectopic bone plates were used with the aim of knowing as gamma radiation indirectly modifies to cellular level the osteoblast differentiation, cells that are involved in the formation and mineralization of bone extracellular matrix. One of the well known effects of gamma radiation is the generation of free radicals

Bone metastases of differentiated thyroid cancer: the importance of early diagnosis and 131I therapy on prognosis

International Nuclear Information System (INIS)

Zanotti-Fregonara, P.; Rubello, D.; Hindie, E.

2008-01-01

Complete text of publication follows: Distant metastases are found at diagnosis or during follow-up in 10%-15% of patients with differentiated thyroid cancer. Bone is the second most commonly involved site. Patients with bone metastases, whether isolated or associated with lung metastases, have a markedly poor prognosis. Ten-year survival rates range from 13% to 21%. Given such poor prognosis, the use of 131 I therapy has been questioned. However, it might well be that poor prognosis of bone metastases can be overcome if 131 I therapy is delivered at an early stage, when tumor burden is small, as previously demonstrated for pulmonary metastases. A review of a large series of patients showed that only rarely were bone metastases diagnosed at an early stage. Among 109 patients with bone metastases reported by Bernier et al., only 4 had both radioiodine uptake and a negative standard radiography examination. Similarly, Durante et al. reported that only 8 of 115 patients had negative radiography findings at presentation. Prognosis may improve if bone metastases are detected earlier. In a recent study, bone metastases were first detected by 131 I scanning in 8 of 16 patients, when complementary radiologic studies were negative. Six of these patients showed an excellent response to 131 I therapy. Today, the nuclear medicine community is well armed for this challenge toward earlier diagnosis. Postsurgery thyroid remnant ablation is more widely used. The 131 I whole body scan associated with thyroid remnant ablation after thyroidectomy has a major role in early diagnosis of functioning distant metastases at a time when complementary imaging techniques (CT, MRI, bone scanning) are often still showing negative findings. Early diagnosis of specific 131 I-avid bone foci will be improved with the advent and generalization of SPECT/CT. When early diagnosis is achieved, repeated 131 I therapy can be effective by targeting not only visible metastases but also those still too small

A balance of FGF and BMP signals regulates cell cycle exit and Equarin expression in lens cells

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Jarrin, Miguel; Pandit, Tanushree; Gunhaga, Lena

2012-01-01

In embryonic and adult lenses, a balance of cell proliferation, cell cycle exit, and differentiation is necessary to maintain physical function. The molecular mechanisms regulating the transition of proliferating lens epithelial cells to differentiated primary lens fiber cells are poorly characterized. To investigate this question, we used gain- and loss-of-function analyses to modulate fibroblast growth factor (FGF) and/or bone morphogenetic protein (BMP) signals in chick lens/retina explants. Here we show that FGF activity plays a key role for proliferation independent of BMP signals. Moreover, a balance of FGF and BMP signals regulates cell cycle exit and the expression of Ccdc80 (also called Equarin), which is expressed at sites where differentiation of lens fiber cells occurs. BMP activity promotes cell cycle exit and induces Equarin expression in an FGF-dependent manner. In contrast, FGF activity is required but not sufficient to induce cell cycle exit or Equarin expression. Furthermore, our results show that in the absence of BMP activity, lens cells have increased cell cycle length or are arrested in the cell cycle, which leads to decreased cell cycle exit. Taken together, these findings suggest that proliferation, cell cycle exit, and early differentiation of primary lens fiber cells are regulated by counterbalancing BMP and FGF signals. PMID:22718906

Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation.

NARCIS (Netherlands)

Glass, D.A.; Bialek, P.; Ahn, J.D.; Starbuck, M.; Patel, M.S.; Clevers, J.C.; Taketo, M.M.; Long, F.; McMahon, A.P.; Lang, R.A.; Karsenty, G.

2005-01-01

Inactivation of beta-catenin in mesenchymal progenitors prevents osteoblast differentiation; inactivation of Lrp5, a gene encoding a likely Wnt coreceptor, results in low bone mass (osteopenia) by decreasing bone formation. These observations indicate that Wnt signaling controls osteoblast

Bone marrow mesenchymal stem cells stimulate proliferation and neuronal differentiation of retinal progenitor cells.

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Jing Xia

Full Text Available During retina development, retinal progenitor cell (RPC proliferation and differentiation are regulated by complex inter- and intracellular interactions. Bone marrow mesenchymal stem cells (BMSCs are reported to express a variety of cytokines and neurotrophic factors, which have powerful trophic and protective functions for neural tissue-derived cells. Here, we show that the expanded RPC cultures treated with BMSC-derived conditioned medium (CM which was substantially enriched for bFGF and CNTF, expressed clearly increased levels of nuclear receptor TLX, an essential regulator of neural stem cell (NSC self-renewal, as well as betacellulin (BTC, an EGF-like protein described as supporting NSC expansion. The BMSC CM- or bFGF-treated RPCs also displayed an obviously enhanced proliferation capability, while BMSC CM-derived bFGF knocked down by anti-bFGF, the effect of BMSC CM on enhancing RPC proliferation was partly reversed. Under differentiation conditions, treatment with BMSC CM or CNTF markedly favoured RPC differentiation towards retinal neurons, including Brn3a-positive retinal ganglion cells (RGCs and rhodopsin-positive photoreceptors, and clearly diminished retinal glial cell differentiation. These findings demonstrate that BMSCs supported RPC proliferation and neuronal differentiation which may be partly mediated by BMSC CM-derived bFGF and CNTF, reveal potential limitations of RPC culture systems, and suggest a means for optimizing RPC cell fate determination in vitro.

PS1/γ-Secretase-Mediated Cadherin Cleavage Induces β-Catenin Nuclear Translocation and Osteogenic Differentiation of Human Bone Marrow Stromal Cells

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Danielle C. Bonfim

2016-01-01

Full Text Available Bone marrow stromal cells (BMSCs are considered a promising tool for bone bioengineering. However, the mechanisms controlling osteoblastic commitment are still unclear. Osteogenic differentiation of BMSCs requires the activation of β-catenin signaling, classically known to be regulated by the canonical Wnt pathway. However, BMSCs treatment with canonical Wnts in vitro does not always result in osteogenic differentiation and evidence indicates that a more complex signaling pathway, involving cadherins, would be required to induce β-catenin signaling in these cells. Here we showed that Wnt3a alone did not induce TCF activation in BMSCs, maintaining the cells at a proliferative state. On the other hand, we verified that, upon BMSCs osteoinduction with dexamethasone, cadherins were cleaved by the PS1/γ-secretase complex at the plasma membrane, and this event was associated with an enhanced β-catenin translocation to the nucleus and signaling. When PS1/γ-secretase activity was inhibited, the osteogenic process was impaired. Altogether, we provide evidence that PS1/γ-secretase-mediated cadherin cleavage has as an important role in controlling β-catenin signaling during the onset of BMSCs osteogenic differentiation, as part of a complex signaling pathway responsible for cell fate decision. A comprehensive map of these pathways might contribute to the development of strategies to improve bone repair.

Fibroblast growth factor 2 inhibits up-regulation of bone morphogenic proteins and their receptors during osteoblastic differentiation of human mesenchymal stem cells

Energy Technology Data Exchange (ETDEWEB)

Biver, Emmanuel, E-mail: ebiver@yahoo.fr [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Soubrier, Anne-Sophie [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Thouverey, Cyril [Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Cortet, Bernard [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Department of Rheumatology, Lille University Hospital, Roger Salengro Hospital, 59037 Lille cedex (France); Broux, Odile [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France); Caverzasio, Joseph [Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, CH-1211 Geneva 14 (Switzerland); Hardouin, Pierre [Physiopathology of Inflammatory Bone Diseases, EA 4490, University Lille North of France, Quai Masset, Bassin Napoleon, BP120, 62327 Boulogne sur Mer (France)

2012-11-02

Highlights: Black-Right-Pointing-Pointer FGF modulates BMPs pathway in HMSCs by down-regulating BMP/BMPR expression. Black-Right-Pointing-Pointer This effect is mediated by ERK and JNK MAPKs pathways. Black-Right-Pointing-Pointer Crosstalk between FGF and BMPs must be taken into account in skeletal bioengineering. Black-Right-Pointing-Pointer It must also be considered in the use of recombinant BMPs in orthopedic and spine surgeries. -- Abstract: Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of human mesenchymal stem cells (HMSCs) and BMPs in therapeutic perspectives and bone tissue engineering. BMPs are potent inducers of osteoblastic differentiation. They exert their actions via BMP receptors (BMPR), including BMPR1A, BMPR1B and BMPR2. Fibroblast growth factor 2 (FGF2) is expressed by cells of the osteoblastic lineage, increases their proliferation and is secreted during the healing process of fractures or in surgery bone sites. We hypothesized that FGF2 might influence HMSC osteoblastic differentiation by modulating expressions of BMPs and their receptors. BMP2, BMP4, BMPR1A and mainly BMPR1B expressions were up-regulated during this differentiation. FGF2 inhibited HMSCs osteoblastic differentiation and the up-regulation of BMPs and BMPR. This effect was prevented by inhibiting the ERK or JNK mitogen-activated protein kinases which are known to be activated by FGF2. These data provide a mechanism explaining the inhibitory effect of FGF2 on osteoblastic differentiation of HMSCs. These crosstalks between growth and osteogenic factors should be considered in the use of recombinant BMPs in therapeutic purpose of fracture repair or skeletal bioengineering.

Identification of genes differentially regulated in rat alveolar bone wound healing by subtractive hybridization.

Science.gov (United States)

Ohira, T; Myokai, F; Shiomi, N; Yamashiro, K; Yamamoto, T; Murayama, Y; Arai, H; Nishimura, F; Takashiba, S

2004-07-01

Periodontal healing requires the participation of regulatory molecules, cells, and scaffold or matrix. Here, we hypothesized that a certain set of genes is expressed in alveolar bone wound healing. Reciprocal subtraction gave 400 clones from the injured alveolar bone of Wistar rats. Identification of 34 genes and analysis of their expression in injured tissue revealed several clusters of unique gene regulation patterns, including the up-regulation at 1 wk of cytochrome c oxidase regulating electron transfer and energy metabolism, presumably occurring at the site of inflammation; up-regulation at 2.5 wks of pro-alpha-2 type I collagen involving the formation of a connective tissue structure; and up-regulation at 1 and 2 wks and down-regulation at 2.5 and 4 wks of ubiquitin carboxyl-terminal hydrolase l3 involving cell cycle, DNA repair, and stress response. The differential expression of genes may be associated with the processes of inflammation, wound contraction, and formation of a connective tissue structure.

Differentiating levels of surgical experience on a virtual reality temporal bone simulator.

Science.gov (United States)

Zhao, Yi C; Kennedy, Gregor; Hall, Richard; O'Leary, Stephen

2010-11-01

Virtual reality simulation is increasingly being incorporated into surgical training and may have a role in temporal bone surgical education. Here we test whether metrics generated by a virtual reality surgical simulation can differentiate between three levels of experience, namely novices, otolaryngology residents, and experienced qualified surgeons. Cohort study. Royal Victorian Eye and Ear Hospital. Twenty-seven participants were recruited. There were 12 experts, six residents, and nine novices. After orientation, participants were asked to perform a modified radical mastoidectomy on the simulator. Comparisons of time taken, injury to structures, and forces exerted were made between the groups to determine which specific metrics would discriminate experience levels. Experts completed the simulated task in significantly shorter time than the other two groups (experts 22 minutes, residents 36 minutes, and novices 46 minutes; P = 0.001). Novices exerted significantly higher average forces when dissecting close to vital structures compared with experts (0.24 Newton [N] vs 0.13 N, P = 0.002). Novices were also more likely to injure structures such as dura compared to experts (23 injuries vs 3 injuries, P = 0.001). Compared with residents, the experts modulated their force between initial cortex dissection and dissection close to vital structures. Using the combination of these metrics, we were able to correctly classify the participants' level of experience 90 percent of the time. This preliminary study shows that measurements of performance obtained from within a virtual reality simulator can differentiate between levels of users' experience. These results suggest that simulator training may have a role in temporal bone training beyond foundational training. Copyright © 2010 American Academy of Otolaryngology–Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.

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 Central Nervous System and Bone Metabolism: An Evolving Story.

Science.gov (United States)

Dimitri, Paul; Rosen, Cliff

2017-05-01

Our understanding of the control of skeletal metabolism has undergone a dynamic shift in the last two decades, primarily driven by our understanding of energy metabolism. Evidence demonstrating that leptin not only influences bone cells directly, but that it also plays a pivotal role in controlling bone mass centrally, opened up an investigative process that has changed the way in which skeletal metabolism is now perceived. Other central regulators of bone metabolism have since been identified including neuropeptide Y (NPY), serotonin, endocannabinoids, cocaine- and amphetamine-regulated transcript (CART), adiponectin, melatonin and neuromedin U, controlling osteoblast and osteoclast differentiation, proliferation and function. The sympathetic nervous system was originally identified as the predominant efferent pathway mediating central signalling to control skeleton metabolism, in part regulated through circadian genes. More recent evidence points to a role of the parasympathetic nervous system in the control of skeletal metabolism either through muscarinic influence of sympathetic nerves in the brain or directly via nicotinic receptors on osteoclasts, thus providing evidence for broader autonomic skeletal regulation. Sensory innervation of bone has also received focus again widening our understanding of the complex neuronal regulation of bone mass. Whilst scientific advance in this field of bone metabolism has been rapid, progress is still required to understand how these model systems work in relation to the multiple confounders influencing skeletal metabolism, and the relative balance in these neuronal systems required for skeletal growth and development in childhood and maintaining skeletal integrity in adulthood.

Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in Vitro

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Mélanie Spilmont

2015-11-01

Full Text Available The nutritional benefits of pomegranate have attracted great scientific interest. The pomegranate, including the pomegranate peel, has been used worldwide for many years as a fruit with medicinal activity, mostly antioxidant properties. Among chronic diseases, osteoporosis, which is associated with bone remodelling impairment leading to progressive bone loss, could eventually benefit from antioxidant compounds because of the involvement of oxidative stress in the pathogenesis of osteopenia. In this study, with in vivo and ex vivo experiments, we investigated whether the consumption of pomegranate peel extract (PGPE could limit the process of osteopenia. We demonstrated that in ovariectomized (OVX C57BL/6J mice, PGPE consumption was able to significantly prevent the decrease in bone mineral density (−31.9%; p < 0.001 vs. OVX mice and bone microarchitecture impairment. Moreover, the exposure of RAW264.7 cells to serum harvested from mice that had been given a PGPE-enriched diet elicited reduced osteoclast differentiation and bone resorption, as shown by the inhibition of the major osteoclast markers. In addition, PGPE appeared to substantially stimulate osteoblastic MC3T3-E1 alkaline phosphatase (ALP activity at day 7, mineralization at day 21 and the transcription level of osteogenic markers. PGPE may be effective in preventing the bone loss associated with ovariectomy in mice, and offers a promising alternative for the nutritional management of this disease.

Pomegranate Peel Extract Prevents Bone Loss in a Preclinical Model of Osteoporosis and Stimulates Osteoblastic Differentiation in Vitro.

Science.gov (United States)

Spilmont, Mélanie; Léotoing, Laurent; Davicco, Marie-Jeanne; Lebecque, Patrice; Miot-Noirault, Elisabeth; Pilet, Paul; Rios, Laurent; Wittrant, Yohann; Coxam, Véronique

2015-11-11

The nutritional benefits of pomegranate have attracted great scientific interest. The pomegranate, including the pomegranate peel, has been used worldwide for many years as a fruit with medicinal activity, mostly antioxidant properties. Among chronic diseases, osteoporosis, which is associated with bone remodelling impairment leading to progressive bone loss, could eventually benefit from antioxidant compounds because of the involvement of oxidative stress in the pathogenesis of osteopenia. In this study, with in vivo and ex vivo experiments, we investigated whether the consumption of pomegranate peel extract (PGPE) could limit the process of osteopenia. We demonstrated that in ovariectomized (OVX) C57BL/6J mice, PGPE consumption was able to significantly prevent the decrease in bone mineral density (-31.9%; p < 0.001 vs. OVX mice) and bone microarchitecture impairment. Moreover, the exposure of RAW264.7 cells to serum harvested from mice that had been given a PGPE-enriched diet elicited reduced osteoclast differentiation and bone resorption, as shown by the inhibition of the major osteoclast markers. In addition, PGPE appeared to substantially stimulate osteoblastic MC3T3-E1 alkaline phosphatase (ALP) activity at day 7, mineralization at day 21 and the transcription level of osteogenic markers. PGPE may be effective in preventing the bone loss associated with ovariectomy in mice, and offers a promising alternative for the nutritional management of this disease.

Antiseptic solutions modulate the paracrine-like activity of bone chips: differential impact of chlorhexidine and sodium hypochlorite.

Science.gov (United States)

Sawada, Kosaku; Caballé-Serrano, Jordi; Bosshardt, Dieter D; Schaller, Benoit; Miron, Richard J; Buser, Daniel; Gruber, Reinhard

2015-09-01

Chemical decontamination increases the availability of bone grafts; however, it remains unclear whether antiseptic processing changes the biological activity of bone. Bone chips were incubated with four different antiseptic solutions including (1) povidone-iodine (0.5%), (2) chlorhexidine diguluconate (0.2%), (3) hydrogen peroxide (1%) and (4) sodium hypochlorite (0.25%). After 10 min. of incubation, changes in the capacity of the bone-conditioned medium (BCM) to modulate gene expression of gingival fibroblasts was investigated. Conditioned medium obtained from freshly prepared bone chips increased the expression of TGF-β target genes interleukin 11 (IL11), proteoglycan4 (PRG4), NADPH oxidase 4 (NOX4), and decreased the expression of adrenomedullin (ADM), and pentraxin 3 (PTX3) in gingival fibroblasts. Incubation of bone chips with 0.2% chlorhexidine, followed by vigorously washing resulted in a BCM with even higher expression of IL11, PRG4 and NOX4. These findings were also detected with a decrease in cell viability and an activation of apoptosis signalling. Chlorhexidine alone, at low concentrations, increased IL11, PRG4 and NOX4 expression, independent of the TGF-β receptor I kinase activity. In contrast, 0.25% sodium hypochlorite almost entirely abolished the activity of BCM, whereas the other two antiseptic solutions, 1% hydrogen peroxide and 0.5% povidone-iodine, had relatively no impact respectively. These in vitro findings demonstrate that incubation of bone chips with chlorhexidine differentially affects the activity of the respective BCM compared to the other antiseptic solutions. The data further suggest that the main effects are caused by chlorhexidine remaining in the BCM after repeated washing of the bone chips. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Interleukin 17 enhances bone morphogenetic protein-2-induced ectopic bone formation

NARCIS (Netherlands)

Croes, M.; Kruyt, M. C.; Groen, W. M.; Van Dorenmalen, K. M.A.; Dhert, W. J.A.; Öner, F. C.; Alblas, J.

2018-01-01

Interleukin 17 (IL-17) stimulates the osteogenic differentiation of progenitor cells in vitro through a synergy with bone morphogenetic protein (BMP)-2. This study investigates whether the diverse responses mediated by IL-17 in vivo also lead to enhanced BMP-2-induced bone formation. Since IL-17 is

Bone and bone marrow scintigraphy in a patient with sickle cell-thalassemia and recurrent pain attacks

International Nuclear Information System (INIS)

Mikosch, P.; Gallowitsch, H.-J.; Lind, P.; Jauk, B.; Kaulfersch, W.

2003-01-01

The case of an eight years old African boy who suffers from sickle cell-thalassemia is presented. In the course of the disease frequent pain attacks occurred within the abdomen and extremities, recently also within the trunk. Local pain, at some occasions in combination with local swelling and always positive laboratory parameters for inflammation, hindered a solely clinical differentiation between bone infarcts and osteomyelitis. Bone scintigraphy, eventually in combination with bone marrow scintigraphy, can assist the clinician in the differentiation of aseptic bone infarcts versus secondary osteomyelitis. Based on the presented case scintigraphic results for bone infarcts, osteomyelitis and special scintigraphic pattern seen in sickle cell disease are presented. Furthermore, problems regarding the interpretation of the scintigraphies in relation to the delayed time after the beginning of pain attacks are discussed. (author)

Pulsed Electromagnetic Field Regulates MicroRNA 21 Expression to Activate TGF-β Signaling in Human Bone Marrow Stromal Cells to Enhance Osteoblast Differentiation

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Nagarajan Selvamurugan

2017-01-01

Full Text Available Pulsed electromagnetic fields (PEMFs have been documented to promote bone fracture healing in nonunions and increase lumbar spinal fusion rates. However, the molecular mechanisms by which PEMF stimulates differentiation of human bone marrow stromal cells (hBMSCs into osteoblasts are not well understood. In this study the PEMF effects on hBMSCs were studied by microarray analysis. PEMF stimulation of hBMSCs’ cell numbers mainly affected genes of cell cycle regulation, cell structure, and growth receptors or kinase pathways. In the differentiation and mineralization stages, PEMF regulated preosteoblast gene expression and notably, the transforming growth factor-beta (TGF-β signaling pathway and microRNA 21 (miR21 were most highly regulated. PEMF stimulated activation of Smad2 and miR21-5p expression in differentiated osteoblasts, and TGF-β signaling was essential for PEMF stimulation of alkaline phosphatase mRNA expression. Smad7, an antagonist of the TGF-β signaling pathway, was found to be miR21-5p’s putative target gene and PEMF caused a decrease in Smad7 expression. Expression of Runx2 was increased by PEMF treatment and the miR21-5p inhibitor prevented the PEMF stimulation of Runx2 expression in differentiating cells. Thus, PEMF could mediate its effects on bone metabolism by activation of the TGF-β signaling pathway and stimulation of expression of miR21-5p in hBMSCs.

The effect of extracellular calcium and inorganic phosphate on the growth and osteogenic differentiation of mesenchymal stem cells in vitro: implication for bone tissue engineering

Energy Technology Data Exchange (ETDEWEB)

Liu Yukan; Lu Qiaozhi; Ji Huijiao; Zhao Xiaoli; Zhang Ming [College of Life Science, ZheJiang University, Hangzhou 310058 (China); Pei Rui [XiJing Hospital, Fourth Military Medical University, Xi An 710032 (China); Zhou Guoshun [Huzhou Central Hospital, Huzhou, Zhejiang Province 313000 (China); Tang, Rui Kang, E-mail: Lyk_cn@yahoo.com.c [Department of Chemistry, College of Science, ZheJiang University, Hangzhou 310027 (China)

2009-04-15

The aim of this study is to demonstrate the effect of extracellular calcium ion (Ca{sup 2+}) and inorganic phosphate (Pi) concentrations on the growth and differentiation of bone-marrow-derived mesenchymal stem cells (MSCs), which is essential to understand the interaction between calcium phosphate ceramic (CPC) scaffolds and seeded cells during the construction of tissue-engineered bones. MSCs were separated from rabbits and cultured in media with different concentrations of Ca{sup 2+} and Pi supplements. Their proliferation, apoptosis, mineralization and osteogenic differentiation were determined by the MTT assay, TUNEL assay, Vonkossa stain and RT-PCR examination. A two-way ANOVA calculation with comparisons of estimated marginal means by LSD was used for statistical analysis. Results showed that the optimal extracellular Ca{sup 2+} and Pi concentrations for the cells to proliferate and differentiate were 1.8 mM and 0.09 mM, respectively, which are the concentrations supplied in many commonly used culture media such as DMEM and alpha-MEM. Cell proliferation and differentiation decreased significantly with greater or lower concentrations of the Pi supplement. Greater Pi concentrations also led to significant cell apoptosis. Greater Ca{sup 2+} concentrations did not change cell proliferation but significantly inhibited cell differentiation. In addition, greater Ca{sup 2+} concentrations could significantly enhance cell mineralization. In conclusion, extracellular Ca{sup 2+} and Pi significantly influence the growth and osteogenic differentiation of MSCs. It is important to take the cellular effect of Ca{sup 2+} and Pi into consideration when designing or constructing scaffolds for bone tissue engineering with CPC.

Compensatory Cellular Reactions to Nonsteroidal Anti-Inflammatory Drugs on Osteogenic Differentiation in Canine Bone Marrow-Derived Mesenchymal Stem Cells

Science.gov (United States)

OH, Namgil; KIM, Sangho; HOSOYA, Kenji; OKUMURA, Masahiro

2014-01-01

ABSTRACT The suppressive effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the bone healing process have remained controversial, since no clinical data have clearly shown the relationship between NSAIDs and bone healing. The aim of this study was to assess the compensatory response of canine bone marrow-derived mesenchymal stem cells (BMSCs) to several classes of NSAIDs, including carprofen, meloxicam, indomethacin and robenacoxib, on osteogenic differentiation. Each of the NSAIDs (10 µM) was administered during 20 days of the osteogenic process with human recombinant IL-1β (1 ng/ml) as an inflammatory stimulator. Gene expression of osteoblast differentiation markers (alkaline phosphatase and osteocalcin), receptors of PGE2 (EP2 and EP4) and enzymes for prostaglandin (PG) E2 synthesis (COX-1, COX-2, cPGES and mPGES-1) was measured by using quantitative reverse transcription-polymerase chain reaction. Protein production levels of alkaline phosphatase, osteocalcin and PGE2 were quantified using an alkaline phosphatase activity assay, osteocalcin immunoassay and PGE2 immunoassay, respectively. Histologic analysis was performed using alkaline phosphatase staining, von Kossa staining and alizarin red staining. Alkaline phosphatase and calcium deposition were suppressed by all NSAIDs. However, osteocalcin production showed no significant suppression by NSAIDs. Gene expression levels of PGE2-related receptors and enzymes were upregulated during continuous treatment with NSAIDs, while certain channels for PGE2 synthesis were utilized differently depending on the kind of NSAIDs. These data suggest that canine BMSCs have a compensatory mechanism to restore PGE2 synthesis, which would be an intrinsic regulator to maintain differentiation of osteoblasts under NSAID treatment. PMID:24419976

Electrospun Gelatin/β-TCP Composite Nanofibers Enhance Osteogenic Differentiation of BMSCs and In Vivo Bone Formation by Activating Ca2+-Sensing Receptor Signaling

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Xuehui Zhang

2015-01-01

Full Text Available Calcium phosphate- (CaP- based composite scaffolds have been used extensively for the bone regeneration in bone tissue engineering. Previously, we developed a biomimetic composite nanofibrous membrane of gelatin/β-tricalcium phosphate (TCP and confirmed their biological activity in vitro and bone regeneration in vivo. However, how these composite nanofibers promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs is unknown. Here, gelatin/β-TCP composite nanofibers were fabricated by incorporating 20 wt% β-TCP nanoparticles into electrospun gelatin nanofibers. Electron microscopy showed that the composite β-TCP nanofibers had a nonwoven structure with a porous network and a rough surface. Spectral analyses confirmed the presence and chemical stability of the β-TCP and gelatin components. Compared with pure gelatin nanofibers, gelatin/β-TCP composite nanofibers caused increased cell attachment, proliferation, alkaline phosphatase activity, and osteogenic gene expression in rat BMSCs. Interestingly, the expression level of the calcium-sensing receptor (CaSR was significantly higher on the composite nanofibrous scaffolds than on pure gelatin. For rat calvarial critical sized defects, more extensive osteogenesis and neovascularization occurred in the composite scaffolds group compared with the gelatin group. Thus, gelatin/β-TCP composite scaffolds promote osteogenic differentiation of BMSCs in vitro and bone regeneration in vivo by activating Ca2+-sensing receptor signaling.

Multifocal bone and bone marrow lesions in children - MRI findings

Energy Technology Data Exchange (ETDEWEB)

Raissaki, Maria; Demetriou, Stelios; Spanakis, Konstantinos; Skiadas, Christos; Karantanas, Apostolos H. [University of Crete, Faculty of Medicine, Department of Radiology, University Hospital of Heraklion, Heraklion, Crete (Greece); Katzilakis, Nikolaos; Stiakaki, Eftichia [University of Crete, Faculty of Medicine, Department of Pediatric Hematology-Oncology, University Hospital of Heraklion, Heraklion, Crete (Greece); Velivassakis, Emmanouil G. [University Hospital of Heraklion, Orthopedic Clinic, Heraklion, Crete (Greece)

2017-03-15

Polyostotic bone and bone marrow lesions in children may be due to various disorders. Radiographically, lytic lesions may become apparent after loss of more than 50% of the bone mineral content. Scintigraphy requires osteoblastic activity and is not specific. MRI may significantly contribute to the correct diagnosis and management. Accurate interpretation of MRI examinations requires understanding of the normal conversion pattern of bone marrow in childhood and of the appearances of red marrow rests and hyperplasia. Differential diagnosis is wide: Malignancies include metastases, multifocal primary sarcomas and hematological diseases. Benign entities include benign tumors and tumor-like lesions, histiocytosis, infectious and inflammatory diseases, multiple stress fractures/reactions and bone infarcts/ischemia. (orig.)

Alfacalcidol improves muscle power, muscle function and balance in elderly patients with reduced bone mass.

Science.gov (United States)

Schacht, E; Ringe, Johann D

2012-01-01

We investigated the effect of daily therapy with 1 mcg alfacalcidol (Doss(®)-TEVA/AWD-pharma) on muscle power, muscle function, balance performance and fear of falls in an open, multi-centered, uncontrolled, prospective study on a cohort of patients with reduced bone mass. Among the 2,097 participants, 87.1% were post-menopausal women and 12.9% were men. Mean age was 74.8 years and mean body mass index (BMI) 26.3 kg/m². A total of 75.3% of the study population had osteoporosis, 81% a diagnosis of "increased risk of falls" and 70.1% had a creatinine clearance (CrCl) of power tests at onset and after 3 and 6 months: the timed up and go test (TUG) and the chair rising test (CRT). At baseline and after 6 months, participants performed the tandem gait test (TGT) and filled out a questionnaire evaluating fear of falling. Successful performance in the muscle tests is associated with a significantly lower risk of falls and non-vertebral fractures in elderly patients (successful test performance: TUG ≤ 10 s (sec), CRT ≤ 10 s, TGT ≥ 8 steps). A significant improvement in the performance of the two muscle tests was proved already after 3 months of treatment with alfacalcidol and further increased by the end of the therapeutic intervention. There were significant increases in the number of participants able to successfully perform the tests: 24.6% at baseline and 46.3% at the end of trial for the TUG (P balance test (TGT) increased from 36.0% at onset to 58.6% at the end of the trial (P power, muscle function and balance and reduces fear of falls. The significant improvement in the three muscle and balance tests and fear of falls may have a preventative effect on falls and fractures. We suggest that the quantitative risk tests used in this study could be reliable surrogate parameters for the risk of falls and fractures in elderly patients.

Bone metastases of differentiated thyroid cancer: the importance of early diagnosis and {sup 131}I therapy on prognosis

Energy Technology Data Exchange (ETDEWEB)

Zanotti-Fregonara, P. [CEA, DSV, I2BM, SHFJ, UMNRC, Orsay (France); Rubello, D. [Santa Maria Misericordia Hosp, Rovigo (Italy); Hindie, E. [Hop StLouis, Paris (France)

2008-07-01

Complete text of publication follows: Distant metastases are found at diagnosis or during follow-up in 10%-15% of patients with differentiated thyroid cancer. Bone is the second most commonly involved site. Patients with bone metastases, whether isolated or associated with lung metastases, have a markedly poor prognosis. Ten-year survival rates range from 13% to 21%. Given such poor prognosis, the use of {sup 131}I therapy has been questioned. However, it might well be that poor prognosis of bone metastases can be overcome if {sup 131}I therapy is delivered at an early stage, when tumor burden is small, as previously demonstrated for pulmonary metastases. A review of a large series of patients showed that only rarely were bone metastases diagnosed at an early stage. Among 109 patients with bone metastases reported by Bernier et al., only 4 had both radioiodine uptake and a negative standard radiography examination. Similarly, Durante et al. reported that only 8 of 115 patients had negative radiography findings at presentation. Prognosis may improve if bone metastases are detected earlier. In a recent study, bone metastases were first detected by {sup 131}I scanning in 8 of 16 patients, when complementary radiologic studies were negative. Six of these patients showed an excellent response to {sup 131}I therapy. Today, the nuclear medicine community is well armed for this challenge toward earlier diagnosis. Postsurgery thyroid remnant ablation is more widely used. The {sup 131}I whole body scan associated with thyroid remnant ablation after thyroidectomy has a major role in early diagnosis of functioning distant metastases at a time when complementary imaging techniques (CT, MRI, bone scanning) are often still showing negative findings. Early diagnosis of specific {sup 131}I-avid bone foci will be improved with the advent and generalization of SPECT/CT. When early diagnosis is achieved, repeated {sup 131}I therapy can be effective by targeting not only visible

Bone formation in cranial, mandibular, tibial and iliac bone grafts in rats

DEFF Research Database (Denmark)

Solheim, E; Pinholt, E M; Talsnes, O

1995-01-01

Several studies have suggested that grafts from membranous derived bone (e.g., calvarial grafts) retain their volume better than those from endochondral derived bone (e.g., iliac bone grafts). Increased osteogenesis in grafts of the former type has been offered as the explanation. However, simple...... volume measurements of the recovered grafts do not differentiate between viable and dead bone. We studied fresh syngeneic full-thickness bone grafts from calvaria, mandibula, tibia diaphysis, and iliac bone implanted in the back muscles of young Lewis rats. Bone formation in grafts recovered 3 weeks...... that the anatomical area of harvest is important regarding new bone formation in syngeneic bone grafts. However, the results do not support the contention that better maintenance of volume of calvarial grafts compared with iliac bone grafts is due to enhanced osteogenesis in the former....

Forced expression of Sox2 or Nanog in human bone marrow derived mesenchymal stem cells maintains their expansion and differentiation capabilities

International Nuclear Information System (INIS)

Go, Masahiro J.; Takenaka, Chiemi; Ohgushi, Hajime

2008-01-01

Mesenchymal stem cells (MSCs) derived from human bone marrow have capability to differentiate into cells of mesenchymal lineage. The cells have already been applied in various clinical situations because of their expansion and differentiation capabilities. The cells lose their capabilities after several passages, however. With the aim of conferring higher capability on human bone marrow MSCs, we introduced the Sox2 or Nanog gene into the cells. Sox2 and Nanog are not only essential for pluripotency and self-renewal of embryonic stem cells, but also expressed in somatic stem cells that have superior expansion and differentiation potentials. We found that Sox2-expressing MSCs showed consistent proliferation and osteogenic capability in culture media containing basic fibroblast growth factor (bFGF) compared to control cells. Significantly, in the presence of bFGF in culture media, most of the Sox2-expressing cells were small, whereas the control cells were elongated in shape. We also found that Nanog-expressing cells even in the absence of bFGF had much higher capabilities for expansion and osteogenesis than control cells. These results demonstrate not only an effective way to maintain proliferation and differentiation potentials of MSCs but also an important implication about the function of bFGF for self-renewal of stem cells including MSCs

Conditioned media from differentiating craniofacial bone marrow stromal cells influence mineralization and proliferation in periodontal ligament stem cells.

Science.gov (United States)

Jin, Zhenyu; Feng, Yuan; Liu, Hongwei

2016-10-01

Previous reports have mainly focused on the behavioral responses of human periodontal ligament stem cells (hPDLSCs) in interaction with tibia bone marrow stromal cells (BMSCs). However, there is little study on the biologic features of hPDLSCs under the induction of maxilla BMSCs (M-BMSCs) at different phases of osteogenic differentiation. We hypothesized that M-BMSCs undergoing osteogenic differentiation acted on the proliferation, differentiation, and bone-forming capacity of hPDLSCs. In this paper, primary hPDLSCs and human M-BMSCs (hM-BMSCs) were expanded in vitro. After screening of surface markers for characterization, hPDLSCs were cocultured with different phases of differentiating hM-BMSCs. Cell proliferation and alkaline phosphatase activity were examined, and mineralization-associated markers such as osteocalcin and runt-related transcription factor 2 of hPDLSCs in coculture with uninduced/osteoinduced hM-BMSCs were evaluated. hPDLSCs in hM-BMSCs-conditioned medium (hM-BMSCs-CM) group showed a reduction in proliferation compared with untreated hPDLSCs, while osteoinduced hM-BMSCs for 10 day-conditioned medium (hM-BMSCs-CM-10ds) and osteoinduced hM-BMSCs for 15 day-conditioned medium (hM-BMSCs-CM-15ds) enhance the proliferation of hPDLSCs. hM-BMSCs of separate differentiation stages temporarily inhibited osteogenesis of hPDLSCs in the early days. Upon extending time periods, uninduced/osteoinduced hM-BMSCs markedly enhanced osteogenesis of hPDLSCs to different degrees. The transplantation results showed hM-BMSCs-CM-15ds treatment promoted tissue regeneration to generate cementum/periodontal ligament-like structure characterized by hard-tissue formation. This research supported the notion that hM-BMSCs triggered osteogenesis of hPDLSCs suggesting important implications for periodontal engineering.

Nutrition, bone health, and the young dancer

NARCIS (Netherlands)

Brown, D.D.; Solomon, R.; Solomon, J.; Micheli, L.

2017-01-01

Optimized bone health is a dynamic process that utilizes hormonal, nutritional, and biomechanical balance. For those who dance recreationally and in particular as young professionals, healthy bones become especially important given the demands of dance training. An imbalance in one of the areas

Differential Bees Flux Balance Analysis with OptKnock for in silico microbial strains optimization.

Directory of Open Access Journals (Sweden)

Yee Wen Choon

Full Text Available Microbial strains optimization for the overproduction of desired phenotype has been a popular topic in recent years. The strains can be optimized through several techniques in the field of genetic engineering. Gene knockout is a genetic engineering technique that can engineer the metabolism of microbial cells with the objective to obtain desirable phenotypes. However, the complexities of the metabolic networks have made the process to identify the effects of genetic modification on the desirable phenotypes challenging. Furthermore, a vast number of reactions in cellular metabolism often lead to the combinatorial problem in obtaining optimal gene deletion strategy. Basically, the size of a genome-scale metabolic model is usually large. As the size of the problem increases, the computation time increases exponentially. In this paper, we propose Differential Bees Flux Balance Analysis (DBFBA with OptKnock to identify optimal gene knockout strategies for maximizing the production yield of desired phenotypes while sustaining the growth rate. This proposed method functions by improving the performance of a hybrid of Bees Algorithm and Flux Balance Analysis (BAFBA by hybridizing Differential Evolution (DE algorithm into neighborhood searching strategy of BAFBA. In addition, DBFBA is integrated with OptKnock to validate the results for improving the reliability the work. Through several experiments conducted on Escherichia coli, Bacillus subtilis, and Clostridium thermocellum as the model organisms, DBFBA has shown a better performance in terms of computational time, stability, growth rate, and production yield of desired phenotypes compared to the methods used in previous works.

Intracellular glutathione status regulates mouse bone marrow monocyte-derived macrophage differentiation and phagocytic activity

International Nuclear Information System (INIS)

Kim, Jin-Man; Kim, Hyunsoo; Kwon, Soon Bok; Lee, Soo Young; Chung, Sung-Chang; Jeong, Dae-Won; Min, Byung-Moo

2004-01-01

Although a redox shift can regulate the development of cells, including proliferation, differentiation, and survival, the role of the glutathione (GSH) redox status in macrophage differentiation remains unclear. In order to elucidate the role of a redox shift, macrophage-like cells were differentiated from the bone marrow-derived monocytes that were treated with a macrophage colony stimulating factor (M-CSF or CSF-1) for 3 days. The macrophagic cells were characterized by a time-dependent increase in three major symptoms: the number of phagocytic cells, the number of adherent cells, and the mRNA expression of c-fms, a M-CSF receptor that is one of the macrophage-specific markers and mediates development signals. Upon M-CSF-driven macrophage differentiation, the GSH/GSSG ratio was significantly lower on day 1 than that observed on day 0 but was constant on days 1-3. To assess the effect of the GSH-depleted and -repleted status on the differentiation and phagocytosis of the macrophages, GSH depletion by BSO, a specific inhibitor of the de novo GSH synthesis, inhibited the formation of the adherent macrophagic cells by the down-regulation of c-fms, but did not affect the phagocytic activity of the macrophages. To the contrary, GSH repletion by the addition of NAC, which is a GSH precursor, or reduced GSH in media had no effect on macrophage differentiation, and led to a decrease in the phagocytic activity. Furthermore, we observed that there is checkpoint that is capable of releasing from the inhibition of the formation of the adherent macrophagic cells according to GSH depletion by BSO. Summarizing, these results indicate that the intracellular GSH status plays an important role in the differentiation and phagocytosis of macrophages

Bone marrow-derived cells are differentially involved in pathological and physiological retinal angiogenesis in mice

Energy Technology Data Exchange (ETDEWEB)

Zou, He [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan); Otani, Atsushi, E-mail: otan@kuhp.kyoto-u.ac.jp [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan); Oishi, Akio; Yodoi, Yuko; Kameda, Takanori; Kojima, Hiroshi; Yoshimura, Nagahisa [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan)

2010-01-08

Purpose: Bone marrow-derived cells have been shown to play roles in angiogenesis. Although these cells have been shown to promote angiogenesis, it is not yet clear whether these cells affect all types of angiogenesis. This study investigated the involvement of bone marrow-derived cells in pathological and physiological angiogenesis in the murine retina. Materials and methods: The oxygen-induced retinopathy (OIR) model was used as a retinal angiogenesis model in newborn mice. To block the influence of bone marrow-derived cells, the mice were irradiated with a 4-Gy dose of radiation from a {sup 137}Cs source. Irradiation was performed in four different conditions with radio dense 2-cm thick lead disks; (1) H group, the head were covered with these discs to protect the eyes from radiation; (2) A group, all of the body was covered with these discs; (3) N group, mice were completely unshielded; (4) C group, mice were put in the irradiator but were not irradiated. On P17, the retinal areas showing pathological and physiological retinal angiogenesis were measured and compared to the retinas of nonirradiated mice. Results: Although irradiation induced leukocyte depletion, it did not affect the number of other cell types or body weight. Retinal nonperfusion areas were significantly larger in irradiated mice than in control mice (P < 0.05), indicating that physiological angiogenesis was impaired. However, the formation of tuft-like angiogenesis processes was more prominent in the irradiated mice (P < 0.05), indicating that pathological angiogenesis was intact. Conclusions: Bone marrow-derived cells seem to be differentially involved in the formation of physiological and pathological retinal vessels. Pathological angiogenesis in the murine retina does not require functional bone marrow-derived cells, but these cells are important for the formation of physiological vessels. Our results add a new insight into the pathology of retinal angiogenesis and bolster the hypothesis that

Bone marrow-derived cells are differentially involved in pathological and physiological retinal angiogenesis in mice

International Nuclear Information System (INIS)

Zou, He; Otani, Atsushi; Oishi, Akio; Yodoi, Yuko; Kameda, Takanori; Kojima, Hiroshi; Yoshimura, Nagahisa

2010-01-01

Purpose: Bone marrow-derived cells have been shown to play roles in angiogenesis. Although these cells have been shown to promote angiogenesis, it is not yet clear whether these cells affect all types of angiogenesis. This study investigated the involvement of bone marrow-derived cells in pathological and physiological angiogenesis in the murine retina. Materials and methods: The oxygen-induced retinopathy (OIR) model was used as a retinal angiogenesis model in newborn mice. To block the influence of bone marrow-derived cells, the mice were irradiated with a 4-Gy dose of radiation from a 137 Cs source. Irradiation was performed in four different conditions with radio dense 2-cm thick lead disks; (1) H group, the head were covered with these discs to protect the eyes from radiation; (2) A group, all of the body was covered with these discs; (3) N group, mice were completely unshielded; (4) C group, mice were put in the irradiator but were not irradiated. On P17, the retinal areas showing pathological and physiological retinal angiogenesis were measured and compared to the retinas of nonirradiated mice. Results: Although irradiation induced leukocyte depletion, it did not affect the number of other cell types or body weight. Retinal nonperfusion areas were significantly larger in irradiated mice than in control mice (P < 0.05), indicating that physiological angiogenesis was impaired. However, the formation of tuft-like angiogenesis processes was more prominent in the irradiated mice (P < 0.05), indicating that pathological angiogenesis was intact. Conclusions: Bone marrow-derived cells seem to be differentially involved in the formation of physiological and pathological retinal vessels. Pathological angiogenesis in the murine retina does not require functional bone marrow-derived cells, but these cells are important for the formation of physiological vessels. Our results add a new insight into the pathology of retinal angiogenesis and bolster the hypothesis that bone

Time-sequential changes of differentially expressed miRNAs during the process of anterior lumbar interbody fusion using equine bone protein extract, rhBMP-2 and autograft

Science.gov (United States)

Chen, Da-Fu; Zhou, Zhi-Yu; Dai, Xue-Jun; Gao, Man-Man; Huang, Bao-Ding; Liang, Tang-Zhao; Shi, Rui; Zou, Li-Jin; Li, Hai-Sheng; Bünger, Cody; Tian, Wei; Zou, Xue-Nong

2014-03-01

The precise mechanism of bone regeneration in different bone graft substitutes has been well studied in recent researches. However, miRNAs regulation of the bone formation has been always mysterious. We developed the anterior lumbar interbody fusion (ALIF) model in pigs using equine bone protein extract (BPE), recombinant human bone morphogenetic protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS), and autograft as bone graft substitute, respectively. The miRNA and gene expression profiles of different bone graft materials were examined using microarray technology and data analysis, including self-organizing maps, KEGG pathway and Biological process GO analyses. We then jointly analyzed miRNA and mRNA profiles of the bone fusion tissue at different time points respectively. Results showed that miRNAs, including let-7, miR-129, miR-21, miR-133, miR-140, miR-146, miR-184, and miR-224, were involved in the regulation of the immune and inflammation response, which provided suitable inflammatory microenvironment for bone formation. At late stage, several miRNAs directly regulate SMAD4, Estrogen receptor 1 and 5-hydroxytryptamine (serotonin) receptor 2C for bone formation. It can be concluded that miRNAs play important roles in balancing the inflammation and bone formation.

Decreased bone turnover with balanced resorption and formation prevent cortical bone loss during disuse (hibernation) in grizzly bears (Ursus arctos horribilis)

OpenAIRE

McGee, Meghan E.; Maki, Aaron J.; Johnson, Steven E.; Lynne Nelson, O.; Robbins, Charles T.; Donahue, Seth W.

2007-01-01

Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. ...

Global MicroRNA Profiling in Human Bone Marrow Skeletal—Stromal or Mesenchymal–Stem Cells Identified Candidates for Bone Regeneration

DEFF Research Database (Denmark)

Chang, Chi Chih; Venø, Morten T.; Chen, Li

2018-01-01

Bone remodeling and regeneration are highly regulated multistep processes involving posttranscriptional regulation by microRNAs (miRNAs). Here, we performed a global profiling of differentially expressed miRNAs in bone-marrow-derived skeletal cells (BMSCs; also known as stromal or mesenchymal stem......RNAs for enhancing bone tissue regeneration. Scaffolds functionalized with miRNA nano-carriers enhanced osteoblastogenesis in 3D culture and retained this ability at least 2 weeks after storage. Additionally, anti-miR-222 enhanced in vivo ectopic bone formation through targeting the cell-cycle inhibitor CDKN1B...... cells) during in vitro osteoblast differentiation. We functionally validated the regulatory effects of several miRNAs on osteoblast differentiation and identified 15 miRNAs, most significantly miR-222 and miR-423, as regulators of osteoblastogenesis. In addition, we tested the possible targeting of mi...

Osteoclast differentiation inhibitors: a patent review (2008 - 2012).

Science.gov (United States)

Kim, Seong Hwan; Moon, Seong-Hee

2013-12-01

Mononuclear macrophage/monocyte-lineage hematopoietic precursors differentiate into multinucleated osteoclasts. Abnormally increased numbers and/or overactivation of osteoclasts can lead to bone loss. Therefore, pharmaceutical inhibition of osteoclast differentiation is one therapeutic strategy for mitigating the occurrence of bone loss-associated disorders and related fractures. This review surveys the patents and patent applications from 2008 to 2012 that are related to inventions of therapeutics and/or methods for inhibiting osteoclast differentiation. Over the past 20 years, the identification and validation of signaling molecules involved in osteoclast differentiation has led to a better understanding of the molecular mechanism, and to the development of new therapeutic agents for treating bone loss-associated disorders. Since 2008, 34 WO patents or patent applications have been filed that relate to inventions of therapeutics and/or methods for chemical-based, natural product-based, or biological-based inhibitors of osteoclast differentiation. Here, analysis of these patents and patent applications is presented, and summarize the disclosed osteoclast differentiation-inhibiting target molecules. This report can support further advances in the development of anti-osteoclastogenic therapeutics for bone loss-associated disorders, including osteoporosis, rheumatoid arthritis, Paget's disease, periodontal disease, osteosarcoma, and cancer bone metastasis.

Differentiation of Rat bone marrow Mesenchymal stem cells into Adipocytes and Cardiomyocytes after treatment with platelet lysate.

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Homayouni Moghadam, Farshad; Tayebi, Tahereh; Barzegar, Kazem

2016-01-01

Mesenchymal stem cells (MSCs) are multipotential cells and their therapeutic potency is under intense investigation. Studying the effect of different induction factors on MSCs could increase our knowledge about the differentiation potency of these cells. One of the most important sources of these factors in mammalian body is platelet. Platelet lysate (PL) contains many growth factors and therefore, it can be used as a differentiation inducer. In the present study, the effect of PL on differentiation of rat bone marrow MSCs into cardiomyocytes was studied. To study the differentiation-inducing effect of PL, MSCs were treated with 2.5, 5 and 10% PL. Early results of this study showed that PL in high concentrations (10%) induces adipogenic differentiation of MSCs. Therefore, to evaluate differentiation to cardiomyocytes, MSCs were cultured in media containing lower levels of PL (2.5% and 5%) and then cardiomyogenic differentiation was induced by treatment with 5-azacytidine. Differentiation of MSCs was evaluated using direct observation of beating cells, immunostaining and real-time PCR techniques. The results of qPCR showed that treatment with PL alone increased the expression of cardiac alpha actinin (CAA) being predictable by earlier observation of beating cells in PL-treated groups. The results of staining assays against cardiac alpha actinin also showed that there were stained cells in PL-treated groups. The results of the present study showed that PL is a powerful induction factor for differentiation of MSCs into different cell lines such as cardiomyocytes and adipocytes.

Diagnosing aneurysmal and unicameral bone cysts with magnetic resonance imaging.

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Sullivan, R J; Meyer, J S; Dormans, J P; Davidson, R S

1999-09-01

The differential between aneurysmal bone cysts and unicameral bone cysts usually is clear clinically and radiographically. Occasionally there are cases in which the diagnosis is not clear. Because natural history and treatment are different, the ability to distinguish between these two entities before surgery is important. The authors reviewed, in a blinded fashion, the preoperative magnetic resonance images to investigate criteria that could be used to differentiate between the two lesions. All patients had operative or pathologic confirmation of an aneurysmal bone cyst or unicameral bone cyst. The authors analyzed the preoperative magnetic resonance images of 14 patients with diagnostically difficult bone cysts (eight children with unicameral bone cysts and six children with aneurysmal bone cysts) and correlated these findings with diagnosis after biopsy or cyst aspiration and contrast injection. The presence of a double density fluid level within the lesion strongly indicated that the lesion was an aneurysmal bone cyst, rather than a unicameral bone cyst. Other criteria that suggested the lesion was an aneurysmal bone cyst were the presence of septations within the lesion and signal characteristics of low intensity on T1 images and high intensity on T2 images. The authors identified a way of helping to differentiate between aneurysmal bone cysts and unicameral bone cysts on magnetic resonance images. Double density fluid level, septation, and low signal on T1 images and high signal on T2 images strongly suggest the bone cyst in question is an aneurysmal bone cyst, rather than a unicameral bone cyst. This may be helpful before surgery for the child who has a cystic lesion for which radiographic features do not allow a clear differentiation of unicameral bone cyst from aneurysmal bone cyst.

Giant cell tumor in long bones: the significance of marginal sclerosis for the differential diagnosis

International Nuclear Information System (INIS)

Kim, Hee Jin; Suh, Jin Suck; Park, Chang Yun

1993-01-01

Plain radiographs of thirty nine patients with giant cell tumor of long bone and CT scans of twenty patients among the thirty patients were reviewed retrospectively to evaluate the frequency and significance of sclerosis of the tumor margin. The sclerosis of the tumor margin was observed on plain radiographs in thirteen patients(33.3%) and they were located either on epiphyseal or on both epiphyseal or metaphyseal portion of the tumor. The authors concluded that the giant cell tumor should not be excluded from the differential entities even though the tumor has the marginal sclerosis

Synergetic topography and chemistry cues guiding osteogenic differentiation in bone marrow stromal cells through ERK1/2 and p38 MAPK signaling pathway.

Science.gov (United States)

Zhang, Xinran; Li, Haotian; Lin, Chucheng; Ning, Congqin; Lin, Kaili

2018-01-30

Both the topographic surface and chemical composition modification can enhance rapid osteogenic differentiation and bone formation. Till now, the synergetic effects of topography and chemistry cues guiding biological responses have been rarely reported. Herein, the ordered micro-patterned topography and classically essential trace element of strontium (Sr) ion doping were selected to imitate topography and chemistry cues, respectively. The ordered micro-patterned topography on Sr ion-doped bioceramics was successfully duplicated using the nylon sieve as the template. Biological response results revealed that the micro-patterned topography design or Sr doping could promote cell attachment, ALP activity, and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Most importantly, the samples both with micro-patterned topography and Sr doping showed the highest promotion effects, and could synergistically activate the ERK1/2 and p38 MAPK signaling pathways. The results suggested that the grafts with both specific topography and chemistry cues have synergetic effects on osteogenic activity of BMSCs and provide an effective approach to design functional bone grafts and cell culture substrates.

Ewing's sarcoma of the tarsal bone

International Nuclear Information System (INIS)

Kwon, Jung Hyeok; Kim, Yong Sun; Kim, Tae Hun; Park, In Kyu; Kim, Yong Joo; Kang, Duk Sik; Sohn, Kyung Rak

1985-01-01

The Ewing's sarcoma comprises approximately less than 10 percent of malignant bone tumors and 5 percent of all bone tumors, occurs in almost all bones of the body, and presents a widely divergent roentgenographic manifestations. The tarsal bones are involved only 2 percent in the Ewing's sarcoma. Two cases experienced by authors and ten cases published in literatures of Ewing's sarcoma of the tarsal bone were analyzed retrospectively. The result were as follows: 1. Of the tarsal bones, the calcaneus was 7 cases, the talus 4 cases, cuneiform 1 case. 2. Female was affected more commonly than male, the ratio being 4 to 1 in the tarsal bones. 3. About sixty percent of total cases in the tarsal bones had evidence of diffuse sclerotic pattern. All the cases of the talus had evidence of diffuse sclerotic pattern. 4. The diseases to be considered in differential diagnosis are as follows: avascular necrosis, tuberculous osteomyelitis, osteosarcoma, and pyogenic osteomyelitis. 5. The diffuse sclerosis radiographically showed a close relation with dead bone resulting from avascular necrosis due to tumor infiltration histologically. Periosteal reactive new bone and osteoid deposition on the dead bone were also correlated with diffuse sclerosis. 6. Because it is difficult to differentiate sclerotic lesions in the tarsal bones by radiographic methods alone, all such lesions should be subject to biopsy as early as possible

Ewing's sarcoma of the tarsal bone

Energy Technology Data Exchange (ETDEWEB)

Kwon, Jung Hyeok; Kim, Yong Sun; Kim, Tae Hun; Park, In Kyu; Kim, Yong Joo; Kang, Duk Sik; Sohn, Kyung Rak [College of Medicine, Kyungpook National University, Daegu (Korea, Republic of)

1985-06-15

The Ewing's sarcoma comprises approximately less than 10 percent of malignant bone tumors and 5 percent of all bone tumors, occurs in almost all bones of the body, and presents a widely divergent roentgenographic manifestations. The tarsal bones are involved only 2 percent in the Ewing's sarcoma. Two cases experienced by authors and ten cases published in literatures of Ewing's sarcoma of the tarsal bone were analyzed retrospectively. The result were as follows: 1. Of the tarsal bones, the calcaneus was 7 cases, the talus 4 cases, cuneiform 1 case. 2. Female was affected more commonly than male, the ratio being 4 to 1 in the tarsal bones. 3. About sixty percent of total cases in the tarsal bones had evidence of diffuse sclerotic pattern. All the cases of the talus had evidence of diffuse sclerotic pattern. 4. The diseases to be considered in differential diagnosis are as follows: avascular necrosis, tuberculous osteomyelitis, osteosarcoma, and pyogenic osteomyelitis. 5. The diffuse sclerosis radiographically showed a close relation with dead bone resulting from avascular necrosis due to tumor infiltration histologically. Periosteal reactive new bone and osteoid deposition on the dead bone were also correlated with diffuse sclerosis. 6. Because it is difficult to differentiate sclerotic lesions in the tarsal bones by radiographic methods alone, all such lesions should be subject to biopsy as early as possible.

Grizzly bears (Ursus arctos horribilis) and black bears (Ursus americanus) prevent trabecular bone loss during disuse (hibernation).

Science.gov (United States)

McGee-Lawrence, Meghan E; Wojda, Samantha J; Barlow, Lindsay N; Drummer, Thomas D; Castillo, Alesha B; Kennedy, Oran; Condon, Keith W; Auger, Janene; Black, Hal L; Nelson, O Lynne; Robbins, Charles T; Donahue, Seth W

2009-12-01

Disuse typically causes an imbalance in bone formation and bone resorption, leading to losses of cortical and trabecular bone. In contrast, bears maintain balanced intracortical remodeling and prevent cortical bone loss during disuse (hibernation). Trabecular bone, however, is more detrimentally affected than cortical bone in other animal models of disuse. Here we investigated the effects of hibernation on bone remodeling, architectural properties, and mineral density of grizzly bear (Ursus arctos horribilis) and black bear (Ursus americanus) trabecular bone in several skeletal locations. There were no differences in bone volume fraction or tissue mineral density between hibernating and active bears or between pre- and post-hibernation bears in the ilium, distal femur, or calcaneus. Though indices of cellular activity level (mineral apposition rate, osteoid thickness) decreased, trabecular bone resorption and formation indices remained balanced in hibernating grizzly bears. These data suggest that bears prevent bone loss during disuse by maintaining a balance between bone formation and bone resorption, which consequently preserves bone structure and strength. Further investigation of bone metabolism in hibernating bears may lead to the translation of mechanisms preventing disuse-induced bone loss in bears into novel treatments for osteoporosis.

Bone metastases from gastric cancer. Clinical evaluation on bone scintigram

Energy Technology Data Exchange (ETDEWEB)

Seto, Mikito; Tonami, Norihisa; Koizumi, Kiyoshi; Sui, Osamu; Hisada, Kinichi [Kanazawa Univ. (Japan). School of Medicine

1983-07-01

We have studied bone scintigrams in 60 patients with gastric cancer. Of these 60 patients, bone metastases were found in 15 patients (25 %). There were no evidence of bone metastases in polypoid lesions, cancers of the antrum, carcinomas in situ, advanced cancers without invasion to serosa, cancer with N/sub 0/ or N/sub 1/ regional lymph node metastases, highly differentiated adenocarcinomas and papillary adenocarcinomas. On the contrary, high rates of bone metastases were seen in cancers of the corpus, advanced cancers with invasion to neighbouring structures and tubular adenocarcinomas. Of these 15 patients with bone metastasis, 3 patients showed very similar clinical features and the findings of ''diffuse bone metastases on bone scintigrams.'' Cancer of the antrum showed high rates of liver metastases, while cancers of the corpus showed high rates of bone metastases. Sixty percent of the patients with bone metastases did not have liver metastases and there seemed to be no significant relationship between liver metastases and bone metastases. From these results we suppose that non-portal tract through the vertebral venous plexus instead of portal tract may be the other route of bone metastases from gastric cancer.

Balanced microwave filters

CERN Document Server

Hong, Jiasheng; Medina, Francisco; Martiacuten, Ferran

2018-01-01

This book presents and discusses strategies for the design and implementation of common-mode suppressed balanced microwave filters, including, narrowband, wideband, and ultra-wideband filters This book examines differential-mode, or balanced, microwave filters by discussing several implementations of practical realizations of these passive components. Topics covered include selective mode suppression, designs based on distributed and semi-lumped approaches, multilayer technologies, defect ground structures, coupled resonators, metamaterials, interference techniques, and substrate integrated waveguides, among others. Divided into five parts, Balanced Microwave Filters begins with an introduction that presents the fundamentals of balanced lines, circuits, and networks. Part 2 covers balanced transmission lines with common-mode noise suppression, including several types of common-mode filters and the application of such filters to enhance common-mode suppression in balanced bandpass filters. Next, Part 3 exa...

In vitro induction of alkaline phosphatase levels predicts in vivo bone forming capacity of human bone marrow stromal cells

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Henk-Jan Prins

2014-03-01

Full Text Available One of the applications of bone marrow stromal cells (BMSCs that are produced by ex vivo expansion is for use in in vivo bone tissue engineering. Cultured stromal cells are a mixture of cells at different stages of commitment and expansion capability, leading to a heterogeneous cell population that each time can differ in the potential to form in vivo bone. A parameter that predicts for in vivo bone forming capacity is thus far lacking. We employed single colony-derived BMSC cultures to identify such predictive parameters. Using limiting dilution, we have produced sixteen single CFU-F derived BMSC cultures from human bone marrow and found that only five of these formed bone in vivo. The single colony-derived BMSC strains were tested for proliferation, osteogenic-, adipogenic- and chondrogenic differentiation capacity and the expression of a variety of associated markers. The only robust predictors of in vivo bone forming capacity were the induction of alkaline phosphatase, (ALP mRNA levels and ALP activity during in vitro osteogenic differentiation. The predictive value of in vitro ALP induction was confirmed by analyzing “bulk-cultured” BMSCs from various bone marrow biopsies. Our findings show that in BMSCs, the additional increase in ALP levels over basal levels during in vitro osteogenic differentiation is predictive of in vivo performance.

Micro-/Nano- sized hydroxyapatite directs differentiation of rat bone marrow derived mesenchymal stem cells towards an osteoblast lineage

Science.gov (United States)

Huang, Yan; Zhou, Gang; Zheng, Lisha; Liu, Haifeng; Niu, Xufeng; Fan, Yubo

2012-03-01

Regenerative medicine consisting of cells and materials provides a new way for the repair and regeneration of tissues and organs. Nano-biomaterials are highlighted due to their advantageous features compared with conventional micro-materials. The aim of this study is to investigate the effects of micro-/nano- sized hydroxyapatite (μ/n-HA) on the osteogenic differentiation of rat bone marrow derived mesenchymal stem cells (rBMSCs). μ/n-HA were prepared by a microwave synthesizer and precipitation method, respectively. Different sizes of μ/n-HA were characterized by IR, XRD, SEM, TEM and co-cultured with rBMSCs. It was shown that rBMSCs expressed higher levels of osteoblast-related markers by n-HA than μ-HA stimulation. The size of HA is an important factor for affecting the osteogenic differentiation of rBMSCs. This provides a new avenue for mechanistic studies of stem cell differentiation and a new approach to obtain more committed differentiated cells.

Rat bone marrow progenitor cells transduced in situ by rSV40 vectors differentiate into multiple central nervous system cell lineages.

Science.gov (United States)

Louboutin, Jean-Pierre; Liu, Bianling; Reyes, Beverly A S; Van Bockstaele, Elisabeth J; Strayer, David S

2006-12-01

Using bone marrow-directed gene transfer, we tested whether bone marrow-derived cells may function as progenitors of central nervous system (CNS) cells in adult animals. SV40-derived gene delivery vectors were injected directly into femoral bone marrow, and we examined transgene expression in blood and brain for 0-16 months thereafter by immunostaining for FLAG epitope marker. An average of 5% of peripheral blood cells and 25% of femoral marrow cells were FLAG(+) throughout the study. CNS FLAG-expressing cells were mainly detected in the dentate gyrus (DG) and periventricular subependymal zone (PSZ). Although absent before 1 month and rare at 4 months, DG and PSZ FLAG(+) cells were abundant 16 months after bone marrow injection. Approximately 5% of DG cells expressed FLAG, including neurons (48.6%) and microglia (49.7%), and occasional astrocytes (1.6%), as determined by double immunostaining for FLAG and lineage markers. These data suggest that one or more populations of cells resident within adult bone marrow can migrate to the brain and differentiate into CNS-specific cells.

Osterix enhances proliferation and osteogenic potential of bone marrow stromal cells

International Nuclear Information System (INIS)

Tu Qisheng; Valverde, Paloma; Chen, Jake

2006-01-01

Osterix (Osx) is a zinc-finger-containing transcription factor that is expressed in osteoblasts of all endochondral and membranous bones. In Osx null mice osteoblast differentiation is impaired and bone formation is absent. In this study, we hypothesized that overexpression of Osx in murine bone marrow stromal cells (BMSC) would be able to enhance their osteoblastic differentiation and mineralization in vitro. Retroviral transduction of Osx in BMSC cultured in non-differentiating medium did not affect expression of Runx2/Cbfa1, another key transcription factor of osteoblast differentiation, but induced an increase in the expression of other markers associated with the osteoblastic lineage including alkaline phosphatase, bone sialoprotein, osteocalcin, and osteopontin. Retroviral transduction of Osx in BMSC also increased their proliferation, alkaline phosphatase activity, and ability to form bone nodules. These events occurred without significant changes in the expression of α1(II) procollagen or lipoprotein lipase, which are markers of chondrogenic and adipogenic differentiation, respectively

Steering the osteoclast through the demineralization-collagenolysis balance

DEFF Research Database (Denmark)

Søe, Kent; Merrild, Ditte Marie Horslev; Delaissé, Jean-Marie

2013-01-01

are generated when collagen degradation is slower than demineralization, and trenches when collagen degradation is as fast as demineralization. Next we treated the osteoclasts with a low dose of a carbonic anhydrase inhibitor to slightly decrease the rate of demineralization, thereby allowing collagen......, forming a pit, and continues parallel to the bone surface, forming a trench. Importantly, we show that the progress of the osteoclast along this route depends on the balance between the rate of collagenolysis and demineralization. We propose that the osteocytes and bone lining cells surrounding...... the osteoclast may act on this balance to steer the osteoclast resorptive activity in order to give the excavations a specific shape....

Bone Marrow Stromal Cells Contribute to Bone Formation Following Infusion into Femoral Cavities of a Mouse Model of Osteogenesis Imperfecta

Science.gov (United States)

Li, Feng; Wang, Xujun; Niyibizi, Christopher

2010-01-01

Currently, there are conflicting data in literature regarding contribution of bone marrow stromal cells (BMSCs) to bone formation when the cells are systemically delivered in recipient animals. To understand if BMSCs contribute to bone cell phenotype and bone formation in osteogenesis imperfecta bones (OI), MSCs marked with GFP were directly infused into the femurs of a mouse model of OI (oim). The contribution of the cells to the cell phenotype and bone formation was assessed by histology, immunohistochemistry and biomechanical loading of recipient bones. Two weeks following infusion of BMSCs, histological examination of the recipient femurs demonstrated presence of new bone when compared to femurs injected with saline which showed little or no bone formation. The new bone contained few donor cells as demonstrated by GFP fluorescence. At six weeks following cell injection, new bone was still detectable in the recipient femurs but was enhanced by injection of the cells suspended in pepsin solublized type I collagen. Immunofluorescence and immunohistochemical staining showed that donor GFP positive cells in the new bone were localized with osteocalcin expressing cells suggesting that the cells differentiated into osteoblasts in vivo. Biomechanical loading to failure in thee point bending, revealed that, femurs infused with BMSCs in PBS or in soluble type I collagen were biomechanically stronger than those injected with PBS or type I collagen alone. Taken together, the results indicate that transplanted cells differentiated into osteoblasts in vivo and contributed to bone formation in vivo; we also speculate that donor cells induced differentiation or recruitment of endogenous cells to initiate reparative process at early stages following transplantation. PMID:20570757

Progesterone and Bone: Actions Promoting Bone Health in Women

Directory of Open Access Journals (Sweden)

Vanadin Seifert-Klauss

2010-01-01

Full Text Available Estradiol (E2 and progesterone (P4 collaborate within bone remodelling on resorption (E2 and formation (P4. We integrate evidence that P4 may prevent and, with antiresorptives, treat women's osteoporosis. P4 stimulates osteoblast differentiation in vitro. Menarche (E2 and onset of ovulation (P4 both contribute to peak BMD. Meta-analysis of 5 studies confirms that regularly cycling premenopausal women lose bone mineral density (BMD related to subclinical ovulatory disturbances (SODs. Cyclic progestin prevents bone loss in healthy premenopausal women with amenorrhea or SOD. BMD loss is more rapid in perimenopause than postmenopause—decreased bone formation due to P4 deficiency contributes. In 4 placebo-controlled RCTs, BMD loss is not prevented by P4 in postmenopausal women with increased bone turnover. However, 5 studies of E2-MPA co-therapy show greater BMD increases versus E2 alone. P4 fracture data are lacking. P4 prevents bone loss in pre- and possibly perimenopausal women; progesterone co-therapy with antiresorptives may increase bone formation and BMD.

Role of human amnion-derived mesenchymal stem cells in promoting osteogenic differentiation by influencing p38 MAPK signaling in lipopolysaccharide -induced human bone marrow mesenchymal stem cells

International Nuclear Information System (INIS)

Wang, Yuli; Wu, Hongxia; Shen, Ming; Ding, Siyang; Miao, Jing; Chen, Ning

2017-01-01

Periodontitis is a chronic inflammatory disease induced by bacterial pathogens, which not only affect connective tissue attachments but also cause alveolar bone loss. In this study, we investigated the anti-inflammatory effects of Human amnion-derived mesenchymal stem cells (HAMSCs) on human bone marrow mesenchymal stem cells (HBMSCs) under lipopolysaccharide (LPS)-induced inflammatory conditions. Proliferation levels were measured by flow cytometry and immunofluorescence staining of 5-ethynyl-2′-deoxyuridine (EdU). Osteoblastic differentiation and mineralization were investigated using chromogenic alkaline phosphatase activity (ALP) activity substrate assays, Alizarin red S staining, and RT-PCR analysis of HBMSCs osteogenic marker expression. Oxidative stress induced by LPS was investigated by assaying reactive oxygen species (ROS) level and superoxide dismutase (SOD) activity. Here, we demonstrated that HAMSCs increased the proliferation, osteoblastic differentiation, and SOD activity of LPS-induced HBMSCs, and down-regulated the ROS level. Moreover, our results suggested that the activation of p38 MAPK signal transduction pathway is essential for reversing the LPS-induced bone-destructive processes. SB203580, a selective inhibitor of p38 MAPK signaling, significantly suppressed the anti-inflammatory effects in HAMSCs. In conclusion, HAMSCs show a strong potential in treating inflammation-induced bone loss by influencing p38 MAPK signaling. - Highlights: • LPS inhibites osteogenic differentiation in HBMSCs via suppression of p38 MAPK signaling pathway. • HAMSCs promote LPS-induced HBMSCs osteogenic differentiation through p38 MAPK signaling pathway. • HAMSCs reverse LPS-induced oxidative stress in LPS-induced HBMSCs through p38 MAPK signaling pathway.

Osteoblast CFTR inactivation reduces differentiation and osteoprotegerin expression in a mouse model of cystic fibrosis-related bone disease.

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Michael S Stalvey

Full Text Available Low bone mass and increased fracture risk are recognized complications of cystic fibrosis (CF. CF-related bone disease (CFBD is characterized by uncoupled bone turnover--impaired osteoblastic bone formation and enhanced osteoclastic bone resorption. Intestinal malabsorption, vitamin D deficiency and inflammatory cytokines contribute to CFBD. However, epidemiological investigations and animal models also support a direct causal link between inactivation of skeletal cystic fibrosis transmembrane regulator (CFTR, the gene that when mutated causes CF, and CFBD. The objective of this study was to examine the direct actions of CFTR on bone. Expression analyses revealed that CFTR mRNA and protein were expressed in murine osteoblasts, but not in osteoclasts. Functional studies were then performed to investigate the direct actions of CFTR on osteoblasts using a CFTR knockout (Cftr-/- mouse model. In the murine calvarial organ culture assay, Cftr-/- calvariae displayed significantly less bone formation and osteoblast numbers than calvariae harvested from wildtype (Cftr+/+ littermates. CFTR inactivation also reduced alkaline phosphatase expression in cultured murine calvarial osteoblasts. Although CFTR was not expressed in murine osteoclasts, significantly more osteoclasts formed in Cftr-/- compared to Cftr+/+ bone marrow cultures. Indirect regulation of osteoclastogenesis by the osteoblast through RANK/RANKL/OPG signaling was next examined. Although no difference in receptor activator of NF-κB ligand (Rankl mRNA was detected, significantly less osteoprotegerin (Opg was expressed in Cftr-/- compared to Cftr+/+ osteoblasts. Together, the Rankl:Opg ratio was significantly higher in Cftr-/- murine calvarial osteoblasts contributing to a higher osteoclastogenesis potential. The combined findings of reduced osteoblast differentiation and lower Opg expression suggested a possible defect in canonical Wnt signaling. In fact, Wnt3a and PTH-stimulated canonical Wnt

Evaluation of postural balance in postmenopausal women and its relationship with bone mineral density- a cross sectional study

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Cangussu Luciana

2012-01-01

Full Text Available Abstract Background Low bone mineral density (BMD and falls are common problems encountered in the postmenopausal women. The purpose was to evaluate the association between postural balance and BMD in postmenopausal women and its relation to risk for falls. Methods In this cross-sectional study, 225 women in amenorrhea > 12 months and age ≥ 45 years were included and divided, according to BMD, in T-score values > -2.0 SD (n = 140 and ≤ -2 SD (n = 85. Those with neurological or musculoskeletal disorders, history of vestibulopathies, uncorrected visual deficit or drug use that could affect balance were excluded. History of falls (last 24 months, clinical and anthropometric characteristics were evaluated. Postural balance was assessed by stabilometry (force platform. For statistical analysis were used Wilcoxon's Test, Chi-Square Test and logistic regression method for fall risk (Odds Ratio-OR. Results Patients with BMD > -2.0 SD were younger, with shorter time since menopause, and showed higher BMI as compared to those with low BMD (≤ -2 SD (p 0.05 for stabilometric parameters. Risk for falls increased with age (OR 1.07; CI 95% 1.01-1.13, current smoking (OR 2.19; CI 95% 1.22-3.21 and corrected visual deficit (OR 9.06; CI 95% 1.14-4.09. In contrast, hormone therapy (HT use was significantly associated with reduced risk for falls (OR 0.48; CI 95% 0.26-0.88. Conclusions In postmenopausal women, BMD did not show association with postural balance or risk for falls. Age, smoking and corrected visual deficit were clinical indicators of risk for falls whereas HT use showed to be a protective factor.

Role of bone photonic densitometry in uremic osteodystrophy

International Nuclear Information System (INIS)

Specchi Bighi, E.; Baldelli, S.; Argalia, G.

1987-01-01

The aim of this investigation is to evaluate the role of bone photonic densitometry in uremic osteodystrophy. Bone mineral contenent (BMC) and bone density (BD) have been measured in 80 hemodialyzed patients by double photonic emission densitometry. Photonic densitometry shows an higher sensibility to quantitative changes in bone mineral contenent than metacarpal index (IM). Photonic densitometry is unable to differentiate osteoporosis from osteomalacia; this differential diagnosis can be obtained by radiological analysis: low BD and low IM means osteoporosis, low BD and resorptive changes in cortical bone means osteomalacia and/or hyperparathyroidism. Photonic densitometry is particulary suitable for uremic osteodystrophy follow-up because of its easy ripetibility and innocuousness and for its close correlation with iPTH variations

Denosumab for bone diseases: translating bone biology into targeted therapy.

Science.gov (United States)

Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

2011-12-01

Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

Dissecting Tumor-Stromal Interactions in Breast Cancer Bone Metastasis

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Yibin Kang

2016-06-01

Full Text Available Bone metastasis is a frequent occurrence in breast cancer, affecting more than 70% of late stage cancer patients with severe complications such as fracture, bone pain, and hypercalcemia. The pathogenesis of osteolytic bone metastasis depends on cross-communications between tumor cells and various stromal cells residing in the bone microenvironment. Several growth factor signaling pathways, secreted micro RNAs (miRNAs and exosomes are functional mediators of tumor-stromal interactions in bone metastasis. We developed a functional genomic approach to systemically identified molecular pathways utilized by breast cancer cells to engage the bone stroma in order to generate osteolytic bone metastasis. We showed that elevated expression of vascular cell adhesion molecule 1 (VCAM1 in disseminated breast tumor cells mediates the recruitment of pre-osteoclasts and promotes their differentiation to mature osteoclasts during the bone metastasis formation. Transforming growth factor β (TGF-β is released from bone matrix upon bone destruction, and signals to breast cancer to further enhance their malignancy in developing bone metastasis. We furthered identified Jagged1 as a TGF-β target genes in tumor cells that engaged bone stromal cells through the activation of Notch signaling to provide a positive feedback to promote tumor growth and to activate osteoclast differentiation. Substantially change in miRNA expression was observed in osteoclasts during their differentiation and maturation, which can be exploited as circulating biomarkers of emerging bone metastasis and therapeutic targets for the treatment of bone metastasis. Further research in this direction may lead to improved diagnosis and treatment strategies for bone metastasis.

Correlative study of SPECT bone scan, serum tPSA and fPSA/tPSA ratio and the pathological grade of prostate cancer with bone metastasis

International Nuclear Information System (INIS)

Xu Haiqing; Duan Jun

2011-01-01

Objective: To study the rules and characteristics of SPECT bone scan, serum TPSA, fPSA/tPSA ratio and the pathological grade of prostate cancer with bone metastasis. Methods: Nuclear medicine SPECT bone scan as the gold standard, retrospective analysis of the in vitro radioimmunoassay in 107 patients with prostate cancer serum PSA (prostate specific antigen) levels, serum fPSA/tPSA ratio and whole body bone imaging studies and pathological classification. Results: 107 patients with prostate cancer : 49 patients had bone metastases, accounting for 45.8% (49/107), in which groups of different pathological comparison between the incidence of bone metastasis significantly, the lower the degree of differentiation, the more the incidence of bone metastases high; with elevated levels of tPSA, the incidence of bone metastasis increased significantly; serum tPSA 4 - 40 ng/ml, the use of fPSA/tPSA ratio may improve the diagnostic specificity of prostate cancer. Conclusion: Patients with bone metastases of prostate cancer incidence and degree of differentiation of prostate cancer, serum PSA levels and fPSA/tPSA ratio of a certain relationship. The lower degree of differentiation,the higher the incidence of bone metastasis. (authors)

Addition of Wollastonite Fibers to Calcium Phosphate Cement Increases Cell Viability and Stimulates Differentiation of Osteoblast-Like Cells

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Juliana Almeida Domingues

2017-01-01

Full Text Available Calcium phosphate cement (CPC that is based on α-tricalcium phosphate (α-TCP is considered desirable for bone tissue engineering because of its relatively rapid degradation properties. However, such cement is relatively weak, restricting its use to areas of low mechanical stress. Wollastonite fibers (WF have been used to improve the mechanical strength of biomaterials. However, the biological properties of WF remain poorly understood. Here, we tested the response of osteoblast-like cells to being cultured on CPC reinforced with 5% of WF (CPC-WF. We found that both types of cement studied achieved an ion balance for calcium and phosphate after 3 days of immersion in culture medium and this allowed subsequent long-term cell culture. CPC-WF increased cell viability and stimulated cell differentiation, compared to nonreinforced CPC. We hypothesize that late silicon release by CPC-WF induces increased cell proliferation and differentiation. Based on our findings, we propose that CPC-WF is a promising material for bone tissue engineering applications.

Hydroxyapatite/collagen bone-like nanocomposite.

Science.gov (United States)

Kikuchi, Masanori

2013-01-01

Our group has succeeded to synthesize material with bone-like nanostructure and bone-like inorganic and organic composition via self-organization mechanism between them using simultaneous titration method under controlled pH and temperature. The hydroxyapatite/collagen (HAp/Col) bone-like nanocomposite completely incorporated into bone remodeling process to be substituted by new bone. Cells cultured on the HAp/Col revealed very interesting reactions. Osteoblast-like MG63 cells showed upregulation of alkaline phosphatase >3 times greater than MG63 cells cultured on tissue culture polystyrene (TCPS). MG63 cells 3-dimensionally cultured in a "HAp/Col sponge," a porous HAp/Col having sponge-like viscoelasticity, accumulated calcium phosphate nodules on extracellular matrices they secreted. Bone marrow cells co-cultured with osteoblasts on HAp/Col differentiated to osteoclasts without differentiation supplements. This phenomenon is not found in cells cultured on hydroxyapatite ceramics and TCPS, and rarely in cells cultured on dentin. These results suggest that HAp/Col is a good candidate for tissue engineering of bone as well as bone filler. In a clinical test as a bone filler, the HAp/Col sponge was significantly better than porous β-tricalcium phosphate. The HAp/Col sponge has been approved by the Japanese government and will be used as greatly needed bone filler in patients. In addition to the above, HAp/Col coating on titanium revealed higher osteo-conductivity than HAp-coated titanium and bare titanium and improved direct bonding between titanium and newly formed bone. The HAp/Col coating may be used for metal devices requiring osseointegration.

The Satellite Cell Niche Regulates the Balance between Myoblast Differentiation and Self-Renewal via p53.

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Flamini, Valentina; Ghadiali, Rachel S; Antczak, Philipp; Rothwell, Amy; Turnbull, Jeremy E; Pisconti, Addolorata

2018-03-13

Satellite cells are adult muscle stem cells residing in a specialized niche that regulates their homeostasis. How niche-generated signals integrate to regulate gene expression in satellite cell-derived myoblasts is poorly understood. We undertook an unbiased approach to study the effect of the satellite cell niche on satellite cell-derived myoblast transcriptional regulation and identified the tumor suppressor p53 as a key player in the regulation of myoblast quiescence. After activation and proliferation, a subpopulation of myoblasts cultured in the presence of the niche upregulates p53 and fails to differentiate. When satellite cell self-renewal is modeled ex vivo in a reserve cell assay, myoblasts treated with Nutlin-3, which increases p53 levels in the cell, fail to differentiate and instead become quiescent. Since both these Nutlin-3 effects are rescued by small interfering RNA-mediated p53 knockdown, we conclude that a tight control of p53 levels in myoblasts regulates the balance between differentiation and return to quiescence. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Embryonic stem cells in scaffold-free three-dimensional cell culture: osteogenic differentiation and bone generation.

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Handschel, Jörg; Naujoks, Christian; Depprich, Rita; Lammers, Lydia; Kübler, Norbert; Meyer, Ulrich; Wiesmann, Hans-Peter

2011-07-14

Extracorporeal formation of mineralized bone-like tissue is still an unsolved challenge in tissue engineering. Embryonic stem cells may open up new therapeutic options for the future and should be an interesting model for the analysis of fetal organogenesis. Here we describe a technique for culturing embryonic stem cells (ESCs) in the absence of artificial scaffolds which generated mineralized miromasses. Embryonic stem cells were harvested and osteogenic differentiation was stimulated by the addition of dexamethasone, ascorbic acid, and ß-glycerolphosphate (DAG). After three days of cultivation microspheres were formed. These spherical three-dimensional cell units showed a peripheral zone consisting of densely packed cell layers surrounded by minerals that were embedded in the extracellular matrix. Alizarine red staining confirmed evidence of mineralization after 10 days of DAG stimulation in the stimulated but not in the control group. Transmission electron microscopy demonstrated scorching crystallites and collagenous fibrils as early indication of bone formation. These extracellular structures resembled hydroxyl apatite-like crystals as demonstrated by distinct diffraction patterns using electron diffraction analysis. The micromass culture technique is an appropriate model to form three-dimensional bone-like micro-units without the need for an underlying scaffold. Further studies will have to show whether the technique is applicable also to pluripotent stem cells of different origin. © 2011 Handschel et al; licensee BioMed Central Ltd.

Embryonic stem cells in scaffold-free three-dimensional cell culture: osteogenic differentiation and bone generation

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Meyer Ulrich

2011-07-01

Full Text Available Abstract Extracorporeal formation of mineralized bone-like tissue is still an unsolved challenge in tissue engineering. Embryonic stem cells may open up new therapeutic options for the future and should be an interesting model for the analysis of fetal organogenesis. Here we describe a technique for culturing embryonic stem cells (ESCs in the absence of artificial scaffolds which generated mineralized miromasses. Embryonic stem cells were harvested and osteogenic differentiation was stimulated by the addition of dexamethasone, ascorbic acid, and ß-glycerolphosphate (DAG. After three days of cultivation microspheres were formed. These spherical three-dimensional cell units showed a peripheral zone consisting of densely packed cell layers surrounded by minerals that were embedded in the extracellular matrix. Alizarine red staining confirmed evidence of mineralization after 10 days of DAG stimulation in the stimulated but not in the control group. Transmission electron microscopy demonstrated scorching crystallites and collagenous fibrils as early indication of bone formation. These extracellular structures resembled hydroxyl apatite-like crystals as demonstrated by distinct diffraction patterns using electron diffraction analysis. The micromass culture technique is an appropriate model to form three-dimensional bone-like micro-units without the need for an underlying scaffold. Further studies will have to show whether the technique is applicable also to pluripotent stem cells of different origin.

Structurally-diverse, PPARγ-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells

International Nuclear Information System (INIS)

Watt, James; Schlezinger, Jennifer J.

2015-01-01

Environmental obesogens are a newly recognized category of endocrine disrupting chemicals that have been implicated in contributing to the rising rates of obesity in the United States. While obesity is typically regarded as an increase in visceral fat, adipocyte accumulation in the bone has been linked to increased fracture risk, lower bone density, and osteoporosis. Exposure to environmental toxicants that activate peroxisome proliferator activated receptor γ (PPARγ), a critical regulator of the balance of differentiation between adipogenesis and osteogenesis, may contribute to the increasing prevalence of osteoporosis. However, induction of adipogenesis and suppression of osteogenesis are separable activities of PPARγ, and ligands may selectively alter these activities. It currently is unknown whether suppression of osteogenesis is a common toxic endpoint of environmental PPARγ ligands. Using a primary mouse bone marrow culture model, we tested the hypothesis that environmental toxicants acting as PPARγ agonists divert the differentiation pathway of bone marrow-derived multipotent mesenchymal stromal cells towards adipogenesis and away from osteogenesis. The toxicants tested included the organotins tributyltin and triphenyltin, a ubiquitous phthalate metabolite (mono-(2-ethylhexyl) phthalate, MEHP), and two brominated flame retardants (tetrabromobisphenol-a, TBBPA, and mono-(2-ethylhexyl) tetrabromophthalate, METBP). All of the compounds activated PPARγ1 and 2. All compounds increased adipogenesis (lipid accumulation, Fabp4 expression) and suppressed osteogenesis (alkaline phosphatase activity, Osx expression) in mouse primary bone marrow cultures, but with different potencies and efficacies. Despite structural dissimilarities, there was a strong negative correlation between efficacies to induce adipogenesis and suppress osteogenesis, with the organotins being distinct in their exceptional ability to suppress osteogenesis. As human exposure to a mixture of

Porous tantalum coatings prepared by vacuum plasma spraying enhance bmscs osteogenic differentiation and bone regeneration in vitro and in vivo.

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Ze Tang

Full Text Available Tantalum, as a potential metallic implant biomaterial, is attracting more and more attention because of its excellent anticorrosion and biocompatibility. However, its significantly high elastic modulus and large mechanical incompatibility with bone tissue make it unsuitable for load-bearing implants. In this study, porous tantalum coatings were first successfully fabricated on titanium substrates by vacuum plasma spraying (VPS, which would exert the excellent biocompatibility of tantalum and alleviate the elastic modulus of tantalum for bone tissue. We evaluated cytocompatibility and osteogenesis activity of the porous tantalum coatings using human bone marrow stromal cells (hBMSCs and its ability to repair rabbit femur bone defects. The morphology and actin cytoskeletons of hBMSCs were observed via electron microscopy and confocal, and the cell viability, proliferation and osteogenic differentiation potential of hBMSCs were examined quantitatively by PrestoBlue assay, Ki67 immunofluorescence assay, real-time PCR technology and ALP staining. For in vivo detection, the repaired femur were evaluated by histomorphology and double fluorescence labeling 3 months postoperation. Porous tantalum coating surfaces promoted hBMSCs adhesion, proliferation, osteogenesis activity and had better osseointegration and faster new bone formation rate than titanium coating control. Our observation suggested that the porous tantalum coatings had good biocompatibility and could enhance osseoinductivity in vitro and promote new bone formation in vivo. The porous tantalum coatings prepared by VPS is a promising strategy for bone regeneration.

Recent progress in the differentiation of bone marrow derived ...

African Journals Online (AJOL)

ONOS

2010-08-09

Aug 9, 2010 ... Bone marrow mesenchymal stem cells (BMMSCs) are one of the cells found in bone marrow stromal. A large number of ..... BMMSCs and myocardial cells using biomimetic electrical ... effect ventricular remodeling after infarction. Meyern et al. ... to small sample sizes and different experimental con- ditions.

Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation

DEFF Research Database (Denmark)

Abdallah, Basem M; Haack-Sørensen, Mandana; Burns, Jorge S

2005-01-01

Human bone marrow mesenchymal stem cells (hMSC) represent a population of stem cells that are capable of differentiation into multiple lineages. However, these cells exhibit senescence-associated growth arrest and phenotypic changes during long-term in vitro culture. We have recently demonstrated...

Black rice (Oryza sativa L.) extracts induce osteoblast differentiation and protect against bone loss in ovariectomized rats.

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Jang, Woo-Seok; Seo, Cho-Rong; Jang, Hwan Hee; Song, No-Joon; Kim, Jong-Keun; Ahn, Jee-Yin; Han, Jaejoon; Seo, Woo Duck; Lee, Young Min; Park, Kye Won

2015-01-01

Osteoporosis, an age associated skeletal disease, exhibits increased adipogenesis at the expense of osteogenesis from common osteoporotic bone marrow cells. In this study, black rice (Oryza sativa L.) extracts (BRE) were identified as osteogenic inducers. BRE stimulated the alkaline phosphatase (ALP) activity in both C3H10T1/2 and primary bone marrow cells. Similarly, BRE increased mRNA expression of ALP and osterix. Oral administration of BRE in OVX rats prevented decreases in bone density and strength. By contrast, BRE inhibited adipocyte differentiation of mesenchymal C3H10T1/2 cells and prevented increases in body weight and fat mass in high fat diet fed obese mice, further suggesting the dual effects of BRE on anti-adipogenesis and pro-osteogenesis. UPLC analysis identified cyanidin-3-O-glucoside and peonidin-3-O-glucoside as main anti-adipogenic effectors but not for pro-osteogenic induction. In mechanism studies, BRE selectively stimulated Wnt-driven luciferase activities. BRE treatment also induced Wnt-specific target genes such as Axin2, WISP2, and Cyclin D1. Taken together, these data suggest that BRE is a potentially useful ingredient to protect against age related osteoporosis and diet induced obesity.

Novel strontium-doped bioactive glass nanoparticles enhance proliferation and osteogenic differentiation of human bone marrow stromal cells

Energy Technology Data Exchange (ETDEWEB)

Strobel, L. A. [University of Erlangen-Nuremberg Medical Center, Department of Plastic and Hand Surgery (Germany); Hild, N.; Mohn, D.; Stark, W. J. [ETH Zurich, Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering (Switzerland); Hoppe, A. [University of Erlangen-Nuremberg, Department of Materials Science and Engineering, Institute of Biomaterials (Germany); Gbureck, U. [University of Wuerzburg, Department for Functional Materials in Medicine and Dentistry (Germany); Horch, R. E.; Kneser, U. [University of Erlangen-Nuremberg Medical Center, Department of Plastic and Hand Surgery (Germany); Boccaccini, A. R., E-mail: aldo.boccaccini@ww.uni-erlangen.de [University of Erlangen-Nuremberg, Department of Materials Science and Engineering, Institute of Biomaterials (Germany)

2013-07-15

The present study investigates a new family of bioactive glass nanoparticles with and without Sr-doping focusing on the influence of the nanoparticles on human bone marrow stromal cells (hBMSCs) in vitro. The bioactive glass nanoparticles were fabricated by flame spray synthesis and a particle diameter of 30-35 nm was achieved. Glass nanoparticles were undoped (BG 13-93-0Sr) or doped with 5 wt% strontium (Sr) (BG 13-93-5Sr) and used at concentrations of 10 and 100 {mu}g/cm Superscript-Two (particles per culture plate area), respectively. Cells were cultured for 14 days after which the samples were analysed regarding metabolic activity and expression of various bone-specific genes. Cell growth and morphology indicated the high cytocompatibility of the nanoparticulate bioactive glass. The presence of the nanoparticles enhanced cell growth compared to the plain polystyrene control group. At a concentration of 100 {mu}g/cm Superscript-Two , Sr-doped particles led to significantly enhanced gene expression of osteocalcin, collagen type 1 and vascular endothelial growth factor. Thus, Sr-doped nanoparticles showing a dose-dependent increase of osteogenic differentiation in hBMSCs are a promising biomaterial for bone regeneration purposes.

Novel strontium-doped bioactive glass nanoparticles enhance proliferation and osteogenic differentiation of human bone marrow stromal cells

International Nuclear Information System (INIS)

Strobel, L. A.; Hild, N.; Mohn, D.; Stark, W. J.; Hoppe, A.; Gbureck, U.; Horch, R. E.; Kneser, U.; Boccaccini, A. R.

2013-01-01

The present study investigates a new family of bioactive glass nanoparticles with and without Sr-doping focusing on the influence of the nanoparticles on human bone marrow stromal cells (hBMSCs) in vitro. The bioactive glass nanoparticles were fabricated by flame spray synthesis and a particle diameter of 30–35 nm was achieved. Glass nanoparticles were undoped (BG 13-93-0Sr) or doped with 5 wt% strontium (Sr) (BG 13-93-5Sr) and used at concentrations of 10 and 100 μg/cm² (particles per culture plate area), respectively. Cells were cultured for 14 days after which the samples were analysed regarding metabolic activity and expression of various bone-specific genes. Cell growth and morphology indicated the high cytocompatibility of the nanoparticulate bioactive glass. The presence of the nanoparticles enhanced cell growth compared to the plain polystyrene control group. At a concentration of 100 μg/cm², Sr-doped particles led to significantly enhanced gene expression of osteocalcin, collagen type 1 and vascular endothelial growth factor. Thus, Sr-doped nanoparticles showing a dose-dependent increase of osteogenic differentiation in hBMSCs are a promising biomaterial for bone regeneration purposes

Novel strontium-doped bioactive glass nanoparticles enhance proliferation and osteogenic differentiation of human bone marrow stromal cells

Science.gov (United States)

Strobel, L. A.; Hild, N.; Mohn, D.; Stark, W. J.; Hoppe, A.; Gbureck, U.; Horch, R. E.; Kneser, U.; Boccaccini, A. R.

2013-07-01

The present study investigates a new family of bioactive glass nanoparticles with and without Sr-doping focusing on the influence of the nanoparticles on human bone marrow stromal cells (hBMSCs) in vitro. The bioactive glass nanoparticles were fabricated by flame spray synthesis and a particle diameter of 30-35 nm was achieved. Glass nanoparticles were undoped (BG 13-93-0Sr) or doped with 5 wt% strontium (Sr) (BG 13-93-5Sr) and used at concentrations of 10 and 100 μg/cm² (particles per culture plate area), respectively. Cells were cultured for 14 days after which the samples were analysed regarding metabolic activity and expression of various bone-specific genes. Cell growth and morphology indicated the high cytocompatibility of the nanoparticulate bioactive glass. The presence of the nanoparticles enhanced cell growth compared to the plain polystyrene control group. At a concentration of 100 μg/cm², Sr-doped particles led to significantly enhanced gene expression of osteocalcin, collagen type 1 and vascular endothelial growth factor. Thus, Sr-doped nanoparticles showing a dose-dependent increase of osteogenic differentiation in hBMSCs are a promising biomaterial for bone regeneration purposes.

Bone induction by surface-double-modified true bone ceramics in vitro and in vivo

International Nuclear Information System (INIS)

Li, Jingfeng; Chen, Liaobin; Deng, Yu; Zheng, Qixin; Guo, Xiaodong; Zou, Zhenwei; Liu, Yudong; Lan, Shenghui

2013-01-01

True bone ceramic (TBC), obtained by twice sintering fresh bovine cancellous bone at high temperatures, is an osteoconductive and bioactive bone substitute material that exhibits excellent biocompatibility with hard tissue. The authors have previously synthesized a novel BMP-2-related peptide, P24, and found that it could enhance the osteoblastic differentiation of cells. The objective of the present study was to construct a double-modified TBC via mineralization into simulated body fluid and P24 incorporation for enhanced bone formation. In vitro experiments revealed that surface mineralization-modified (SMM) TBC scaffolds demonstrated efficiency for sustained release of P24. The P24/SMM-TBC composite exhibited increased osteogenic activity by cell adhesion rate determination, MTT assay, alkaline phosphatase staining, and calcium nodule staining with alizarin red compared with SMM-TBC and TBC. In vivo studies showed that the P24/SMM-TBC composite scaffold promoted significant bone defect repair, in marked contrast to stand-alone SMM-TBC and TBC, based on the results of radiographic evaluation and histological examination. These findings indicate that SMM-TBC is a good scaffold for the controlled release of P24 and that the P24/SMM-TBC composite could improve the adhesion, proliferation and differentiation of cells and repair bone defects. The double-modified P24/SMM-TBC composite biomaterial shows potential for clinical application in bone tissue engineering. (paper)

Identification of Stages of Erythroid Differentiation in Bone Marrow and Erythrocyte Subpopulations in Blood Circulation that Are Preferentially Lost in Autoimmune Hemolytic Anemia in Mouse.

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Sreoshi Chatterjee

Full Text Available Repeated weekly injections of rat erythrocytes produced autoimmune hemolytic anemia (AIHA in C57BL/6 mice after 5-6 weeks. Using the double in vivo biotinylation (DIB technique, recently developed in our laboratory, turnover of erythrocyte cohorts of different age groups during AIHA was monitored. Results indicate a significant decline in the proportion of reticulocytes, young and intermediate age groups of erythrocytes, but a significant increase in the proportion of old erythrocytes in blood circulation. Binding of the autoantibody was relatively higher to the young erythrocytes and higher levels of intracellular reactive oxygen species (ROS were also seen in these cells. Erythropoietic activity in the bone marrows and the spleen of AIHA induced mice was examined by monitoring the relative proportion of erythroid cells at various stages of differentiation in these organs. Cells at different stages of differentiation were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71 monoclonal antibodies. Erythroid cells in bone marrow declined significantly in AIHA induced mice, erythroblast C being most affected (50% decline. Erythroblast C also recorded high intracellular ROS level along with increased levels of membrane-bound autoantibody. No such decline was observed in spleen. A model of AIHA has been proposed indicating that binding of autoantibodies may not be a sufficient condition for destruction of erythroid cells in bone marrow and in blood circulation. Last stage of erythropoietic differentiation in bone marrow and early stages of erythrocytes in blood circulation are specifically susceptible to removal in AIHA.

Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies

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Pascariello Caterina

2008-05-01

Full Text Available Abstract Background Aldehyde dehydrogenase (ALDH is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH+ cells has been addressed by one single study (Gentry et al, 2007. The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by in vitro induction of erythroid differentiation; iii detection of ALDH+ cellular subsets in bone marrow from pure red cell aplasia patients. Results In normal bone marrow, we identified three populations of cells, namely ALDH+CD34+, ALDH-CD34+ and ALDH+CD34- (median percentages were 0.52, 0.53 and 0.57, respectively. As compared to ALDH-CD34+ cells, ALDH+CD34+ cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH+CD34- population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH+CD34- cells showed a CD71bright, CD105+, CD45- phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a. Finally, ALDH+CD34- precursors were not detectable in patients with pure red cell aplasia (PRCA. Conclusion Our study, comparing surface antigen expression of

Interleukin-3 Does Not Affect the Differentiation of Mast Cells Derived from Human Bone Marrow Progenitors

Science.gov (United States)

Shimizu, Yuji; Matsumoto, Kenji; Okayama, Yoshimichi; Kentaro, Sakai; Maeno, Toshitaka; Suga, Tatsuo; Miura, Toru; Takai, Shinji; Kurabayashi, Masahiko; Saito, Hirohisa

2008-01-01

Although IL-3 is commonly used for culture of human progenitor-derived mast cells together with Stem cell factor (SCF) and IL-6, the effect of IL-3 on human mast cell differentiation has not been well elucidated. Human bone marrow CD34+ progenitors were cultured for up to 12 weeks in the presence of rhSCF and rhIL-6 either with rhIL-3 (IL-3 (+)) or without rhIL-3 (IL-3 (−)) for the initial 1-week of culture. Total cell number increased at 2 weeks in IL-3 (+), as compared to IL-3 (−), but changes in the appearance of mast cells were delayed. When IL-3 was present for the initial 1-week culture, granules looked more mature with IL-3 than without IL-3. However, tryptase and chymase contents, and surface antigen expression (CD18, CD51, CD54, and CD117) were not altered by IL-3. Surface expression and mRNA level of FcεRIα and histamine release by crosslinking of FcεRIα did not differ from one preparation to the next. GeneChip analysis revealed that no significant differences were observed between IL-3 (+) and IL-3 (−) cells either when inactivated or activated by aggregation of FcεRIα. These findings indicate that initial incubation of human bone marrow CD34+ progenitors with IL-3 does not affect the differentiation of mast cells. PMID:18214796

Naringin promotes osteogenic differentiation of bone marrow stromal cells by up-regulating Foxc2 expression via the IHH signaling pathway.

Science.gov (United States)

Lin, Fei-Xiang; Du, Shi-Xin; Liu, De-Zhong; Hu, Qin-Xiao; Yu, Guo-Yong; Wu, Chu-Cheng; Zheng, Gui-Zhou; Xie, Da; Li, Xue-Dong; Chang, Bo

2016-01-01

Naringin is an active compound extracted from Rhizoma Drynariae, and studies have revealed that naringin can promote proliferation and osteogenic differentiation of bone marrow stromal cells (BMSCs). In this study, we explored whether naringin could promote osteogenic differentiation of BMSCs by upregulating Foxc2 expression via the Indian hedgehog (IHH) signaling pathway. BMSCs were cultured in basal medium, basal medium with naringin, osteogenic induction medium, osteogenic induction medium with naringin and osteogenic induction medium with naringin in the presence of the IHH inhibitor cyclopamine (CPE). We examined cell proliferation by using a WST-8 assay, and differentiation by Alizarin Red S staining (for mineralization) and alkaline phosphatase (ALP) activity. In addition, we detected core-binding factor α1 (Cbfα1), osteocalcin (OCN), bone sialoprotein (BSP), peroxisome proliferation-activated receptor gamma 2 (PPARγ2) and Foxc2 expression by using RT-PCR. We also determined Foxc2 and IHH protein levels by western blotting. Naringin increased the mineralization of BMSCs, as shown by Alizarin red S assays, and induced ALP activity. In addition, naringin significantly increased the mRNA levels of Foxc2, Cbfα1, OCN, and BSP, while decreasing PPARγ2 mRNA levels. Furthermore, the IHH inhibitor CPE inhibited the osteogenesis-potentiating effects of naringin. Naringin increased Foxc2 and stimulated the activation of IHH, as evidenced by increased expression of proteins that were inhibited by CPE. Our findings indicate that naringin promotes osteogenic differentiation of BMSCs by up-regulating Foxc2 expression via the IHH signaling pathway.

Role of inflammation in the aging bones.

Science.gov (United States)

Abdelmagid, Samir M; Barbe, Mary F; Safadi, Fayez F

2015-02-15

Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro-inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid in the understanding of the potential role(s) of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts in relation to aging. Copyright © 2014 Elsevier Inc. All rights reserved.

Generation of insulin-producing cells from human bone marrow-derived mesenchymal stem cells: comparison of three differentiation protocols.

Science.gov (United States)

Gabr, Mahmoud M; Zakaria, Mahmoud M; Refaie, Ayman F; Khater, Sherry M; Ashamallah, Sylvia A; Ismail, Amani M; El-Badri, Nagwa; Ghoneim, Mohamed A

2014-01-01

Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs) to form insulin-producing cells (IPCs). We compared the relative efficiency of three differentiation protocols. Human bone marrow-derived MSCs (HBM-MSCs) were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol), trichostatin-A-based (two-step protocol), and β -mercaptoethanol-based (three-step protocol). At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. By immunolabeling, the proportion of generated IPCs was modest ( ≃ 3%) in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted.

Epigenetic regulation of fetal bone development and placental transfer of nutrients: progress for osteoporosis.

Science.gov (United States)

Bocheva, Georgeta; Boyadjieva, Nadka

2011-12-01

Osteoporosis is a common age-related disorder and causes acute and long-term disability and economic cost. Many factors influence the accumulation of bone minerals, including heredity, diet, physical activity, gender, endocrine functions, and risk factors such as alcohol, drug abuse, some pharmacological drugs or cigarette smoking. The pathology of bone development during intrauterine life is a factor for osteoporosis. Moreover, the placental transfer of nutrients plays an important role in the building of bones of fetuses. The importance of maternal calcium intake and vitamin D status are highlighted in this review. Various environmental factors including nutrition state or maternal stress may affect the epigenetic state of a number of genes during fetal development of bones. Histone modifications as histone hypomethylation, histone hypermethylation, hypoacetylation, etc. are involved in chromatin remodeling, known to contribute to the epigenetic landscape of chromosomes, and play roles in both fetal bone development and osteoporosis. This review will give an overview of epigenetic modulation of bone development and placental transfer of nutrients. In addition, the data from animal and human studies support the role of epigenetic modulation of calcium and vitamin D in the pathogenesis of osteoporosis. We review the evidence suggesting that various genes are involved in regulation of osteoclast formation and differentiation by osteoblasts and stem cells. Epigenetic changes in growth factors as well as cytokines play a rol in fetal bone development. On balance, the data suggest that there is a link between epigenetic changes in placental transfer of nutrients, including calcium and vitamin D, abnormal intrauterine bone development and pathogenesis of osteoporosis.

Bone marrow stromal cells on a three-dimensional bioactive fiber mesh undergo osteogenic differentiation in the absence of osteogenic media supplements: the effect of silanol groups.

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Rodrigues, Márcia T; Leonor, Isabel B; Gröen, Nathalie; Viegas, Carlos A; Dias, Isabel R; Caridade, Sofia G; Mano, João F; Gomes, Manuela E; Reis, Rui L

2014-10-01

Osteogenic differentiation is a tightly regulated process dependent on the stimuli provided by the micro-environment. Silicon-substituted materials are known to have an influence on the osteogenic phenotype of undifferentiated and bone-derived cells. This study aims to investigate the bioactivity profile as well as the mechanical properties of a blend of starch and poly-caprolactone (SPCL) polymeric fiber mesh scaffolds functionalized with silanol (Si-OH) groups as key features for bone tissue engineering strategies. The scaffolds were made from SPCL by a wet spinning technique. A calcium silicate solution was used as a non-solvent to develop an in situ functionalization with Si-OH groups in a single-step approach. We also explored the relevance of silicon incorporated in SPCL-Si scaffolds to the in vitro osteogenic process of goat bone marrow stromal cells (gBMSCs) with and without osteogenic supplements in the culture medium. We hypothesized that SPCL-Si scaffolds could act as physical and chemical millieus to induce per se the osteogenic differentiation of gBMSCs. Results show that osteogenic differentiation of gBMSCs and the production of a mineralized extracellular matrix on bioactive SPCL-Si scaffolds occur for up to 2weeks, even in the absence of osteogenic supplements in the culture medium. The omission of media supplements to induce osteogenic differentiation is a promising feature towards simplified and cost-effective cell culturing procedures of a potential bioengineered product, and concomitant translation into the clinical field. Thus, the present work demonstrates that SPCL-Si scaffolds and their intrinsic properties sustain gBMSC osteogenic features in vitro, even in the absence of osteogenic supplements to the culture medium, and show great potential for bone regeneration strategies. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Tissue-engineered bone formation using human bone marrow stromal cells and novel β-tricalcium phosphate

International Nuclear Information System (INIS)

Liu Guangpeng; Zhao Li; Cui Lei; Liu Wei; Cao Yilin

2007-01-01

In this study we investigated not only the cellular proliferation and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) on the novel β-tricalcium phosphate (β-TCP) scaffolds in vitro but also bone formation by ectopic implantation in athymic mice in vivo. The interconnected porous β-TCP scaffolds with pores of 300-500 μm in size were prepared by the polymeric sponge method. β-TCP scaffolds with the dimension of 3 mm x 3 mm x 3 mm were combined with hBMSCs, and incubated with (+) or without (-) osteogenic medium in vitro. Cell proliferation and osteogenic differentiation on the scaffolds were evaluated by scanning electron microscopy (SEM) observation, MTT assay, alkaline phosphatase (ALP) activity and osteocalcin (OCN) content measurement. SEM observation showed that hBMSCs attached well on the scaffolds and proliferated rapidly. No significant difference in the MTT assay could be detected between the two groups, but the ALP activity and OCN content of scaffolds (+) were much higher than those of the scaffolds (-) (p < 0.05). These results indicated that the novel porous β-TCP scaffolds can support the proliferation and subsequent osteogenic differentiation of hBMSCs in vitro. After being cultured in vitro for 14 days, the scaffolds (+) and (-) were implanted into subcutaneous sites of athymic mice. In β-TCP scaffolds (+), woven bone formed after 4 weeks of implantation and osteogenesis progressed with time. Furthermore, tissue-engineered bone could be found at 8 weeks, and remodeled lamellar bone was also observed at 12 weeks. However, no bone formation could be found in β-TCP scaffolds (-) at each time point checked. The above findings illustrate that the novel porous β-TCP scaffolds developed in this work have prominent osteoconductive activity and the potential for applications in bone tissue engineering

Tissue-engineered bone formation using human bone marrow stromal cells and novel {beta}-tricalcium phosphate

Energy Technology Data Exchange (ETDEWEB)

Liu Guangpeng [National Tissue Engineering Research and Development Center, Shanghai 200235 (China); Zhao Li [National Tissue Engineering Research and Development Center, Shanghai 200235 (China); Cui Lei [National Tissue Engineering Research and Development Center, Shanghai 200235 (China); Liu Wei [National Tissue Engineering Research and Development Center, Shanghai 200235 (China); Cao Yilin [National Tissue Engineering Research and Development Center, Shanghai 200235 (China)

2007-06-01

In this study we investigated not only the cellular proliferation and osteogenic differentiation of human bone marrow stromal cells (hBMSCs) on the novel {beta}-tricalcium phosphate ({beta}-TCP) scaffolds in vitro but also bone formation by ectopic implantation in athymic mice in vivo. The interconnected porous {beta}-TCP scaffolds with pores of 300-500 {mu}m in size were prepared by the polymeric sponge method. {beta}-TCP scaffolds with the dimension of 3 mm x 3 mm x 3 mm were combined with hBMSCs, and incubated with (+) or without (-) osteogenic medium in vitro. Cell proliferation and osteogenic differentiation on the scaffolds were evaluated by scanning electron microscopy (SEM) observation, MTT assay, alkaline phosphatase (ALP) activity and osteocalcin (OCN) content measurement. SEM observation showed that hBMSCs attached well on the scaffolds and proliferated rapidly. No significant difference in the MTT assay could be detected between the two groups, but the ALP activity and OCN content of scaffolds (+) were much higher than those of the scaffolds (-) (p < 0.05). These results indicated that the novel porous {beta}-TCP scaffolds can support the proliferation and subsequent osteogenic differentiation of hBMSCs in vitro. After being cultured in vitro for 14 days, the scaffolds (+) and (-) were implanted into subcutaneous sites of athymic mice. In {beta}-TCP scaffolds (+), woven bone formed after 4 weeks of implantation and osteogenesis progressed with time. Furthermore, tissue-engineered bone could be found at 8 weeks, and remodeled lamellar bone was also observed at 12 weeks. However, no bone formation could be found in {beta}-TCP scaffolds (-) at each time point checked. The above findings illustrate that the novel porous {beta}-TCP scaffolds developed in this work have prominent osteoconductive activity and the potential for applications in bone tissue engineering.

Promoting effect of small molecules in cardiomyogenic and neurogenic differentiation of rat bone marrow-derived mesenchymal stem cells

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Khanabdali R

2015-12-01

Full Text Available Ramin Khanabdali,1 Anbarieh Saadat,1 Maizatul Fazilah,1 Khairul Fidaa’ Khairul Bazli,1 Rida-e-Maria Qazi,2 Ramla Sana Khalid,2 Durriyyah Sharifah Hasan Adli,1 Soheil Zorofchian Moghadamtousi,1 Nadia Naeem,2 Irfan Khan,2 Asmat Salim,2 ShamsulAzlin Ahmad Shamsuddin,1 Gokula Mohan1 1Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia; 2Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan Abstract: Small molecules, growth factors, and cytokines have been used to induce differentiation of stem cells into different lineages. Similarly, demethylating agents can trigger differentiation in adult stem cells. Here, we investigated the in vitro differentiation of rat bone marrow mesenchymal stem cells (MSCs into cardiomyocytes by a demethylating agent, zebularine, as well as neuronal-like cells by β-mercaptoethanol in a growth factor or cytokines-free media. Isolated bone marrow-derived MSCs cultured in Dulbecco’s Modified Eagle’s Medium exhibited a fibroblast-like morphology. These cells expressed positive markers for CD29, CD44, and CD117 and were negative for CD34 and CD45. After treatment with 1 µM zebularine for 24 hours, the MSCs formed myotube-like structures after 10 days in culture. Expression of cardiac-specific genes showed that treated MSCs expressed significantly higher levels of cardiac troponin-T, Nkx2.5, and GATA-4 compared with untreated cells. Immunocytochemical analysis showed that differentiated cells also expressed cardiac proteins, GATA-4, Nkx 2.5, and cardiac troponin-T. For neuronal differentiation, MSCs were treated with 1 and 10 mM β-mercaptoethanol overnight for 3 hours in complete and serum-free Dulbecco’s Modified Eagle’s Medium, respectively. Following overnight treatment, neuron-like cells with axonal and dendritic-like projections originating from the

Biomaterials and bone mechanotransduction

Science.gov (United States)

Sikavitsas, V. I.; Temenoff, J. S.; Mikos, A. G.; McIntire, L. V. (Principal Investigator)

2001-01-01

Bone is an extremely complex tissue that provides many essential functions in the body. Bone tissue engineering holds great promise in providing strategies that will result in complete regeneration of bone and restoration of its function. Currently, such strategies include the transplantation of highly porous scaffolds seeded with cells. Prior to transplantation the seeded cells are cultured in vitro in order for the cells to proliferate, differentiate and generate extracellular matrix. Factors that can affect cellular function include the cell-biomaterial interaction, as well as the biochemical and the mechanical environment. To optimize culture conditions, good understanding of these parameters is necessary. The new developments in bone biology, bone cell mechanotransduction, and cell-surface interactions are reviewed here to demonstrate that bone mechanotransduction is strongly influenced by the biomaterial properties.

Dense bone - too much bone: Radiological considerations and differential diagnosis. Pt. 2

Energy Technology Data Exchange (ETDEWEB)

Jacobson, H.G.

1985-02-01

In conclusion, the attempt has been made to demonstrate that three major forms of new bone formation exist: reactive, neoplastic, and the newborn or relative skeletal sclerosis in congenital (developmental) disorders. A classification of skeletal disorders has been presented and four major groups have been selected from the nine categories in this classification. These are: congenital-developmental, metabolic and endocrine, benign neoplasms and malignant neoplasms. In all four categories a large group of entities which may present with new bone (sclerosis) are listed and are discussed in some, but limited, detail. A number of these entities in each of the four categories are illustrated. Some difficulty is encountered in considering the mechanisms for the production of bony sclerosis in the group of congenital-developmental disorders. In such entities as osteopetrosis, the overproduction of cartilage cords and subsequent excessive mineralization is known to be responsible for the dense bone. However, in various skeletal dysplasias (e.g. pyknodysostosis, van Bucherm disease), the exact mechanism for the development of the diffuse sclerotic process is not clearly understood. In the metabolic and endocrine category, the situation as to mechanism is less unclear in considering the reason for the development of bony sclerosis. Yet even in evaluating disorders such as renal osteodystrophy, the reactive bony sclerosis in the presence of secondary hyperparathyroidism and osteomalacia is a source of speculation with no definite proof, as yet.

Postural Balance in Women with Osteoporosis and Effective Factors

OpenAIRE

Duygu Ünlüsoy; Ece Aydoğ; İhsan Ünlüsoy

2011-01-01

Introduction: The most common cause of mortality and morbidity among osteoporotic individuals is bone fracture which in many cases is a direct result of falls. Individual factors contributing to the risk of fall are poor postural balance and lack of muscle strength. Our aims were to assess postural dynamic balance in osteoporotic women and to describe the effective factors on the balance performance. Methods: Twenty osteoporotic women with kyphosis, 50 osteoporotic women without kyph...

Suppressed bone remodeling in black bears conserves energy and bone mass during hibernation.

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McGee-Lawrence, Meghan; Buckendahl, Patricia; Carpenter, Caren; Henriksen, Kim; Vaughan, Michael; Donahue, Seth

2015-07-01

Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results. However, previous studies used serum markers of bone remodeling that are known to accumulate with decreased renal function, which bears have during hibernation. Therefore, we measured serum bone remodeling markers (BSALP and TRACP) that do not accumulate with decreased renal function, in addition to the concentrations of serum calcium and hormones involved in regulating bone remodeling in hibernating and active bears. Bone resorption and formation markers were decreased during hibernation compared with when bears were physically active, and these findings were supported by histomorphometric analyses of bone biopsies. The serum concentration of cocaine and amphetamine regulated transcript (CART), a hormone known to reduce bone resorption, was 15-fold higher during hibernation. Serum calcium concentration was unchanged between hibernation and non-hibernation seasons. Suppressed and balanced bone resorption and formation in hibernating bears contributes to energy conservation, eucalcemia and the preservation of bone mass and strength, allowing bears to survive prolonged periods of extreme environmental conditions, nutritional deprivation and anuria. © 2015. Published by The Company of Biologists Ltd.

A grape-enriched diet increases bone calcium retention and cortical bone properties in ovariectomized rats.

Science.gov (United States)

Hohman, Emily E; Weaver, Connie M

2015-02-01

Grapes and their associated phytochemicals have been investigated for beneficial effects on cardiovascular health, cancer prevention, and other chronic diseases, but the effect of grape consumption on bone health has not been fully determined. We previously found short-term benefits of grape products on reducing bone turnover in ovariectomized rats. The objective of this study was to determine the long-term benefits of a grape-enriched diet on bone in ovariectomized rats. Rats were ovariectomized at 3 mo of age and were administered a single dose of (45)Ca to prelabel bones at 4 mo of age. After a 1-mo equilibration period, baseline urinary (45)Ca excretion was determined. Rats (n = 22/group) were then randomly assigned to a modified AIN93M diet containing 25% freeze-dried grape powder or to a control diet for 8 wk. Urinary (45)Ca excretion was monitored throughout the study to determine changes in bone (45)Ca retention. Calcium balance was assessed after 1 and 8 wk of consuming the experimental diets, and a calcium kinetic study was performed at 8 wk. After 8 wk, femurs were collected for micro-computed tomographic imaging, 3-point bending, and reference point indentation. Rats fed the grape-enriched diet had 44% greater net bone calcium retention than did rats fed the control diet. There were no differences in calcium balance due to diet at either week 1 or week 8, but there was a significant increase in net calcium absorption (10.6%) and retention (5.7%) from week 1 to week 8 in the grape-enriched diet group only. Grape-enriched diet-fed rats had 3% greater cortical thickness and 11% greater breaking strength. There were no differences in femur bone mineral density, trabecular microarchitecture, or reference point indentation variables due to diet. This study of ovariectomized rats indicates that the consumption of grape products may improve calcium utilization and suppress bone turnover, resulting in improvements in bone quality. © 2015 American Society for

Promotion of osteogenic differentiation of stem cells and increase of bone-bonding ability in vivo using urease-treated titanium coated with calcium phosphate and gelatin

Science.gov (United States)

Huang, Zhong-Ming; Qi, Yi-Ying; Du, Shao-Hua; Feng, Gang; Unuma, Hidero; Yan, Wei-Qi

2013-10-01

Because of its excellent biocompatibility and low allergenicity, titanium has been widely used for bone replacement and tissue engineering. To produce a desirable composite with enhanced bone response and mechanical strength, in this study bioactive calcium phosphate (CaP) and gelatin composites were coated onto titanium (Ti) via a novel urease technique. The cellular responses to the CaP/gelatin/Ti (CaP/gel/Ti) and bone bonding ability were evaluated with proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) on CaP/gel/Ti and CaP/Ti in vitro. The results showed that the optical density values, alkaline phosphatase expression and genes expression of MSCs on CaP/gel/Ti were similar to those on CaP/Ti, yet significantly higher than those on pure Ti (p layer. An interfacial layer, containing Ti, Ca and P, was found to form at the interface between bone and the implant on all three groups by EDS analysis. However, the content of Ca, P in the surface of CaP/gel/Ti implants was more than in the other two groups at each time point. The CaP/gel/Ti modified by the urease method was not only beneficial for MSCs proliferation and osteogenic differentiation, but also favorable for bone bonding ability on Ti implants in vivo, suggesting that Ti functionalized with CaP and gelatin might have a great potential in clinical joint replacement or dental implants.

Musculoskeletal Strength, Balance Performance, and Self-Efficacy in Elderly Ving Tsun Chinese Martial Art Practitioners: Implications for Fall Prevention

Science.gov (United States)

Fong, Shirley S. M.; Ng, Shamay S. M.; Liu, Karen P. Y.; Pang, Marco Y. C.; Lee, H. W.; Chung, Joanne W. Y.; Lam, Priscillia L.; Guo, X.

2014-01-01

Objectives. To (1) compare the bone strength, lower limb muscular strength, functional balance performance, and balance self-efficacy between Ving Tsun (VT) martial art practitioners and nonpractitioners and (2) identify the associations between lower limb muscular strength, functional balance performance, and balance self-efficacy among the VT-trained participants. Methods. Thirty-five VT practitioners (mean age ± SD = 62.7 ± 13.3 years) and 49 nonpractitioners (mean age ± SD = 65.9 ± 10.5 years) participated in the study. The bone strength of the distal radius, lower limb muscular strength, functional balance performance, and balance self-efficacy were assessed using an ultrasound bone sonometer, the five times sit-to-stand test (FTSTS), the Berg balance scale (BBS), and the Chinese version of the activities-specific balance confidence scale, respectively. A multivariate analysis of covariance was performed to compare all the outcome variables between the two groups. Results. Elderly VT practitioners had higher radial bone strength on the dominant side (P < 0.05), greater lower limb muscular strength (P = 0.001), better functional balance performance (P = 0.003), and greater balance confidence (P < 0.001) than the nonpractitioners. Additionally, only the FTSTS time revealed a significant association with the BBS score (r = −0.575,  P = 0.013). Conclusions. VT may be a suitable health-maintenance exercise for the elderly. Our findings may inspire the development of VT fall-prevention exercises for the community-dwelling healthy elderly. PMID:25530782

Musculoskeletal Strength, Balance Performance, and Self-Efficacy in Elderly Ving Tsun Chinese Martial Art Practitioners: Implications for Fall Prevention

Directory of Open Access Journals (Sweden)

Shirley S. M. Fong

2014-01-01

Full Text Available Objectives. To (1 compare the bone strength, lower limb muscular strength, functional balance performance, and balance self-efficacy between Ving Tsun (VT martial art practitioners and nonpractitioners and (2 identify the associations between lower limb muscular strength, functional balance performance, and balance self-efficacy among the VT-trained participants. Methods. Thirty-five VT practitioners (mean age ± SD = 62.7 ± 13.3 years and 49 nonpractitioners (mean age ± SD = 65.9 ± 10.5 years participated in the study. The bone strength of the distal radius, lower limb muscular strength, functional balance performance, and balance self-efficacy were assessed using an ultrasound bone sonometer, the five times sit-to-stand test (FTSTS, the Berg balance scale (BBS, and the Chinese version of the activities-specific balance confidence scale, respectively. A multivariate analysis of covariance was performed to compare all the outcome variables between the two groups. Results. Elderly VT practitioners had higher radial bone strength on the dominant side (P<0.05, greater lower limb muscular strength (P=0.001, better functional balance performance (P=0.003, and greater balance confidence (P<0.001 than the nonpractitioners. Additionally, only the FTSTS time revealed a significant association with the BBS score (r=-0.575, P=0.013. Conclusions. VT may be a suitable health-maintenance exercise for the elderly. Our findings may inspire the development of VT fall-prevention exercises for the community-dwelling healthy elderly.

Musculoskeletal strength, balance performance, and self-efficacy in elderly ving tsun chinese martial art practitioners: implications for fall prevention.

Science.gov (United States)

Fong, Shirley S M; Ng, Shamay S M; Liu, Karen P Y; Pang, Marco Y C; Lee, H W; Chung, Joanne W Y; Lam, Priscillia L; Guo, X

2014-01-01

Objectives. To (1) compare the bone strength, lower limb muscular strength, functional balance performance, and balance self-efficacy between Ving Tsun (VT) martial art practitioners and nonpractitioners and (2) identify the associations between lower limb muscular strength, functional balance performance, and balance self-efficacy among the VT-trained participants. Methods. Thirty-five VT practitioners (mean age ± SD = 62.7 ± 13.3 years) and 49 nonpractitioners (mean age ± SD = 65.9 ± 10.5 years) participated in the study. The bone strength of the distal radius, lower limb muscular strength, functional balance performance, and balance self-efficacy were assessed using an ultrasound bone sonometer, the five times sit-to-stand test (FTSTS), the Berg balance scale (BBS), and the Chinese version of the activities-specific balance confidence scale, respectively. A multivariate analysis of covariance was performed to compare all the outcome variables between the two groups. Results. Elderly VT practitioners had higher radial bone strength on the dominant side (P < 0.05), greater lower limb muscular strength (P = 0.001), better functional balance performance (P = 0.003), and greater balance confidence (P < 0.001) than the nonpractitioners. Additionally, only the FTSTS time revealed a significant association with the BBS score (r = -0.575,  P = 0.013). Conclusions. VT may be a suitable health-maintenance exercise for the elderly. Our findings may inspire the development of VT fall-prevention exercises for the community-dwelling healthy elderly.

Differential growth responses to water balance of coexisting deciduous tree species are linked to wood density in a Bolivian tropical dry forest.

Science.gov (United States)

Mendivelso, Hooz A; Camarero, J Julio; Royo Obregón, Oriol; Gutiérrez, Emilia; Toledo, Marisol

2013-01-01

A seasonal period of water deficit characterizes tropical dry forests (TDFs). There, sympatric tree species exhibit a diversity of growth rates, functional traits, and responses to drought, suggesting that each species may possess different strategies to grow under different conditions of water availability. The evaluation of the long-term growth responses to changes in the soil water balance should provide an understanding of how and when coexisting tree species respond to water deficit in TDFs. Furthermore, such differential growth responses may be linked to functional traits related to water storage and conductance. We used dendrochronology and climate data to retrospectively assess how the radial growth of seven coexisting deciduous tree species responded to the seasonal soil water balance in a Bolivian TDF. Linear mixed-effects models were used to quantify the relationships between basal area increment and seasonal water balance. We related these relationships with wood density and sapwood production to assess if they affect the growth responses to climate. The growth of all species responded positively to water balance during the wet season, but such responses differed among species as a function of their wood density. For instance, species with a strong growth response to water availability averaged a low wood density which may facilitate the storage of water in the stem. By contrast, species with very dense wood were those whose growth was less sensitive to water availability. Coexisting tree species thus show differential growth responses to changes in soil water balance during the wet season. Our findings also provide a link between wood density, a trait related to the ability of trees to store water in the stem, and wood formation in response to water availability.

Experimental variation of the level and the ratio of angiogenic and osteogenic signaling affects the spatiotemporal expression of bone-specific markers and organization of bone formation in ectopic sites.

Science.gov (United States)

Moser, Norman; Goldstein, Jan; Kauffmann, Phillip; Epple, Matthias; Schliephake, Henning

2018-04-01

The aim of the present study was to test the hypothesis that the ratio of angiogenic and osteogenic signaling affects ectopic bone formation when delivered in different amounts. Porous composite PDLLA/CaCO 3 scaffolds were loaded with rhBMP2 and rhVEGF in different dosage combinations and implanted into the gluteal muscles of 120 adult male Wistar rats. Bone formation and expression of alkaline phosphatase and Runx2 were quantified by histomorphometry. Spatial distribution across the scaffolds was assessed by using a grid that discriminated between the periphery and center of the scaffolds. The evaluation showed that the combined delivery of bone morphogenetic protein BMP2 and VEGF in different dosage combinations did not enhance the overall quantity of ectopic bone formation compared to the delivery of BMP2 alone. The addition of VEGF generally upregulated Runx2 after 4 weeks, which may have retarded terminal osteogenic differentiation. However, slow combined delivery of 1.5-2.0 μg BMP2 combined with 50 ng VEGF165 over a period of 5 weeks supported a more even distribution of bone formation across the implanted scaffolds whereas higher amounts of VEGF did not elicit this effect. The findings suggest that structural organization rather than the quantity of ectopic bone formation is affected by the dosage and the ratio of BMP2 and VEGF levels at the observed intervals. The development of carriers for dual growth factor delivery has to take into account the necessity to carefully balance the ratio of growth release.

Repression of COUP-TFI Improves Bone Marrow-Derived Mesenchymal Stem Cell Differentiation into Insulin-Producing Cells

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Tao Zhang

2017-09-01

Full Text Available Identifying molecular mechanisms that regulate insulin expression in bone marrow-derived mesenchymal stem cells (bmMSCs can provide clues on how to stimulate the differentiation of bmMSCs into insulin-producing cells (IPCs, which can be used as a therapeutic approach against type 1 diabetes (T1D. As repression factors may inhibit differentiation, the efficiency of this process is insufficient for cell transplantation. In this study, we used the mouse insulin 2 (Ins2 promoter sequence and performed a DNA affinity precipitation assay combined with liquid chromatography-mass spectrometry to identify the transcription factor, chicken ovalbumin upstream promoter transcriptional factor I (COUP-TFI. Functionally, bmMSCs were reprogrammed into IPCs via COUP-TFI suppression and MafA overexpression. The differentiated cells expressed higher levels of genes specific for islet endocrine cells, and they released C-peptide and insulin in response to glucose stimulation. Transplantation of IPCs into streptozotocin-induced diabetic mice caused a reduction in hyperglycemia. Mechanistically, COUP-TFI bound to the DR1 (direct repeats with 1 spacer element in the Ins2 promoter, thereby negatively regulating promoter activity. Taken together, the data provide a novel mechanism by which COUP-TFI acts as a negative regulator in the Ins2 promoter. The differentiation of bmMSCs into IPCs could be improved by knockdown of COUP-TFI, which may provide a novel stem cell-based therapy for T1D. Keywords: siRNAs, differentiation, stem cell transplantation, diabetes, mesenchymal stem cells

Anti-osteoporotic activity of harpagide by regulation of bone formation in osteoblast cell culture and ovariectomy-induced bone loss mouse models.

Science.gov (United States)

Chung, Hwa-Jin; Kyung Kim, Won; Joo Park, Hyen; Cho, Lan; Kim, Me-Riong; Kim, Min Jeong; Shin, Joon-Shik; Ho Lee, Jin; Ha, In-Hyuk; Kook Lee, Sang

2016-02-17

Harpagide, an iridoid glucoside, is a constituent of the root of Harpagophytum procumbens var. sublobatum (Engl.) Stapf, Devil's claw which has been used in patients with osteoarthritis (OA). In the present study, we investigated the anti-osteoporotic potential of harpagide and its underlying mechanism of action in in vitro cell culture and in vivo bone loss animal models. Harpagide was obtained from the alkalic hydrolysis of harpagoside, a major constituent of H. procumbens var. sublobatum Analysis of biomarkers for bone formation in osteoblastic MC3T3-E1 cells and bone resorption in osteoclast cells derived from mouse bone marrow cells was performed to evaluate the mechanism of action. The protective activity of harpagide against bone loss was also evaluated in ovariectomized (OVX) mouse model. Harpagide improved bone properties by stimulating the process of differentiation and maturation of osteoblast cells and suppressing the process of RANKL-induced differentiation of osteoclast cells. In OVX-induced bone loss mouse model, oral administration of harpagide significantly improved recovery of bone mineral density, trabecular bone volume, and trabecular number in the femur. Harpagide also prevented increase of trabecular separation and structure model index induced by OVX. Harpagide effectively inhibited the serum levels of biochemical markers of bone loss, including alkaline phosphatase, osteocalcin, C-terminal telopeptide, and tartrate-resistant acid phosphatase. Taken together, the present study demonstrates that harpagide has a potential for prevention of bone loss in OVX mice by regulating the stimulation of osteoblast differentiation and the suppression of osteoclast formation. Therefore, these findings suggest that harpagide might serve as a bioactive compound derived from H. procumbens var. sublobatum for improvement of age-dependent bone destruction disease. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Salicortin inhibits osteoclast differentiation and bone resorption by down-regulating JNK and NF-κB/NFATc1 signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Nie, Shaobo [Department of Orthopaedics, PLA General Hospital, Beijing 100853 (China); Xu, Jiawei [Department of Orthopaedics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China); Zhang, Chenghua [Department of Orthopaedics, Changle County Hospital of Traditional Chinese Medicine, Weifang 262400 (China); Xu, Chen [Department of Orthopaedics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China); Liu, Ming, E-mail: ming_li4717@sina.com [Department of Orthopaedics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China); Yu, Degang, E-mail: ydg163@126.com [Department of Orthopaedics, Shanghai Ninth People' s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011 (China)

2016-01-29

Receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation, and survival. Salicortin is a phenolic glycoside that has been isolated from many plants such as Populus and Salix species, and has been shown to have anti-amnesic and anti-adipogenic effects. In this study, we investigated the effect of salicortin on RANKL-induced osteoclasts formation, bone resorption, and activation of osteoclast-related signaling pathways. Salicortin suppressed RANKL-induced osteoclastogenesis in bone marrow macrophage cultures in a dose-dependent manner, and inhibited osteoclastic bone resorption activity without any cytotoxicity. Salicortin inhibited RANKL-induced c-Jun N-terminal kinase and NF-κB activation, concomitant with retarded IκBα phosphorylation and inhibition of p65 nuclear translocation, leading to impaired transcription of nuclear factor of activated T cells c1 (NFATc1) and expression of osteoclastic-specific genes. Taken together, our findings demonstrate that salicortin inhibits NF-κB and NFATc1 activation, leading to attenuation of osteoclastogenesis and bone resorption. Thus, salicortin may be of interest in developments of treatment for osteoclast related diseases. - Highlights: • Salicortin suppresses osteoclastogenesis in vitro. • Salicortin impairs the JNK and NF-κB/NFATc1 signaling pathway. • Salicortin may be of interest in developments of osteoporosis treatment.

Salicortin inhibits osteoclast differentiation and bone resorption by down-regulating JNK and NF-κB/NFATc1 signaling pathways

International Nuclear Information System (INIS)

Nie, Shaobo; Xu, Jiawei; Zhang, Chenghua; Xu, Chen; Liu, Ming; Yu, Degang

2016-01-01

Receptor activator of nuclear factor (NF)-κB ligand (RANKL)-activated signaling is essential for osteoclast differentiation, activation, and survival. Salicortin is a phenolic glycoside that has been isolated from many plants such as Populus and Salix species, and has been shown to have anti-amnesic and anti-adipogenic effects. In this study, we investigated the effect of salicortin on RANKL-induced osteoclasts formation, bone resorption, and activation of osteoclast-related signaling pathways. Salicortin suppressed RANKL-induced osteoclastogenesis in bone marrow macrophage cultures in a dose-dependent manner, and inhibited osteoclastic bone resorption activity without any cytotoxicity. Salicortin inhibited RANKL-induced c-Jun N-terminal kinase and NF-κB activation, concomitant with retarded IκBα phosphorylation and inhibition of p65 nuclear translocation, leading to impaired transcription of nuclear factor of activated T cells c1 (NFATc1) and expression of osteoclastic-specific genes. Taken together, our findings demonstrate that salicortin inhibits NF-κB and NFATc1 activation, leading to attenuation of osteoclastogenesis and bone resorption. Thus, salicortin may be of interest in developments of treatment for osteoclast related diseases. - Highlights: • Salicortin suppresses osteoclastogenesis in vitro. • Salicortin impairs the JNK and NF-κB/NFATc1 signaling pathway. • Salicortin may be of interest in developments of osteoporosis treatment.

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

Osteoblast recruitment routes in human cancellous bone remodeling

DEFF Research Database (Denmark)

Kristensen, Helene Bjørg; Andersen, Thomas Levin; Marcussen, Niels

2014-01-01

It is commonly proposed that bone forming osteoblasts recruited during bone remodeling originate from bone marrow perivascular cells, bone remodeling compartment canopy cells, or bone lining cells. However, an assessment of osteoblast recruitment during adult human cancellous bone remodeling...... is lacking. We addressed this question by quantifying cell densities, cell proliferation, osteoblast differentiation markers, and capillaries in human iliac crest biopsy specimens. We found that recruitment occurs on both reversal and bone-forming surfaces, as shown by the cell density and osterix levels...

Physiological role of growth factors and bone morphogenetic proteins in osteogenesis and bone fracture healing: а review

Directory of Open Access Journals (Sweden)

S. Sagalovsky

2015-01-01

Full Text Available The repair of large bone defects remains a major clinical orthopedic challenge. Bone regeneration and fracture healing is a complex physiological mechanisms regulated by a large number of biologically active molecules. Multiple factors regulate this cascade of molecular events, which affects different stages in the osteoblast and chondroblast lineage during such processes as migration, proliferation, chemotaxis, differentiation, inhibition, and extracellular protein synthesis. A recent review has focused on the mechanisms by which growth and differentiation factors regulate the fracture healing process. Rapid progress in skeletal cellular and molecular biology has led to identification of many signaling molecules associated with formation of skeletal tissues, including a large family of growth factors (transforming growth factor-β and bone morphogenetic proteins, fibroblast growth factor, insulin-like growth factor, vascular endothelial growth factor, platelet-derived growth factor, cytokines and interleukins. There is increasing evidence indicating that they are critical regulators of cellular proliferation, differentiation, extracellular matrix biosynthesis and bone mineralization. A clear understanding of cellular and molecular pathways involved in fracture healing is not only critical for improvement of fracture treatments, but it may also enhance further our knowledge of mechanisms involved in skeletal growth and repair, as well as mechanisms of aging. This suggests that, in the future, they may play a major role in the treatment of bone disease and fracture repair.

Bone island (enostosis): current concept - a review

International Nuclear Information System (INIS)

Greenspan, A.

1995-01-01

A bone island can be virtually diagnosed based on its characteristic clinical and radiologic features. Typically asymptomatic, the lesion is usually an incidental finding, with a preference for the pelvis, femur, and other long bones, although it may be found anywhere in the skeleton, including the spine. Plain radiography reveals a homogeneously dense, sclerotic focus in the cancellous bone with distinctive radiating bony streaks (''thorny radiation'') that blend with the trabeculae of the host bone, creating a feathered or brush-like border. On CT scan, a bone island appears as a low-attenuation focus, and on MRI sequences it shows low signal intensity like cortical bone. A distinguishing feature of bone islands is that they are usually ''cold'' on skeletal scintigraphy. Thus, bone scan has been and continues to be the means of differentiating bone islands from the more aggressive entities. However, reports of histologically confirmed bone islands that were scintigraphically active have raised a note of caution about relying on this modality in the differential consideration of lesions otherwise characteristic of bone islands. Guides to the correct diagnosis should be looked for in the individual clinical situation and in the morphologic features of the lesion on plain radiography, CT, and MRI, without regard to the lesion's activity on bone scan. If such a lesion, however, is symptomatic and ''hot'' on scintigraphy, it demands close observation with follow-up imaging studies. (orig./VHE)

Using Proteomics to 1) Identify the Bone Marrow Homing Receptors Expressed on Human Hematopoietic Stem Cells and 2) Elucidate Critical Signaling Pathways Responsible for the Blockage of Hematopoietic Differentiation in Leukemia

KAUST Repository

Chin, Chee J.

2011-01-01

Successful hematopoiesis requires the trafficking of hematopoietic stem/progenitor cells (HSPCs) to their bone marrow (BM) niche, where they can differentiate to produce all blood lineages. Leukemia arises when there is a blockage of differentiation

Pleiotrophin commits human bone marrow mesenchymal stromal cells towards hypertrophy during chondrogenesis.

Science.gov (United States)

Bouderlique, Thibault; Henault, Emilie; Lebouvier, Angelique; Frescaline, Guilhem; Bierling, Phillipe; Rouard, Helene; Courty, José; Albanese, Patricia; Chevallier, Nathalie

2014-01-01

Pleiotrophin (PTN) is a growth factor present in the extracellular matrix of the growth plate during bone development and in the callus during bone healing. Bone healing is a complicated process that recapitulates endochondral bone development and involves many cell types. Among those cells, mesenchymal stromal cells (MSC) are able to differentiate toward chondrogenic and osteoblastic lineages. We aimed to determine PTN effects on differentiation properties of human bone marrow stromal cells (hBMSC) under chondrogenic induction using histological analysis and quantitative reverse transcription polymerase chain reaction. PTN dramatically potentiated chondrogenic differentiation as indicated by a strong increase of collagen 2 protein, and cartilage-related gene expression. Moreover, PTN increased transcription of hypertrophic chondrocyte markers such as MMP13, collagen 10 and alkaline phosphatase and enhanced calcification and the content of collagen 10 protein. These effects are dependent on PTN receptors signaling and PI3 K pathway activation. These data suggest a new role of PTN in bone regeneration as an inducer of hypertrophy during chondrogenic differentiation of hBMSC.

Pleiotrophin commits human bone marrow mesenchymal stromal cells towards hypertrophy during chondrogenesis.

Directory of Open Access Journals (Sweden)

Thibault Bouderlique

Full Text Available Pleiotrophin (PTN is a growth factor present in the extracellular matrix of the growth plate during bone development and in the callus during bone healing. Bone healing is a complicated process that recapitulates endochondral bone development and involves many cell types. Among those cells, mesenchymal stromal cells (MSC are able to differentiate toward chondrogenic and osteoblastic lineages. We aimed to determine PTN effects on differentiation properties of human bone marrow stromal cells (hBMSC under chondrogenic induction using histological analysis and quantitative reverse transcription polymerase chain reaction. PTN dramatically potentiated chondrogenic differentiation as indicated by a strong increase of collagen 2 protein, and cartilage-related gene expression. Moreover, PTN increased transcription of hypertrophic chondrocyte markers such as MMP13, collagen 10 and alkaline phosphatase and enhanced calcification and the content of collagen 10 protein. These effects are dependent on PTN receptors signaling and PI3 K pathway activation. These data suggest a new role of PTN in bone regeneration as an inducer of hypertrophy during chondrogenic differentiation of hBMSC.

Inhibition of histone acetylation as a tool in bone tissue engineering

NARCIS (Netherlands)

de Boer, Jan; Licht, R.; Bongers, Marloes; van der Klundert, Tessa; Arends, Roel; van Blitterswijk, Clemens

2006-01-01

Our approach to bone tissue engineering is the in vitro expansion and osteogenic differentiation of bone marrow–derived human mesenchymal stem cells (hMSCs) and their subsequent implantation on porous ceramic materials. Current osteogenic differentiation protocols use dexamethasone to initiate the

Generation of Insulin-Producing Cells from Human Bone Marrow-Derived Mesenchymal Stem Cells: Comparison of Three Differentiation Protocols

Directory of Open Access Journals (Sweden)

Mahmoud M. Gabr

2014-01-01

Full Text Available Introduction. Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs to form insulin-producing cells (IPCs. We compared the relative efficiency of three differentiation protocols. Methods. Human bone marrow-derived MSCs (HBM-MSCs were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol, trichostatin-A-based (two-step protocol, and β-mercaptoethanol-based (three-step protocol. At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. Results. By immunolabeling, the proportion of generated IPCs was modest (≃3% in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. Conclusion. The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted.

Non-viral gene therapy for bone tissue engineering

NARCIS (Netherlands)

Wegman, F.

2013-01-01

In bone tissue engineering bone morphogentic protein-2 (BMP-2) is one of the most commonly used growth factors. It induces stem cells to differentiate into the osteogenic lineage to form new bone. Clinically however, high dosages of protein are administered due to fast degradation, which is

Mesenchymal stem cell proliferation and mineralization but not osteogenic differentiation are strongly affected by extracellular pH.

Science.gov (United States)

Fliefel, Riham; Popov, Cvetan; Tröltzsch, Matthias; Kühnisch, Jan; Ehrenfeld, Michael; Otto, Sven

2016-06-01

Osteomyelitis is a serious complication in oral and maxillofacial surgery affecting bone healing. Bone remodeling is not only controlled by cellular components but also by ionic and molecular composition of the extracellular fluids in which calcium phosphate salts are precipitated in a pH dependent manner. To determine the effect of pH on self-renewal, osteogenic differentiation and matrix mineralization of mesenchymal stem cells (MSCs). We selected three different pH values; acidic (6.3, 6.7), physiological (7.0-8.0) and severe alkaline (8.5). MSCs were cultured at different pH ranges, cell viability measured by WST-1, apoptosis detected by JC-1, senescence was analyzed by β-galactosidase whereas mineralization was detected by Alizarin Red and osteogenic differentiation analyzed by Real-time PCR. Self-renewal was affected by pH as well as matrix mineralization in which pH other than physiologic inhibited the deposition of extracellular matrix but did not affect MSCs differentiation as osteoblast markers were upregulated. The expression of osteocalcin and alkaline phosphatase activity was upregulated whereas osteopontin was downregulated under acidic pH. pH affected MSCs self-renewal and mineralization without influencing osteogenic differentiation. Thus, future therapies, based on shifting acid-base balance toward the alkaline direction might be beneficial for prevention or treatment of osteomyelitis. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Effects of extracellular calcium on viability and osteogenic differentiation of bone marrow stromal cells in vitro.

Science.gov (United States)

Cheng, Shaowen; Wang, Wei; Lin, Zhongqin; Zhou, Ping; Zhang, Xiaolei; Zhang, Wei; Chen, Qingyu; Kou, Dongquan; Ying, Xiaozhou; Shen, Yue; Cheng, Xiaojie; Yu, Ziming; Peng, Lei; Lu, Chuanzhu

2013-09-01

Bone marrow stromal cells (BMSCs) have been extensively used for tissue engineering. However, the effect of Ca(2+) on the viability and osteogenic differentiation of BMSCs has yet to be evaluated. To determine the dose-dependent effect of Ca(2+) on viability and osteogenesis of BMSCs in vitro, BMSCs were cultured in calcium-free DMEM medium supplemented with various concentrations of Ca(2+) (0, 1, 2, 3, 4, and 5 mM) from calcium citrate. Cell viability was analyzed by MTT assay and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) assay, Von Kossa staining, and real-time PCR. Ca(2+) stimulated BMSCs viability in a dose-dependent manner. At slightly higher concentrations (4 and 5 mM) in the culture, Ca(2+) significantly inhibited the activity of ALP on days 7 and 14 (P < 0.01 or P < 0.05), significantly suppressed collagen synthesis (P < 0.01 or P < 0.05), and significantly elevated calcium deposition (P < 0.01) and mRNA levels of osteocalcin (P < 0.01 or P < 0.05) and osteopontin (P < 0.01 or P < 0.05). Therefore, elevated concentrations of extracellular calcium may promote cell viability and late-stage osteogenic differentiation, but may suppress early-stage osteogenic differentiation in BMSCs.

Bone scintigraphy in a case of Ollier's disease

Energy Technology Data Exchange (ETDEWEB)

Otsuka, Nobuaki; Ito, Yasuhiko; Morita, Rikushi [Kawasaki Medical School, Kurashiki, Okayama (Japan)

1983-11-01

Bone scintigraphy with sup(99m)Tc-MDP was performed on a case with a Ollier's disease. Compared with Bone X-ray examinations, increased activity is noted in the ribs, hands (esp. left), left humerus, left tibia and left foot. Tumor scintigraphy with /sup 67/Ga-citrate shows slightly increased accumulation in comparison with sup(99m)Tc-MDP findings. However, apparent change was not noted compared with the previous scans. So, malignant change was negative. Malignant bone tumors usually show high activity, but some benign tumors also show high uptake. So, a differential diagnosis of bone disease using sup(99m)Tc-phosphorous compounds is occasionally difficult. In case of Ollier's disease, a follow-up bone scintigraphy is useful for evaluation of tumor growth, because malignant changes were accompanied by intensive uptake of sup(99m)Tc-MDP. Also, /sup 67/Ga-study is necessary for the differentiation of bone disease.

Neurospheres induced from bone marrow stromal cells are multipotent for differentiation into neuron, astrocyte, and oligodendrocyte phenotypes

International Nuclear Information System (INIS)

Suzuki, Hidenori; Taguchi, Toshihiko; Tanaka, Hiroshi; Kataoka, Hideo; Li Zhenglin; Muramatsu, Keiichi; Gondo, Toshikazu; Kawai, Shinya

2004-01-01

Bone marrow stromal cells (MSCs) can be expanded rapidly in vitro and have the potential to be differentiated into neuronal, glial and endodermal cell types. However, induction for differentiation does not always have stable result. We present a new method for efficient induction and acquisition of neural progenitors, neuronal- and glial-like cells from MSCs. We demonstrate that rat MSCs can be induced to neurospheres and most cells are positive for nestin, which is an early marker of neuronal progenitors. In addition, we had success in proliferation of these neurospheres with undifferentiated characteristics and finally we could obtain large numbers of neuronal and glial phenotypes. Many of the cells expressed β-tubulin III when they were cultivated with our method. MSCs can become a valuable cell source as an autograft for clinical application involving regeneration of the central nervous system

Adaptive bone formation in acellular vertebrae of sea bass (Dicentrarchus labrax L.)

NARCIS (Netherlands)

Kranenbarg, S.; Cleynenbreugel, van T.; Schipper, H.; Leeuwen, van J.L.

2005-01-01

Mammalian bone is an active tissue in which osteoblasts and osteoclasts balance bone mass. This process of adaptive modelling and remodelling is probably regulated by strain-sensing osteocytes. Bone of advanced teleosts is acellular yet, despite the lack of osteocytes, it is capable of an adaptive

Fibrous dysplasia mimicking bone metastasis on both bone scintigraphy and 18F FDG PET CT: Diagnostic dilemma in a patient with breast cancer

International Nuclear Information System (INIS)

KC, Sud Hir Suman; Sharma, Punit; Singh, Har Man Deep; Bal, Chand Rasekhar; Kumar, Rake Sh

2012-01-01

Bone is the most common distant site to which breast cancer metastasizes. Commonly used imaging modalities for imaging bone metastasis are bone scintigraphy, plain radiography, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Although bone scintigraphy gas high sensitivity for detecting bone metastasis, its specificity is low. This is because of the fact that bone scintigraphy images secondary changes in bone rather than just tumor cells 18 F fluorodeoxyglucose ( 18 F FDG) PET CT, on the other hand, directly images the tumor cells' glucose metabolism. Unfortunately, similar to bone scintigraphy, benign bone conditions can also show increased 18 F FDG uptake on PET CT, and PET positive asymptomatic fibrous dysplasia can be misinterpreted as a metastasis. Fibrous dysplasia of bone has wide skeletal distribution, with variability of 18 F FDG uptake and CT appearance. It is therefore important to recognize the characteristics of this skeletal dysplasia, to allow differentiation from skeletal metastasis. Bone lesions with 18 F FDG uptake need to be carefully interpreted when evaluating patients with known malignancy. In doubtful cases, fibrous dysplasia should be given as a differential diagnosis and histopathological diagnosis may be warranted, as highlighted in the present case

The Secretome of Bone Marrow and Wharton Jelly Derived Mesenchymal Stem Cells Induces Differentiation and Neurite Outgrowth in SH-SY5Y Cells

OpenAIRE

Ana O. Pires; Andreia Neves-Carvalho; Nuno Sousa; António J. Salgado

2014-01-01

The goal of this study was to determine and compare the effects of the secretome of mesenchymal stem cells (MSCs) isolated from human bone-marrow (BMSCs) and the Wharton jelly surrounding the vein and arteries of the umbilical cord (human umbilical cord perivascular cells (HUCPVCs)) on the survival and differentiation of a human neuroblastoma cell line (SH-SY5Y). For this purpose, SH-SY5Y cells were differentiated with conditioned media (CM) from the MSCs populations referred above. Retinoic ...

How B cells influence bone biology in health and disease.

Science.gov (United States)

Horowitz, Mark C; Fretz, Jackie A; Lorenzo, Joseph A

2010-09-01

It is now well established that important regulatory interactions occur between the cells in the hematopoietic, immune and skeletal systems (osteoimmunology). B lymphocytes (B cells) are responsible for the generation and production of antibodies or immunoglobulins in the body. Together with T cells these lymphocytes comprise the adaptive immune system, which allows an individual to develop specific responses to an infection and retain memory of that infection, allowing for a faster and more robust response if that same infection occurs again. In addition to this immune function, B cells have a close and multifaceted relationship with bone cells. B cells differentiate from hematopoietic stem cells (HSCs) in supportive niches found on endosteal bone surfaces. Cells in the osteoblast lineage support HSC and B cell differentiation in these niches. B cell differentiation is regulated, at least in part, by a series of transcription factors that function in a temporal manner. While these transcription factors are required for B cell differentiation, their loss causes profound changes in the bone phenotype. This is due, in part, to the close relationship between macrophage/osteoclast and B cell differentiation. Cross talk between B cells and bone cells is reciprocal with defects in the RANKL-RANK, OPG signaling axis resulting in altered bone phenotypes. While the role of B cells during normal bone remodeling appears minimal, activated B cells play an important role in many inflammatory diseases with associated bony changes. This review examines the relationship between B cells and bone cells and how that relationship affects the skeleton and hematopoiesis during health and disease. Copyright 2010 Elsevier Inc. All rights reserved.

Intractable Diseases Treated with Intra-Bone Marrow-Bone Marrow Transplantation

Directory of Open Access Journals (Sweden)

Ming eLi

2014-09-01

Full Text Available Bone marrow transplantation (BMT is used to treat hematological disorders, autoimmune diseases and lymphoid cancers. Intra bone marrow-BMT (IBM-BMT has been proven to be a powerful strategy for allogeneic BMT due to the rapid hematopoietic recovery and the complete restoration of T cell functions. IBM-BMT not only replaces hematopoietic stem cells but also mesenchymal stem cells (MSMCs. MSMCs are multi-potent stem cells that can be isolated from bone marrow, umbilical cord blood, and adipose tissue. MSMCs play an important role in the support of hematopoiesis, and modify and influence the innate and adaptive immune systems. MSMCs also differentiate into mesodermal, endodermal and ectodermal lineage cells to repair tissues. This review aims to summarize the functions of bone marrow-derived- MSMCs, and the treatment of intractable diseases such as rheumatoid arthritis and malignant tumors with IBM-BMT.

Effects of a hybrid micro/nanorod topography-modified titanium implant on adhesion and osteogenic differentiation in rat bone marrow mesenchymal stem cells.

Science.gov (United States)

Zhang, Wenjie; Li, Zihui; Huang, Qingfeng; Xu, Ling; Li, Jinhua; Jin, Yuqin; Wang, Guifang; Liu, Xuanyong; Jiang, Xinquan

2013-01-01

Various methods have been used to modify titanium implant surfaces with the aim of achieving better osseointegration. In this study, we fabricated a clustered nanorod structure on an acid-etched, microstructured titanium plate surface using hydrogen peroxide. We also evaluated biofunctionalization of the hybrid micro/nanorod topography on rat bone marrow mesenchymal stem cells. Scanning electron microscopy and x-ray diffraction were used to investigate the surface topography and phase composition of the modified titanium plate. Rat bone marrow mesenchymal stem cells were cultured and seeded on the plate. The adhesion ability of the cells was then assayed by cell counting at one, 4, and 24 hours after cell seeding, and expression of adhesion-related protein integrin β1 was detected by immunofluorescence. In addition, a polymerase chain reaction assay, alkaline phosphatase and Alizarin Red S staining assays, and osteopontin and osteocalcin immunofluorescence analyses were used to evaluate the osteogenic differentiation behavior of the cells. The hybrid micro/nanoscale texture formed on the titanium surface enhanced the initial adhesion activity of the rat bone marrow mesenchymal stem cells. Importantly, the hierarchical structure promoted osteogenic differentiation of these cells. This study suggests that a hybrid micro/nanorod topography on a titanium surface fabricated by treatment with hydrogen peroxide followed by acid etching might facilitate osseointegration of a titanium implant in vivo.

Suppressed osteoclast differentiation at the chondro-osseous junction mediates endochondral ossification retardation in long bones of Wistar fetal rats with prenatal ethanol exposure

Energy Technology Data Exchange (ETDEWEB)

Pan, Zhengqi [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Zhang, Xianrong [Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China); Shangguan, Yangfan; Hu, Hang [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: lbchen@whu.edu.cn [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China)

2016-08-15

Prenatal ethanol exposure (PEE) inhibits longitudinal growth of fetal bones, but the underlying mechanisms remain unknown. In this study, we aimed to investigate how PEE induces the retardation of long bone development in fetal rats. Pregnant Wistar rats were treated with ethanol or distilled water (control group) by gavage from gestational day (GD) 9 to 20. Fetuses were delivered by cesarean section on GD20. Fetal sera were collected for assessing corticosterone (CORT) level. Fetal long bones were harvested for histochemical, immunohistochemical and gene expression analysis. Primary chondrocytes were treated with ethanol or CORT for analyzing genes expression. PEE fetuses showed a significant reduction in birth weight and body length. The serum CORT concentration in PEE group was significantly increased, while the body weight, body length and femur length all were significantly decreased in the PEE group. The length of the epiphyseal hypertrophy zone was enlarged, whereas the length of the primary ossification center was significantly reduced in PEE fetuses. TUNEL assay showed reduced apoptosis in the PEE group. Further, the gene expression of osteoprotegerin (OPG) was markedly up-regulated. In vitro experiments showed that CORT (but not ethanol) treatment significantly activated the expression of OPG, while the application of glucocorticoid receptor inhibitor, mifepristone, attenuated these change induced by CORT. These results indicated that PEE-induced glucocorticoid over-exposure enhanced the expression of OPG in fetal epiphyseal cartilage and further lead to the suppressed osteoclast differentiation in the chondro-osseous junction and consequently inhibited the endochondral ossification in long bones of fetal rats. - Highlights: • Glucocorticoid but not ethanol enhanced the expression of OPG in chondrocytes. • PEE reduced osteoclast differentiation relative with over-expression of OPG. • PEE inhibited endochondral ossification in fetal long bones of

MRI of bone and soft tissue tumors and tumorlike lesions. Differential diagnosis and atlas

Energy Technology Data Exchange (ETDEWEB)

Meyers, S.P. [Rochester Univ., NY (United States). School of Medicine and Dentistry

2008-07-01

The book is devided into three main sections: the introduction presents a detailed overview of magnetic resonance imaging (MRI) of muscoskeletal tumors and tumorlike lesions and includes multiple tables regarding teh WHO classification of bone and soft tissue tumors, their relative frequencies and pertinent immunohistochemical and genetic data. The second part contains 20 tables of differential diagnosis of lesions based on anatomic locations and/or specific MRI features. Pertinent radiographic and CT findings and key clinical data are summarized. The third part contains 77 Atlas chapters organized into a routine format that enables the efficient acquisition of specific information regarding each lesion. For the majority of the Atlas chapters multiple MRI images are provided to demonstrate the range of imaging findings and locations associated with the lesions.

Differential growth responses to water balance of coexisting deciduous tree species are linked to wood density in a Bolivian tropical dry forest.

Directory of Open Access Journals (Sweden)

Hooz A Mendivelso

Full Text Available A seasonal period of water deficit characterizes tropical dry forests (TDFs. There, sympatric tree species exhibit a diversity of growth rates, functional traits, and responses to drought, suggesting that each species may possess different strategies to grow under different conditions of water availability. The evaluation of the long-term growth responses to changes in the soil water balance should provide an understanding of how and when coexisting tree species respond to water deficit in TDFs. Furthermore, such differential growth responses may be linked to functional traits related to water storage and conductance. We used dendrochronology and climate data to retrospectively assess how the radial growth of seven coexisting deciduous tree species responded to the seasonal soil water balance in a Bolivian TDF. Linear mixed-effects models were used to quantify the relationships between basal area increment and seasonal water balance. We related these relationships with wood density and sapwood production to assess if they affect the growth responses to climate. The growth of all species responded positively to water balance during the wet season, but such responses differed among species as a function of their wood density. For instance, species with a strong growth response to water availability averaged a low wood density which may facilitate the storage of water in the stem. By contrast, species with very dense wood were those whose growth was less sensitive to water availability. Coexisting tree species thus show differential growth responses to changes in soil water balance during the wet season. Our findings also provide a link between wood density, a trait related to the ability of trees to store water in the stem, and wood formation in response to water availability.

Differential Growth Responses to Water Balance of Coexisting Deciduous Tree Species Are Linked to Wood Density in a Bolivian Tropical Dry Forest

Science.gov (United States)

Mendivelso, Hooz A.; Camarero, J. Julio; Royo Obregón, Oriol; Gutiérrez, Emilia; Toledo, Marisol

2013-01-01

A seasonal period of water deficit characterizes tropical dry forests (TDFs). There, sympatric tree species exhibit a diversity of growth rates, functional traits, and responses to drought, suggesting that each species may possess different strategies to grow under different conditions of water availability. The evaluation of the long-term growth responses to changes in the soil water balance should provide an understanding of how and when coexisting tree species respond to water deficit in TDFs. Furthermore, such differential growth responses may be linked to functional traits related to water storage and conductance. We used dendrochronology and climate data to retrospectively assess how the radial growth of seven coexisting deciduous tree species responded to the seasonal soil water balance in a Bolivian TDF. Linear mixed-effects models were used to quantify the relationships between basal area increment and seasonal water balance. We related these relationships with wood density and sapwood production to assess if they affect the growth responses to climate. The growth of all species responded positively to water balance during the wet season, but such responses differed among species as a function of their wood density. For instance, species with a strong growth response to water availability averaged a low wood density which may facilitate the storage of water in the stem. By contrast, species with very dense wood were those whose growth was less sensitive to water availability. Coexisting tree species thus show differential growth responses to changes in soil water balance during the wet season. Our findings also provide a link between wood density, a trait related to the ability of trees to store water in the stem, and wood formation in response to water availability. PMID:24116001