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Sample records for bone metastasis formation

  1. Dissociation of bone formation markers in bone metastasis of prostate cancer.

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    Koizumi, M; Maeda, H.; Yoshimura, K; Yamauchi, T.; Kawai, T.; Ogata, E

    1997-01-01

    To clarify the meaning and clinical value of bone formation markers in bone metastasis from prostate cancer, we investigated the bone formation markers carboxy-terminal propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BA1-p) and osteocalcin, so-called bone gla protein (BGP) in 43 prostate cancer patients with and 46 patients without overt bone metastasis. Patients with bone metastasis were evaluated repeatedly by bone scan at intervals of 3-6 months. The expression...

  2. The Impact of Immune System in Regulating Bone Metastasis Formation by Osteotropic Tumors

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    Lucia D’Amico

    2015-01-01

    Full Text Available Bone metastases are frequent and debilitating consequence for many tumors, such as breast, lung, prostate, and kidney cancer. Many studies report the importance of the immune system in the pathogenesis of bone metastasis. Indeed, bone and immune system are strictly linked to each other because bone regulates the hematopoietic stem cells from which all cells of the immune system derive, and many immunoregulatory cytokines influence the fate of bone cells. Furthermore, both cytokines and factors produced by immune and bone cells promote the growth of tumor cells in bone, contributing to supporting the vicious cycle of bone metastasis. This review summarizes the current knowledge on the interactions among bone, immune, and tumor cells aiming to provide an overview of the osteoimmunology field in bone metastasis from solid tumors.

  3. ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

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    Mourskaia, Anna A; Amir, Eitan; Dong, Zhifeng; Tiedemann, Kerstin; Cory, Sean; Omeroglu, Atilla; Bertos, Nicholas; Ouellet, Véronique; Clemons, Mark; Scheffer, George L.; Park, Morag; Hallett, Michael; Svetlana V Komarova; Siegel, Peter M.

    2012-01-01

    Introduction Bone is the most common site of breast cancer metastasis, and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. Methods To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene-expression profiles from laser-capture micr...

  4. Cancer cell expression of autotaxin controls bone metastasis formation in mouse through lysophosphatidic acid-dependent activation of osteoclasts.

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    Marion David

    Full Text Available BACKGROUND: Bone metastases are highly frequent complications of breast cancers. Current bone metastasis treatments using powerful anti-resorptive agents are only palliative indicating that factors independent of bone resorption control bone metastasis progression. Autotaxin (ATX/NPP2 is a secreted protein with both oncogenic and pro-metastatic properties. Through its lysosphospholipase D (lysoPLD activity, ATX controls the level of lysophosphatidic acid (LPA in the blood. Platelet-derived LPA promotes the progression of osteolytic bone metastases of breast cancer cells. We asked whether ATX was involved in the bone metastasis process. We characterized the role of ATX in osteolytic bone metastasis formation by using genetically modified breast cancer cells exploited on different osteolytic bone metastasis mouse models. METHODOLOGY/PRINCIPAL FINDINGS: Intravenous injection of human breast cancer MDA-B02 cells with forced expression of ATX (MDA-B02/ATX to immunodeficiency BALB/C nude mice enhanced osteolytic bone metastasis formation, as judged by increased bone loss, tumor burden, and a higher number of active osteoclasts at the metastatic site. Mouse breast cancer 4T1 cells induced the formation of osteolytic bone metastases after intracardiac injection in immunocompetent BALB/C mice. These cells expressed active ATX and silencing ATX expression inhibited the extent of osteolytic bone lesions and decreased the number of active osteoclasts at the bone metastatic site. In vitro, osteoclast differentiation was enhanced in presence of MDA-B02/ATX cell conditioned media or recombinant autotaxin that was blocked by the autotaxin inhibitor vpc8a202. In vitro, addition of LPA to active charcoal-treated serum restored the capacity of the serum to support RANK-L/MCSF-induced osteoclastogenesis. CONCLUSION/SIGNIFICANCE: Expression of autotaxin by cancer cells controls osteolytic bone metastasis formation. This work demonstrates a new role for LPA as a

  5. Evaluation of Bone Metastasis from Hepatocellular Carcinoma Using {sup 18F} FDG PET/CT and {sup 99mT}c HDP Bone Scintigraphy: Characteristics of Soft Tissue Formation

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    Seo, Hyo Jung; Choi, Yun Jung; Kim, Hyun Jeong; Jeong, Youg Hyu; Cho, Arthur; Lee, Jae Hoon; Yun, Mijin; Choi, Hye Jin; Lee, Jong Doo; Kang, Won Jun [Yonsei Univ. College of Medicine, Seoul (Korea, Republic of)

    2011-09-15

    Bone metastasis from hepatocellular carcinoma (HCC) can present with soft tissue formation, resulting in oncologic emergency. Contrast enhanced FDG PET/CT and bone scintigraphy were compared to evaluate characteristics of bone metastases with of without soft tissue formation from HCC. of 4,151 patients with HCC, 263 patients had bone metastases. Eighty five patients with bone metastasis from HCC underwent contrast enhanced FDG PET/CT. Fifty four of the enrolled subjects had recent {sup 99mT}c HDP bone scintigraphy available for comparison. Metastatic bone lesions were identified with visual inspection on FDG PET/CT, and maximum standardized uptake value (SUVmax) was used for the quantitative analysis. Confirmation of bone metastasis was based on histopathology, combined imaging modalities, or serial follow up studies. Forty seven patients (55%) presented with soft tissue formation, while the remaining 38 patients presented without soft tissue formation. Frequent sites of bone metastases from HCC were the spine (39%), pelvis (19%), and rib cage (14%). The soft tissue formation group had more frequent bone pain (77 vs. 37%, p<0.0001), higher SUVmax (6.02 vs. 3.52, p<0.007), and higher incidence of photon defect in bone scintigraphy (75 vs. 0%) compared to the non soft tissue formation group. FDG PET/CT had higher detection rate for bone metastasis than bone scintigraphy both in lesion based analysis (98 vs. 53%, p=0.0015) and in patient based analysis (100 vs. 80%, p<0.001). Bone metastasis from HCC showed a high incidence of soft tissue formation requiring emergency treatment. Although the characteristic findings for soft tissue formation such as photon defect in bone scintigraphy are helpful in detection, overall detectability of bone metastasis is higher in FDG PET/CT. Contrast enhanced PET/CT will be useful in finding and delineating soft tissue forming bone metastasis from HCC.

  6. Dual function of ERR alpha in breast cancer and bone metastasis formation: implication of VEGF and osteoprotegerin.

    OpenAIRE

    Fradet, Anais; Sorel, Helene; Bouazza, Lamia; Goehrig, Delphine; Depalle, Baptiste; Bellahcene, Akeila; Castronovo, Vincenzo; Follet, Helene; Descotes, Francoise; Aubin, Jane E; Clezardin, Philippe; Bonnelye, Edith

    2011-01-01

    Bone metastasis is a complication occurring in up to 70% of advanced breast cancer patients. The estrogen receptor-related receptor alpha (ERRalpha) has been implicated in breast cancer and bone development, prompting us to examine whether ERRalpha may function in promoting the osteolytic growth of breast cancer cells in bone. In a mouse xenograft model of metastatic human breast cancer, overexpression of wild-type ERRalpha reduced metastasis, whereas overexpression of a dominant negative mut...

  7. Bone Metastasis from Renal Cell Carcinoma

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    Chen, Szu-Chia; Kuo, Po-Lin

    2016-01-01

    About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastasis that are often osteolytic and cause substantial morbidity, such as pain, pathologic fracture, spinal cord compression and hypercalcemia. The presence of bone metastasis in RCC is also associated with poor prognosis. Bone-targeted treatment using bisphosphonate and denosumab can reduce skeletal complications in RCC, but does not cure the disease or improve survival. Elucidating the molecular mechanisms of tumor-induced changes in the bone microenvironment is needed to develop effective treatment. The “vicious cycle” hypothesis has been used to describe how tumor cells interact with the bone microenvironment to drive bone destruction and tumor growth. Tumor cells secrete factors like parathyroid hormone-related peptide, transforming growth factor-β and vascular endothelial growth factor, which stimulate osteoblasts and increase the production of the receptor activator of nuclear factor κB ligand (RANKL). In turn, the overexpression of RANKL leads to increased osteoclast formation, activation and survival, thereby enhancing bone resorption. This review presents a general survey on bone metastasis in RCC by natural history, interaction among the immune system, bone and tumor, molecular mechanisms, bone turnover markers, therapies and healthcare burden. PMID:27338367

  8. Raman spectroscopy of bone metastasis

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    Esmonde-White, Karen A.; Sottnik, Joseph; Morris, Michael; Keller, Evan

    2012-02-01

    Raman spectroscopy of bone has been used to characterize chemical changes occurring in diseases such as osteoporosis, osteoarthritis and osteomyelitis. Metastasis of cancer into bone causes changes to bone quality that are similar to those observed in osteoporosis, such as decreased bone strength, but with an accelerated timeframe. In particular, osteolytic (bone degrading) lesions in bone metastasis have a marked effect on patient quality of life because of increased risk of fractures, pain, and hypercalcemia. We use Raman spectroscopy to examine bone from two different mouse models of osteolytic bone metastasis. Raman spectroscopy measures physicochemical information which cannot be obtained through standard biochemical and histological measurements. This study was reviewed and approved by the University of Michigan University Committee on the Care and Use of Animals. Two mouse models of prostate cancer bone metastasis, RM1 (n=3) and PC3-luc (n=4) were examined. Tibiae were injected with RM1 or PC3-luc cancer cells, while the contralateral tibiae received a placebo injection for use as controls. After 2 weeks of incubation, the mice were sacrificed and the tibiae were examined by Raman microspectroscopy (λ=785 nm). Spectroscopic markers corresponding to mineral stoichiometry, bone mineralization, and mineral crystallinity were compared in spectra from the cancerous and control tibiae. X-ray imaging of the tibia confirmed extensive osteolysis in the RM1 mice, with tumor invasion into adjoining soft tissue and moderate osteolysis in the PC3-luc mice. Raman spectroscopic markers indicate that osteolytic lesions are less mineralized than normal bone tissue, with an altered mineral stoichiometry and crystallinity.

  9. Current Concepts of Metastasis Formation

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    Peter Gassman

    2011-07-01

    Full Text Available The development of secondary distant organ and lymph node metastasis has an extraordinary impact on the prognosis of patients with solid cancer. In most cases the advent of metastatic growth represents the turning point from a local, potentially curable, disease to a systemic non-curable situation. As a highly regulated process, metastasis formation follows a distinct, non-random pattern characteristic for each tumor entity. Metastasis formation and strategies to prevent this lethal event in the progression of cancer is of fundamental interest for cancer science and patient care. In this special issue of Cancers, papers highlighting cellular mechanisms of metastasis formation, genetic and epigenetic aspects associated with organ and tumor specific metastasis formation, as well as papers outlining experimental and clinical therapeutic concepts for anti-metastatic treatment are included.

  10. Bone Targeted Therapies for Bone Metastasis in Breast Cancer

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    Wajeeha Razaq

    2013-01-01

    Cancer metastasis to the bone develops commonly in patients with various malignancies, and is a major cause of morbidity and diminished quality of life in many affected patients. Emerging treatments for metastatic bone disease have arisen from advances in our understanding of the unique cellular and molecular mechanisms that contribute to the bone metastasis. The tendency of cancer cells to metastasize to bone is probably the end result of many factors including vascular pathways, the highly ...

  11. Nasopharyngeal carcinoma with bone marrow metastasis.

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    Zen, H G; Jame, J M; Chang, A Y; Li, W Y; Law, C K; Chen, K Y; Lin, C Z

    1991-02-01

    Five of 23 patients with recurrent nasopharyngeal carcinoma (NPC) were diagnosed to have bone marrow metastasis. They all had advanced local-regional disease, and were treated with neoadjuvant chemotherapy and definitive radiotherapy after the initial diagnosis. Bone marrow metastasis developed 4-24 months later. The clinical features were anemia (5 of 5), leukopenia (3 of 5), thrombocytopenia (4 of 5), sepsis (3 of 5), tenderness of the sternum (3 of 5), and fever (4 of 5). Patients frequently had elevation of serum lactic dehydrogenase (LDH), alkaline phosphatase (ALK-P), and IgG and IgA antibody titers to Epstein-Barr viral capsid antigen when bone marrow involvement was diagnosed. However, clinical manifestations and laboratory tests were not specific. It is important that three patients had normal bone scans. All five patients had a rapid downhill course; four patients died within 23 days, and the fifth 3 months after the diagnosis of bone marrow metastasis. We concluded that bone marrow was a common metastatic site in NPC patients. Bone marrow metastasis adversely affected patients' survival and required a high index of suspicion for diagnosis. We suggested that bone marrow biopsy should be considered as a routine staging procedure in NPC patients and indicated especially when patients presented with abnormal blood counts, sepsis, bone pain, or tenderness of the sternum. It may be positive in the face of a normal bone scan. PMID:1987743

  12. Wnt and Wnt inhibitors in bone metastasis

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    Sottnik, Joseph L; Christopher L. Hall; Zhang, Jian; Evan T. Keller

    2012-01-01

    Bone metastasis is a clinically devastating development of progressive cancers including prostate carcinoma, breast carcinoma and multiple myeloma. Bone metastases are typically painful, lead to adverse skeletal-related events, such as fracture, and are highly resistant to therapy. A major contribution to the ability of cancers to successfully establish bone metastases is their ability to exploit mechanisms of normal bone remodeling. Wnts are a large family of morphogenic proteins that are cr...

  13. Imaging of bone metastasis: An update

    Institute of Scientific and Technical Information of China (English)

    Gerard; J; O’Sullivan; Fiona; L; Carty; Carmel; G; Cronin

    2015-01-01

    Early detection of skeletal metastasis is critical for accurate staging and optimal treatment. This paper briefly reviews our current understanding of the biological mechanisms through which tumours metastasise to bone and describes the available imaging methods to diagnose bone metastasis and monitor response to treatment. Among the various imaging modalities currently available for imaging skeletal metastasis, hybrid techniques whichfuse morphological and functional data are the most sensitive and specific, and positron emission tomography(PET)/computed tomography and PET/magnetic resonance imaging will almost certainly continue to evolve and become increasingly important in this regard.

  14. Review of Animal Models of Prostate Cancer Bone Metastasis

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    Jessica K. Simmons

    2014-06-01

    Full Text Available Prostate cancer bone metastases are associated with a poor prognosis and are considered incurable. Insight into the formation and growth of prostate cancer bone metastasis is required for development of new imaging and therapeutic strategies to combat this devastating disease. Animal models are indispensable in investigating cancer pathogenesis and evaluating therapeutics. Multiple animal models of prostate cancer bone metastasis have been developed, but few effectively model prostatic neoplasms and osteoblastic bone metastases as they occur in men. This review discusses the animal models that have been developed to investigate prostate cancer bone metastasis, with a focus on canine models and also includes human xenograft and rodent models. Adult dogs spontaneously develop benign prostatic hyperplasia and prostate cancer with osteoblastic bone metastases. Large animal models, such as dogs, are needed to develop new molecular imaging tools and effective focal intraprostatic therapy. None of the available models fully reflect the metastatic disease seen in men, although the various models have provided important insight into the metastatic process. As additional models are developed and knowledge from the different models is combined, the molecular mechanisms of prostate cancer bone metastasis can be deciphered and targeted for development of novel therapies and molecular diagnostic imaging.

  15. Protocadherin-7 induces bone metastasis of breast cancer

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    Li, Ai-Min [Department of Orthopedics, The 5th Central Hospital of Tianjin, Tianjin (China); Tian, Ai-Xian [Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Zhang, Rui-Xue [Department of Clinical Laboratory Diagnosis, Tianjin Medical University, Tianjin (China); Ge, Jie [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Sun, Xuan [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Cao, Xu-Chen, E-mail: caoxuch@126.com [Department of Breast Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China); Key Laboratory of Breast Cancer Prevention and Treatment of the Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin (China)

    2013-07-05

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer.

  16. Protocadherin-7 induces bone metastasis of breast cancer

    International Nuclear Information System (INIS)

    Highlights: •PCDH7 is overexpression in high bone metastatic MDA-MB-231 cells. •PCDH7 is up-regulation in bone metastatic breast cancer tissues. •Suppression of PCDH7 inhibits cell proliferation, migration, and invasion in vitro. •PCDH7 induces breast cancer bone metastasis in vivo. -- Abstract: Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer

  17. Therapy for bone metastasis from different cancers

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    Zheng Zhang; Peng Tan; Baoguo Mi; Chao Song; Yi Deng; Hanfeng Guan

    2016-01-01

    The bone is the most common target organ of cancer metastasis. Bone metastasis leads to considerable morbidity due to skeletal-related events (SREs). These include bone pain, hypercalcemia, pathologic frac-tures, and compression of the spinal cord. Cancers such as those of the lung, breast, prostate, and kidney are more likely to cause SREs than other cancer types. Additionaly, some blood cancers, including multiple myeloma and lymphoma, frequently cause SREs. In this article, we review the conventional therapies for metastatic bone disease, including drug therapy, radiotherapy, and surgery. Among osteoclast-targeting agents, bisphosphonates and nuclear factor kappa-B ligand inhibitors are the most widely used agents to prevent cancer-related bone loss. Unsealed radioisotopes are also considered promising in cancer therapy. Currently, iodine-131, strontium-89, and radium-223 are available for the treatment of bone metastasis. However, the treatments for blood cancers with SREs are diferent from those of other cancers. In those cases, new classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal anti-bodies, and histone deacetylase inhibitors have shown remarkable eficacy. We also discuss the potential development of new therapies for these diseases.

  18. Targeting Bone Remodeling by Isoflavone and 3,3′-Diindolylmethane in the Context of Prostate Cancer Bone Metastasis

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    Yiwei Li; Dejuan Kong; Aamir Ahmad; Bin Bao; Sarkar, Fazlul H

    2012-01-01

    Prostate cancer (PCa) bone metastases have long been believed to be osteoblastic because of bone remodeling leading to the formation of new bone. However, recent studies have shown increased osteolytic activity in the beginning stages of PCa bone metastases, suggesting that targeting both osteolytic and osteoblastic mediators would likely inhibit bone remodeling and PCa bone metastasis. In this study, we found that PCa cells could stimulate differentiation of osteoclasts and osteoblasts throu...

  19. Nanoradiopharmaceuticals for Bone Cancer Metastasis Imaging.

    Science.gov (United States)

    Coelho, Bianca Feliciano; de Souza Albernaz, Marta; Iscaife, Alexandre; Moreira Leite, Katia Ramos; de Souza Junqueira, Mara; Bernardes, Emerson Soares; da Silva, Emerson Oliveira; Santos-Oliveira, Ralph

    2015-01-01

    Drug delivery systems are under intense investigation all around the world, especially in oncology research. Indeed, in some cases, like bone metastasis, nanodrugs may represent the last and best choice for both treatment and imaging of early cancer foci. Nuclear medicine has been using MDP labelled with 99mTc as radiopharmaceuticals for many years; however, their use as nanoradiopharmaceuticals is very innovative and creates a new way to establish radiopharmacy in this new scenario offered by nanotechnology. In this study we developed and tested nano-MDP-labelled with 99mTc in rats induced with bone cancer metastasis and the results showed that it may work in patients. However, some further experiments are required in order to initiate protocols in humans. PMID:25847010

  20. Steps in Prostate Cancer Progression that lead to Bone Metastasis

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    Jin, Jung-Kang; Dayyani, Farshid; Gallick, Gary E.

    2011-01-01

    Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone remain incompletely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bi-directional interactions between the tumor and the bone microenvironment. In this review, we discuss the current...

  1. Pleiotropic activity of lysophosphatidic acid in bone metastasis.

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    Peyruchaud, Olivier; Leblanc, Raphael; David, Marion

    2013-01-01

    Bone is a common metastatic site for solid cancers. Bone homeostasis is tightly regulated by intimate cross-talks between osteoblast (bone forming cells) and osteoclasts (bone resorbing cells). Once in the bone microenvironment, metastatic cells do not alter bone directly but instead perturb the physiological balance of the bone remodeling process controlled by bone cells. Tumor cells produce growth factors and cytokines stimulating either osteoclast activity leading to osteolytic lesions or osteoblast function resulting in osteoblastic metastases. Growth factors, released from the resorbed bone matrix or throughout osteoblastic bone formation, sustain tumor growth. Therefore, bone metastases are the sites of vicious cycles wherein tumor growth and bone metabolism sustain each other. Lysophosphatidic acid (LPA) promotes the growth of primary tumors and metastatic dissemination of cancer cells. We have shown that by acting on cancer cells via the contribution of blood platelets and the LPA-producing enzyme Autotaxin (ATX), LPA promotes the progression of osteolytic bone metastases in animal models. In the light of recent reports it would appear that the role of LPA in the context of bone metastases is complex involving multiple sources of lipid combined with direct and indirect effects on target cells. This review will present our current knowledge on the LPA/ATX axis involvement in osteolytic and osteoblastic skeletal metastases and will discuss the potential activity of LPA upstream and downstream metastasis seeding of cancer cells to bone as well as its implication in cancer induced bone pain. This article is part of a Special Issue entitled Advances in Lysophospholipid Research. PMID:22710393

  2. Metastasis and bone loss: Advancing treatment and prevention

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    Coleman, Robert E.; Lipton, Allan; Roodman, G. David; Guise, Theresa A.; Boyce, Brendon F.; Brufsky, Adam M.; Clézardin, Philippe; Peter I Croucher; Gralow, Julie R.; Hadji, Peyman; Holen, Ingunn; Mundy, Gregory R.; Smith, Matthew R.; Suva, Larry J.

    2010-01-01

    Tumor metastasis to the skeleton affects over 400,000 individuals in the United States annually, more than any other site of metastasis, including significant proportions of patients with breast, prostate, lung and other solid tumors. Research on the bone microenvironment and its role in metastasis suggests a complex role in tumor growth. Parallel preclinical and clinical investigations into the role of adjuvant bone-targeted agents in preventing metastasis and avoiding cancer therapy-induced...

  3. Correlation of the Levels of the Bone Turnover Markers BAP and β-CTX with Bone Metastasis Progress in Lung Cancer Patients

    OpenAIRE

    Tang, Qiong; Zhao, Hui; JIA, RUI; Liu, Linlin

    2013-01-01

    Background and objective Bone metastasis is common in lung cancer patients. The β isomer of the C-terminal telopeptide of type I collagen (β-CTX) and bone-specific alkaline phosphates (BAP) are regarded as important bone turnover markers in bone resorption and formation. Thus, the aims of this study are to determine the correlation of these bone turnover markers with the extent of bone metastasis of lung cancer. Methods A total of 92 patients with bone metastasis of lung cancer from Tianjin U...

  4. Global secretome analysis identifies novel mediators of bone metastasis

    Institute of Scientific and Technical Information of China (English)

    Mario Andres Blanco; Gary LeRoy; Zia Khan; Ma(s)a Ale(c)kovi(c); Barry M Zee; Benjamin A Garcia; Yibin Kang

    2012-01-01

    Bone is the one of the most common sites of distant metastasis of solid tumors.Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma.To comprehensively profile secreted proteins associated with bone metastasis,we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types.By comparing the secretomes of parental cells and their bone metastatic derivatives,we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines.We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis.Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1,CST2,and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1.Overall,our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets.

  5. Global secretome analysis identifies novel mediators of bone metastasis.

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    Blanco, Mario Andres; LeRoy, Gary; Khan, Zia; Alečković, Maša; Zee, Barry M; Garcia, Benjamin A; Kang, Yibin

    2012-09-01

    Bone is the one of the most common sites of distant metastasis of solid tumors. Secreted proteins are known to influence pathological interactions between metastatic cancer cells and the bone stroma. To comprehensively profile secreted proteins associated with bone metastasis, we used quantitative and non-quantitative mass spectrometry to globally analyze the secretomes of nine cell lines of varying bone metastatic ability from multiple species and cancer types. By comparing the secretomes of parental cells and their bone metastatic derivatives, we identified the secreted proteins that were uniquely associated with bone metastasis in these cell lines. We then incorporated bioinformatic analyses of large clinical metastasis datasets to obtain a list of candidate novel bone metastasis proteins of several functional classes that were strongly associated with both clinical and experimental bone metastasis. Functional validation of selected proteins indicated that in vivo bone metastasis can be promoted by high expression of (1) the salivary cystatins CST1, CST2, and CST4; (2) the plasminogen activators PLAT and PLAU; or (3) the collagen functionality proteins PLOD2 and COL6A1. Overall, our study has uncovered several new secreted mediators of bone metastasis and therefore demonstrated that secretome analysis is a powerful method for identification of novel biomarkers and candidate therapeutic targets. PMID:22688892

  6. Usefulness of Bone Metabolic Markers in the Diagnosis of Bone Metastasis from Lung Cancer

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    Chung, Jae Ho; Park, Moo Suk; Kim, Young Sam; Chang, Joon; Kim, Joo Hang; Kim, Sung Kyu; Kim, Se Kyu

    2005-01-01

    Bone metastasis is common in lung cancer patient and the diagnosis of bone metastasis is usually made by using imaging techniques, especially bone scintigraphy. However, the diagnostic yield from bone scintigraphy is limited. The aim of this study is to assess the clinical usefulness of urinary pyridinoline cross-linked N-telopeptides of Type I collagen (NTx), urinary deoxypyridinoline (DPD), and serum alkaline phosphatase (ALP) in the assessment of bone metastasis in patients with lung cance...

  7. Prostatic adenocarcinoma with and without metastasis to bone in dogs

    International Nuclear Information System (INIS)

    The signalment, clinical signs, and histologic tumor pattern were compared retrospectively in 12 dogs having primary prostatic adenocarcinoma with (5 cases) and without metastasis (7 cases) to bone. Weight loss and lumbar pain were observed more frequently in dogs having prostatic adenocarcinoma with metastasis to bone. A distinctive histologic pattern was not associated with prostatic adenocarcinoma that had metastasized to bone. The alveolar papillary pattern was the predominant histologic type observed in both groups. Metastasis to extra pelvic bony sites included the scapulas, ribs, and digits. The results of this study indicate that skeletal metastasis was not uncommon in dogs having prostatic adenocarcinoma

  8. Molecular Mechanisms of Bone Metastasis and Associated Muscle Weakness

    OpenAIRE

    Waning, David L.; Guise, Theresa A.

    2014-01-01

    Bone is a preferred site for breast cancer metastasis and leads to pathological bone loss due to increased osteoclast-induced bone resorption. The homing of tumor cells to the bone depends on the support of the bone microenvironment in which the tumor cells prime the pre-metastatic niche. The colonization and growth of tumor cells then depends on adaptations in the invading tumor cells to take advantage of normal physiological responses by mimicking bone marrow cells. This concerted effort by...

  9. Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

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    Bäuerle, Tobias; Komljenovic, Dorde; Martin R. Berger; Semmler, Wolfhard

    2012-01-01

    Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.

  10. Unusual bone metastasis from follicular carcinoma thyroid: presenting as a primary bone malignancy

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    Saurabh Varshney

    2014-12-01

    Full Text Available Osseous metastasis in patients of thyroid carcinoma is not very common, and appendicular skeleton is very rare. Bone metastasis represents a complication, especially of follicular thyroid carcinoma and severely reduces the quality of life causing pain, and fractures. Diagnosis is typically done by correlating clinical suspicion with imaging. Occult clinical presentations usually delay the detection and management of patients with bone metastasis from thyroid carcinoma. There is limited information about the clinical presentations and prognosis of patients with follicular thyroid carcinoma with bone metastasis. We hereby present a case report of right arm swelling diagnosed as metastatic carcinoma having metastasis from thyroid primary.

  11. Radiotherapy for metastasis from breast and lung cancer. Bone and Brain metastasis

    International Nuclear Information System (INIS)

    Bone or brain metastasis is the common and serious condition restricting the quality of life (QOL) of the cancer patients and radiotherapy frequently plays an important role in relief of their symptoms. Because radiotherapy is given with palliative intent to the patients with limited, if variable, life expectancy, radiation schedules need to be identified which give maximum patient benefit with minimum associated morbidity and minimum disturbance of the patients' remaining life. We retrospectively analyzed 222 patients with the bone or the brain metastasis from lung or breast cancer to evaluate the effect of radiotherapy on their prognosis and QOL. The 3-year survival rates of the patients with breast and lung cancer were 21% and 3%, respectively (p<0.0001), and breast cancer patients seemed to have better prognosis than lung cancer patients for both bone metastasis (p<0.0001) and brain metastasis (p=0.09). Symptom relief by radiotherapy was obtained 84% for bone metastasis and 64% for brain metastasis and it was not affected by primary lesion (lung or breast). Sixty seven per cent of the bone and the brain metastasis was derived from adenocarcinoma and it had a tendency to give the better prognosis comparing with squamous cell carcinoma. Radiation schedules should be flexibly corresponded to the patients' tumor type (metastatic site, primary disease or histology), even if it is 'just' a palliative therapy, considering their prognosis and QOL. (author)

  12. Up-regulation of bone marrow stromal protein 2 (BST2 in breast cancer with bone metastasis

    Directory of Open Access Journals (Sweden)

    Zheng Xin

    2009-04-01

    Full Text Available Abstract Background Bone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer. Methods cDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to bone human breast cancer cell line (MDA-231BO and a primary human breast cancer cell line (MDA-231. The BST2 expression in one bone metastatic breast cancer and seven non-bone metastatic breast cancer cell lines were also determined using real-time RT-PCR and Western blot assays. We then employed tissue array to further study the BST2 expression in human breast cancer using array slides containing 20 independent breast cancer tumors that formed metastatic bone lesions, 30 non-metastasis-forming breast cancer tumors, and 8 normal breast tissues. In order to test the feasibility of utilizing BST2 as a serum marker for the presence of bone metastasis in breast cancer, we had measured the BST2 expression levels in human serums by using ELISA on 43 breast cancer patients with bone metastasis, 43 breast cancer patients without bone metastasis, and 14 normal healthy controls. The relationship between cell migration and proliferation and BST2 expression was also studied in a human breast recombinant model system using migration and FACS analysis. Results The microarray demonstrated over expression of the BST2 gene in the bone metastatic breast cancer cell line (MDA-231BO compared to the primary human breast cancer cell line (MDA-231. The expression of the BST2 gene was significantly increased in the bone metastatic breast cancer cell lines and tumor

  13. Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis

    International Nuclear Information System (INIS)

    Bone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer. cDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to bone human breast cancer cell line (MDA-231BO) and a primary human breast cancer cell line (MDA-231). The BST2 expression in one bone metastatic breast cancer and seven non-bone metastatic breast cancer cell lines were also determined using real-time RT-PCR and Western blot assays. We then employed tissue array to further study the BST2 expression in human breast cancer using array slides containing 20 independent breast cancer tumors that formed metastatic bone lesions, 30 non-metastasis-forming breast cancer tumors, and 8 normal breast tissues. In order to test the feasibility of utilizing BST2 as a serum marker for the presence of bone metastasis in breast cancer, we had measured the BST2 expression levels in human serums by using ELISA on 43 breast cancer patients with bone metastasis, 43 breast cancer patients without bone metastasis, and 14 normal healthy controls. The relationship between cell migration and proliferation and BST2 expression was also studied in a human breast recombinant model system using migration and FACS analysis. The microarray demonstrated over expression of the BST2 gene in the bone metastatic breast cancer cell line (MDA-231BO) compared to the primary human breast cancer cell line (MDA-231). The expression of the BST2 gene was significantly increased in the bone metastatic breast cancer cell lines and tumor tissues compared to non-bone metastatic breast cancer

  14. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

    Directory of Open Access Journals (Sweden)

    Laure Thibaudeau

    2014-02-01

    Full Text Available The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo.

  15. Mechanisms of cancer metastasis to the bone

    Institute of Scientific and Technical Information of China (English)

    Juan Juan YIN; Claire B. POLLOCK; Kathleen KELLY

    2005-01-01

    Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions.

  16. Bone scintigraphy for metastasis detection in canine osteosarcoma

    International Nuclear Information System (INIS)

    The purpose of this study was to assess the usefulness of serial bone scintigraphy in the detection of skeletal and extraskeletal metastases in dogs with appendicular osteosarcoma. Twenty-six dogs with primary, appendicular osteosarcoma were entered into a limb-sparing protocol. Bone scintigraphy was performed upon presentation, after neoadjuvant therapy but prior to surgery and at selective intervals after limb-sparing surgery to evaluate for the presence of metastasis. Thoracic radiographs, and radiographs of other sites, were also made at the time of each bone scan. All dogs had a complete necropsy. No dog had bone or lung metastases detected prior to treatment. The bone scans, medical records, and radiographs of each dog were reviewed retrospectively. All but one dog developed metastatic disease. Bone metastatic sites were confirmed at necropsy in 12 of the 26 dogs. Seven of these 12 dogs had bone metastatic sites which were not producing clinical signs, i.e. an occult metastasis. In five of the seven dogs, the occult site was the first metastatic site detected. Extraskeletal metastases were identified scintigraphically in six of the 26 dogs, but these were clinically apparent prior to bone scintigraphy in each dog. Suspected malignant scintigraphic lesions were proven benign in six dogs. In five dogs with malignant bone lesions at necropsy the last bone scan prior to euthanasia was normal. The time interval between scintigraphy and necropsy was variable in these five dogs. All dogs without bone metastases at necropsy had normal bone scans. This study validates the usefulness of bone scintigraphy for detection of occult bone metastasis and improved ability for tumor staging in dogs with appendicular osteosarcoma

  17. Stereotactic Body Radiation Therapy for Treatment of Spinal Bone Metastasis.

    Science.gov (United States)

    Cihan, Yasemin Benderli

    2016-01-01

    Stereotactic body radiation therapy (SBRT) appears an effective and safe treatment modality for spinal bone metastasis, which can enhance local control and improve quality of life. Life expectation, predicted fracture risk, localization, quality, size and number of metastasis and presence or absence of nerve compression seem to be important factors in decision-making for treatment. Further studies are needed to identify subsets of patient which will most benefit from treatment. PMID:27039816

  18. Incidence of bone metastasis in carcinoma buccal mucosa

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    Virendra Bhandari

    2016-01-01

    Full Text Available Introduction: Head and neck cancer is a leading health problem in India due to the habit of chewing tobacco and bad oral and dental hygiene. Carcinoma buccal mucosa is more common and is 2.5% of all malignancies at our center. Most of the patients present in stage III and IV and the survival in these cases is not very good. Bone metastasis in advanced cases of carcinoma buccal mucosa is rarely reported in the world literature. Materials and Methods: We present here cases developing bone metastasis in carcinoma buccal mucosa in last 5 years. These patients were young with loco-regionally advanced disease where bone metastasis developed within 1-year of definitive treatment. Results: The flat bones and vertebrae were mainly involved and the survival was also short after diagnosis of metastasis despite the treatment with local Radiotherapy and chemotherapy. Conclusion: The exact cause of metastasis cannot be proved, but the probability of subclinical seedling of malignant cells before the eradication of the primary tumor should be considered along with advanced local and nodal disease with high grade of tumor.

  19. Incidence of bone metastasis in carcinoma buccal mucosa

    Science.gov (United States)

    Bhandari, Virendra

    2016-01-01

    Introduction: Head and neck cancer is a leading health problem in India due to the habit of chewing tobacco and bad oral and dental hygiene. Carcinoma buccal mucosa is more common and is 2.5% of all malignancies at our center. Most of the patients present in stage III and IV and the survival in these cases is not very good. Bone metastasis in advanced cases of carcinoma buccal mucosa is rarely reported in the world literature. Materials and Methods: We present here cases developing bone metastasis in carcinoma buccal mucosa in last 5 years. These patients were young with loco-regionally advanced disease where bone metastasis developed within 1-year of definitive treatment. Results: The flat bones and vertebrae were mainly involved and the survival was also short after diagnosis of metastasis despite the treatment with local Radiotherapy and chemotherapy. Conclusion: The exact cause of metastasis cannot be proved, but the probability of subclinical seedling of malignant cells before the eradication of the primary tumor should be considered along with advanced local and nodal disease with high grade of tumor.

  20. Diagnosis of bone metastasis from thyroid carcinoma

    DEFF Research Database (Denmark)

    Bechsgaard, Thor; Lelkaitis, Giedrius; Jensen, Karl E;

    2015-01-01

    (MRI), but histology revealed a metastasis from thyroid carcinoma, although the patient had no previous history of thyroid malignancy and resection of the thyroid gland was without malignancy. Ultrasound-guided biopsy was possible due to cortical destruction and the multidisciplinary approach with re...

  1. Bone Positron Emission Tomography with or without CT Is More Accurate than Bone Scan for Detection of Bone Metastasis

    OpenAIRE

    Lee, Soo Jin; Lee, Won Woo; Kim, Sang Eun

    2013-01-01

    Objective Na18F bone positron emission tomography (bone PET) is a new imaging modality which is useful for the evaluation of bone diseases. Here, we compared the diagnostic accuracies between bone PET and bone scan for the detection of bone metastasis (BM). Materials and Methods Sixteen cancer patients (M:F = 10:6, mean age = 60 ± 12 years) who underwent both bone PET and bone scan were analyzed. Bone PET was conducted 30 minutes after the injection of 370 MBq Na18F, and a bone scan was perfo...

  2. Pubic bone metastasis as first manifestation of lung cancer:

    OpenAIRE

    HOMMA, SHINSUKE; KODAMA, TAKAHIDE; SATOH, HIROAKI; Sekizawa, Kiyohisa; Ueno, Takahiro

    2003-01-01

    Background. Pubic bone metastasis as the initial manifestation of lung cancer is very rare, and it may simulate parasymphyseal insufficiency fracture of thepubic bone, which is observed in postmenopausal women and elderly people. Case report. A 65-year-old woman developed pain in the right flank, which extended to the anterior aspect of the thigh. A pelvic X-ray showed osteolyticlesion in the right pubic ramus. Chest radiograph revealed a nodularmass in the right middle lobe of the lung. Tran...

  3. Natural History of Malignant Bone Disease in Renal Cancer: Final Results of an Italian Bone Metastasis Survey

    OpenAIRE

    D. Santini; Procopio, G; Porta, C; Ibrahim, T; Barni, S.; Mazzara, C; Fontana, A.; Berruti, A; R. Berardi; Vincenzi, B; Ortega, C; Ottaviani, D; Carteni, G; Lanzetta, G; Virzì, V

    2013-01-01

    Background Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC) as disease-related survival improves. There are few data on the natural history of bone disease in RCC. Patients and methods Data on clinicopathology, survival, skeletal-related events (SREs), and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female) with evidence of bone metastasis were statistically analyzed. Results Median time to bone metastasis was 25 months ...

  4. 3D printed nanocomposite matrix for the study of breast cancer bone metastasis.

    Science.gov (United States)

    Zhu, Wei; Holmes, Benjamin; Glazer, Robert I; Zhang, Lijie Grace

    2016-01-01

    Bone is one of the most common metastatic sites of breast cancer, but the underlying mechanisms remain unclear, in part due to an absence of advanced platforms for cancer culture and study that mimic the bone microenvironment. In the present study, we integrated a novel stereolithography-based 3D printer and a unique 3D printed nano-ink consisting of hydroxyapatite nanoparticles suspended in hydrogel to create a biomimetic bone-specific environment for evaluating breast cancer bone invasion. Breast cancer cells cultured in a geometrically optimized matrix exhibited spheroid morphology and migratory characteristics. Co-culture of tumor cells with bone marrow mesenchymal stem cells increased the formation of spheroid clusters. The 3D matrix also allowed for higher drug resistance of breast cancer cells than 2D culture. These results validate that our 3D bone matrix can mimic tumor bone microenvironments, suggesting that it can serve as a tool for studying metastasis and assessing drug sensitivity. From the Clinical Editor: Cancer remains a major cause of mortality for patients in the clinical setting. For breast cancer, bone is one of the most common metastatic sites. In this intriguing article, the authors developed a bone-like environment using 3D printing technology to investigate the underlying biology of bone metastasis. Their results would also allow a new model for other researchers who work on cancer to use. PMID:26472048

  5. Bone Marrow Adipose Tissue: A New Player in Cancer Metastasis to Bone

    Science.gov (United States)

    Morris, Emma V.; Edwards, Claire M.

    2016-01-01

    The bone marrow is a favored site for a number of cancers, including the hematological malignancy multiple myeloma, and metastasis of breast and prostate cancer. This specialized microenvironment is highly supportive, not only for tumor growth and survival but also for the development of an associated destructive cancer-induced bone disease. The interactions between tumor cells, osteoclasts and osteoblasts are well documented. By contrast, despite occupying a significant proportion of the bone marrow, the importance of bone marrow adipose tissue is only just emerging. The ability of bone marrow adipocytes to regulate skeletal biology and hematopoiesis, combined with their metabolic activity, endocrine functions, and proximity to tumor cells means that they are ideally placed to impact both tumor growth and bone disease. This review discusses the recent advances in our understanding of how marrow adipose tissue contributes to bone metastasis and cancer-induced bone disease.

  6. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    International Nuclear Information System (INIS)

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules including specific chemokines and their receptors, are distinct in nature and function, yet play intricate and significant roles in prostate cancer bone metastasis. Examining the impact of these facets of bone metastasis in vivo remains a significant challenge, as animal models that mimic the natural history and malignant progression clinical prostate cancer are rare. The goals of this article are to discuss (1) characteristics of bone that most likely render it a favorable environment for prostate tumor cell growth, (2) chemokine signaling that is critical in the recruitment and migration of prostate cancer cells to the bone, and (3) current animal models utilized in studying prostate cancer bone metastasis. Further research is necessary to elucidate the mechanisms underlying the extravasation of disseminated prostate cancer cells into the bone and to provide a better understanding of the basis of cancer cell survival within the bone microenvironment. The development of animal models that recapitulate more closely the human clinical scenario of prostate cancer will greatly benefit the generation of better therapies

  7. Pubic bone metastasis as first manifestation of lung cancer

    International Nuclear Information System (INIS)

    Background. Pubic bone metastasis as the initial manifestation of lung cancer is very rare, and it may simulate parasymphyseal insufficiency fracture of the pubic bone, which is observed in postmenopausal women and elderly people. Case report. A 65-year-old woman developed pain in the right flank, which extended to the anterior aspect of the thigh. A pelvic X-ray showed osteolytic lesion in the right pubic ramus. Chest radiograph revealed a nodular mass in the right middle lobe of the lung. Transbronchal biopsy of the mass led to the diagnosis of lung adenocarcinoma. The patient was given radiotherapy of osteolytic lesion in her right pubic ramus and the pain was controlled with a combination of morphine sulfate. Conclusions. When unusual bone metastasis is found in the absence of a primary tumor, investigation must include chest radiographs. (author)

  8. Crosstalk between cancer cells and bone microenvironment in bone metastasis

    International Nuclear Information System (INIS)

    Bone, as well as lung and liver, is one of the most preferential metastatic target sites for cancers including breast, prostate, and lung cancers. Although the precise molecular mechanisms underlying this preference need to be elucidated, it appears that bone microenvironments possess unique biological features that enable circulating cancer cells to home, survive and proliferate, and destroy bone. In conjunction, cancers that develop bone metastases likely have the capacity to utilize these unique bone environments for colonization and bone destruction. This crosstalk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. Disruption of this interaction will allow us to design mechanism-based effective and specific therapeutic interventions for bone metastases

  9. Targeting bone remodeling by isoflavone and 3,3'-diindolylmethane in the context of prostate cancer bone metastasis.

    Directory of Open Access Journals (Sweden)

    Yiwei Li

    Full Text Available Prostate cancer (PCa bone metastases have long been believed to be osteoblastic because of bone remodeling leading to the formation of new bone. However, recent studies have shown increased osteolytic activity in the beginning stages of PCa bone metastases, suggesting that targeting both osteolytic and osteoblastic mediators would likely inhibit bone remodeling and PCa bone metastasis. In this study, we found that PCa cells could stimulate differentiation of osteoclasts and osteoblasts through the up-regulation of RANKL, RUNX2 and osteopontin, promoting bone remodeling. Interestingly, we found that formulated isoflavone and 3,3'-diindolylmethane (BR-DIM were able to inhibit the differentiation of osteoclasts and osteoblasts through the inhibition of cell signal transduction in RANKL, osteoblastic, and PCa cell signaling. Moreover, we found that isoflavone and BR-DIM down-regulated the expression of miR-92a, which is known to be associated with RANKL signaling, EMT and cancer progression. By pathway and network analysis, we also observed the regulatory effects of isoflavone and BR-DIM on multiple signaling pathways such as AR/PSA, NKX3-1/Akt/p27, MITF, etc. Therefore, isoflavone and BR-DIM with their multi-targeted effects could be useful for the prevention of PCa progression, especially by attenuating bone metastasis mechanisms.

  10. Malar Bone Metastasis Revealing a Papillary Thyroid Carcinoma

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    Ihsen Slim

    2012-01-01

    Full Text Available Papillary thyroid carcinoma is the most common form of differentiated thyroid carcinoma. It is generally confined to the neck with or without spread to regional lymph nodes. Metastatic thyroid carcinomas are uncommon and mainly include lung and bone. Metastases involving oral and maxillofacial region are extremely rare. We described a case of malar metastasis revealing a follicular variant of papillary thyroid carcinoma, presenting with pain and swelling of the left cheek in a 67-years-old female patient with an unspecified histological left lobo-isthmectomy medical history. To our knowledge, this is the first recorded instance of a malar metastasis from a follicular variant of papillary thyroid carcinoma.

  11. From Prostate to Bone: Key Players in Prostate Cancer Bone Metastasis

    OpenAIRE

    Thobe, Megan N.; Rinker-Schaeffer, Carrie W.; Clark, Robert J; Bainer, Russell O.; Prasad, Sandip M.

    2011-01-01

    Bone is the most common site for metastasis in human prostate cancer patients. Skeletal metastases are a significant cause of morbidity and mortality and overall greatly affect the quality of life of prostate cancer patients. Despite advances in our understanding of the biology of primary prostate tumors, our knowledge of how and why secondary tumors derived from prostate cancer cells preferentially localize bone remains limited. The physiochemical properties of bone, and signaling molecules ...

  12. Tumor-derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells

    OpenAIRE

    Sethi, Nilay; Dai, Xudong; Winter, Christopher G.; Kang, Yibin

    2011-01-01

    Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway’s contribution to metastasis remains unknown. Here we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cyto...

  13. Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo.

    Science.gov (United States)

    Holen, I; Walker, M; Nutter, F; Fowles, A; Evans, C A; Eaton, C L; Ottewell, P D

    2016-03-01

    Clinical trials have shown that adjuvant Zoledronic acid (ZOL) reduces the development of bone metastases irrespective of ER status. However, post-menopausal patients show anti-tumour benefit with ZOL whereas pre-menopausal patients do not. Here we have developed in vivo models of spontaneous ER+ve breast cancer metastasis to bone and investigated the effects of ZOL and oestrogen on tumour cell dissemination and growth. ER+ve (MCF7, T47D) or ER-ve (MDA-MB-231) cells were administered by inter-mammary or inter-cardiac injection into female nude mice ± estradiol. Mice were administered saline or 100 μg/kg ZOL weekly. Tumour growth, dissemination of tumour cells in blood, bone and bone turnover were monitored by luciferase imaging, histology, flow cytometry, two-photon microscopy, micro-CT and TRAP/P1NP ELISA. Estradiol induced metastasis of ER+ve cells to bone in 80-100 % of animals whereas bone metastases from ER-ve cells were unaffected. Administration of ZOL had no effect on tumour growth in the fat pad but significantly inhibited dissemination of ER+ve tumour cells to bone and frequency of bone metastasis. Estradiol and ZOL increased bone volume via different mechanisms: Estradiol increased activity of bone forming osteoblasts whereas administration of ZOL to estradiol supplemented mice decreased osteoclast activity and returned osteoblast activity to levels comparable to that of saline treated mice. ER-ve cells require increased osteoclast activity to grow in bone whereas ER+ve cells do not. Zol does not affect ER+ve tumour growth in soft tissue, however, inhibition of bone turnover by ZOL reduced dissemination and growth of ER+ve breast cancer cells in bone. PMID:26585891

  14. Bioinformatics analysis of breast cancer bone metastasis related gene-CXCR4

    Institute of Scientific and Technical Information of China (English)

    Heng-Wei Zhang; Xian-Fu Sun; Ya-Ning He; Jun-Tao Li; Xu-Hui Guo; Hui Liu

    2013-01-01

    Objective: To analyze breast cancer bone metastasis related gene-CXCR4. Methods: This research screened breast cancer bone metastasis related genes by high-flux gene chip. Results:It was found that the expressions of 396 genes were different including 165 up-regulations and 231 down-regulations. The expression of chemokine receptor CXCR4 was obviously up-regulated in the tissue with breast cancer bone metastasis. Compared with the tissue without bone metastasis, there was significant difference, which indicated that CXCR4 played a vital role in breast cancer bone metastasis. Conclusions: The bioinformatics analysis of CXCR4 can provide a certain basis for the occurrence and diagnosis of breast cancer bone metastasis, target gene therapy and evaluation of prognosis.

  15. Bioinformatics analysis of breast cancer bone metastasis related geneCXCR4

    Institute of Scientific and Technical Information of China (English)

    Heng-Wei; Zhang; Xian-Fu; Sun; Ya-Ning; He; Jun-Tao; Li; Xu-Hui; Guo; Hui; Liu

    2013-01-01

    Objective:To analyze breast cancer bone metastasis related gene-CXCR4.Methods:This research screened breast cancer bone metastasis related genes by high-flux gene chip.Results:It was found that the expressions of 396 genes were different including 165 up-regulations and 231 down-regulations.The expression of chemokine receptor CXCR4 was obviously upregulated in the tissue with breast cancer bone metastasis.Compared with the tissue without hone metastasis,there was significant difference,which indicated that CXCR4 played a vital role in breast cancer bone metastasis.Conclusions:The hioinformatics analysis of CXCR4 can provide a certain basis for the occurrence and diagnosis of breast cancer bone metastasis,target gene therapy and evaluation of prognosis.

  16. Differentiation of multiple myeloma and metastasis : emphasis on bone marrow involvement pattern of spine in sagittal MR images

    International Nuclear Information System (INIS)

    To differentiate multiple myeloma and metastasis of the spine. Retrospective analysis of MR images of the patients with multifocal spinal involvement of multiple myeloma and metastasis was done. Analysis was done in viw points of bone marrow involvement pattern(focal, diffuse, and mixed), margin, number, size and uniformity of the focal lesions, involvement of pedicle and posterior element, and epidural and paravertebral mass formation. Multiple myeloma predominantly showed diffuse pattern (11/21, 52.4%) of marrow involvement, while metastasis showed mainly focal pattern (18/21, 85.7%). Margin of the focal lesions were distinct in majority (8/10, 80%) of multiple myeloma and indistinct in majority (16/21, 76.2%) of metastasis. Size of the focal lesions were smaller in cases of multiple myeloma than those of metastasis, but number and standard deviation of the size of the focal lesions did not show significant difference between the two diseases. Involvement of posterior element were more common in multiple myeloma, and epidural mass formation and paravertebral mass formation were more common in metastasis. The diffuse pattern of marrow involvement alone suggests multiple myeloma. When a focal or a mixed pattern is found, distinct margin and smaller focal lesions are suggestive of multiple myeloma, and indistinct margin and larger focal lesions and epidural/ paravertebral mass formation are suggestive of metastasis

  17. Orbital metastasis: A rare manifestation of scapular bone osteosarcoma

    Directory of Open Access Journals (Sweden)

    Mohammad Taher Rajabi

    2014-01-01

    Full Text Available Purpose: To report a case of orbital metastasis from scapular bone osteosarcoma. Case Report: A 55-year-old man who was a known case of scapular bone osteosarcoma, was referred to our clinic with ocular symptoms including acute painful decreased vision, proptosis, conjunctival injection, and chemosis. He had undergone surgical excision of the original tumor and received systemic chemotherapy 4 months before. Imaging studies and incisional biopsy were performed for the orbital lesion, the histopathological examination confirmed the diagnosis of metastatic osteosarcoma. The patient was referred to the oncologist for palliative chemotherapy and further intervention; however, he deceased 2 months later due to sepsis in the context of immunosuppression. Conclusion: Metastatic involvement of the orbit due to osteosarcoma is a rare condition manifesting with orbital mass, pain, diplopia and ocular motility disturbance. Although there is no effective treatment, the combination of modalities such as chemotherapy, radiotherapy, and surgery may delay progression of the disease.

  18. Bone position emission tomography with or without CT Is more accurate than bone scan for detection of bone metastasis

    International Nuclear Information System (INIS)

    Na18F bone positron emission tomography (bone PET) is a new imaging modality which is useful for the evaluation of bone diseases. Here, we compared the diagnostic accuracies between bone PET and bone scan for the detection of bone metastasis (BM). Sixteen cancer patients (M:F = 10:6, mean age = 60 ± 12 years) who underwent both bone PET and bone scan were analyzed. Bone PET was conducted 30 minutes after the injection of 370 MBq Na18F, and a bone scan was performed 3 hours after the injection of 1295 MBq 99mTc-hydroxymethylene diphosphonate. In the patient-based analysis (8 patients with BM and 8 without BM), the sensitivities of bone PET (100% 8/8) and bone scan (87.5% = 7/8) were not significantly different (p > 0.05), whereas the specificity of bone PET (87.5% = 7/8) was significantly greater than that of the bone scan (25% = 2/8) (p 8F bone PET is more accurate than bone scan for BM evaluation.

  19. Natural history of malignant bone disease in renal cancer: final results of an Italian bone metastasis survey.

    Directory of Open Access Journals (Sweden)

    Daniele Santini

    Full Text Available BACKGROUND: Bone metastasis represents an increasing clinical problem in advanced renal cell carcinoma (RCC as disease-related survival improves. There are few data on the natural history of bone disease in RCC. PATIENTS AND METHODS: Data on clinicopathology, survival, skeletal-related events (SREs, and bone-directed therapies for 398 deceased RCC patients (286 male, 112 female with evidence of bone metastasis were statistically analyzed. RESULTS: Median time to bone metastasis was 25 months for patients without bone metastasis at diagnosis. Median time to diagnosis of bone metastasis by MSKCC risk was 24 months for good, 5 months for intermediate, and 0 months for poor risk. Median number of SREs/patient was one, and 71% of patients experienced at least one SRE. Median times to first, second, and third SRE were 2, 5, and 12 months, respectively. Median survival was 12 months after bone metastasis diagnosis and 10 months after first SRE. Among 181 patients who received zoledronic acid (ZOL, median time to first SRE was significantly prolonged versus control (n = 186 (3 months vs 1 month for control; P<0.05. CONCLUSIONS: RCC patients with bone metastasis are at continuous risk of SREs, and in this survey ZOL effectively reduced this risk.

  20. Potential of targeted drug delivery system for the treatment of bone metastasis.

    Science.gov (United States)

    Vinay, Raichur; KusumDevi, V

    2016-01-01

    Bone metastasis is a devastating complication of cancer that requires an immediate attention. Although our understanding of the metastatic process has improved over the years, yet a number of questions still remain unanswered, and more research is required for complete understanding of the skeletal consequences of metastasis. Furthermore, as no effective treatments are available for some of the most common skeleton disorders such as arthritis, osteoarthritis, osteosarcoma and metastatic bone cancer, there is an urgent need to develop new drugs and drug delivery systems for safe and efficient clinical treatments. Hence this article describes the potential of targeted delivery platforms aimed specifically at bone metastasized tumors. The review gives a brief understanding of the proposed mechanisms of metastasis and focuses primarily on the targeting moieties such as bisphosphonates, which represent the current gold standard in bone metastasis therapies. Special focus has been given to the targeted nanoparticulate systems for treating bone metastasis and its future. Also highlighted are some of the therapeutic targets that can be exploited for designing therapies for bone metastasis. Some of the patented molecules for bone metastasis prevention and treatment have also been discussed. Recently proposed HIFU-CHEM, which utilizes High Intensity Focused ultrasound (HIFU) guided by MRI in combination with temperature-sensitive nanomedicines has also been briefed. The study has been concluded with a focus on the innovations requiring an immediate attention that could improve the treatment modality of bone metastasis. PMID:24839990

  1. An open cohort study of bone metastasis incidence following surgery in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Yoshimoto Masataka

    2010-07-01

    Full Text Available Abstract Background To help design clinical trials of adjuvant bisphosphonate therapy for breast cancer, the temporal incidence of bone metastasis was investigated in a cohort of patients. We have tried to draw the criteria to use adjuvant bisphosphonate. Methods Consecutive breast cancer patients undergoing surgery between 1988 and 1998 (5459 patients were followed up regarding bone metastasis until December 2006. Patients' characteristics at the time of surgery were analyzed by Cox's method, with bone metastasis as events. Patient groups were assigned according to Cox's analysis, and were judged either to require the adjuvant bisphosphonate or not, using the tentative criteria: high risk (>3% person-year, medium risk (1-3%, and low risk ( Results Bone metastasis incidence was constant between 1.0 and 2.8% per person-year more than 10 years. Non-invasive cancer was associated with a very low incidence of bone metastasis (1/436. Multivariate Cox's analysis indicated important factors for bone metastasis were tumor grade (T, nodal grade (pN, and histology. Because T and pN were important factors for bone metastasis prediction, subgroups were made by pTNM stage. Patients at stages IIIA, IIIB and IV had an incidence of >3% per person-year, patients with stage I Conclusions Bone metastasis incidence remained constant for many years. Using pN, T, and histopathology, patients could be classified into high, medium, and low risk groups.

  2. Superparamagnetic iron oxide (SPIO) MRI contrast agent for bone marrow imaging. Differentiating bone metastasis and osteomyelitis

    International Nuclear Information System (INIS)

    We explored appropriate scan timing for bone marrow imaging enhanced using superparamagnetic iron oxide (SPIO) and evaluated the usefulness of SPIO in differentiating metastasis and osteomyelitis in patients. The method of this study was to determine the adequate scan timing after administration of SPIO, 5 healthy subjects were examined using a 1.5T magnetic resonance (MR) imaging scanner. Sagittal images of their lumbar spines were obtained using short-TI inversion recovery (STIR) sequence before and 3, 6, 9, 24, and 48 hours after intravenous injection of 8 μmol Fe/kg SPIO (ferucarbotran). MR signal intensities (SIs) were evaluated. Based on the results, 12 patients, five with bone metastasis and seven with vertebral osteomyelitis, were examined using the same procedure before and 3 hours after intravenous injection of ferucarbotran at the same dose. SIs of the bone metastases, osteomyelitis, and surrounding normal bone marrow were measured, and relative enhancement (RE) was calculated for each lesion. In the healthy volunteers, maximum reduction in signal was observed 3 to 24 hours (P<0.05) after administration of SPIO; thereafter and up to 48 hours, the SI gradually recovered. In the patients, the RE of the bone metastases was -12.2%, which was significantly higher than that in the osteomyelitis (- 35.0%, P<.001) and normal bone marrow (-46.6%, P<.0005). Maximum suppression of signal intensity in bone marrow was seen 3 hours after injection of ferucarbotran, the point at which ferucarbotran allows differentiation of bone metastasis from ostoemyelitis. (author)

  3. Predictors of Survival in Patients With Bone Metastasis of Lung Cancer

    OpenAIRE

    Sugiura, Hideshi; Yamada, Kenji; Sugiura, Takahiko; Hida, Toyoaki; Mitsudomi, Tetsuya

    2008-01-01

    The prognosis of patients with bone metastasis from lung cancer has not been well documented. We assessed the survival rates after bone metastasis and prognostic factors in 118 patients with bone metastases from lung cancer. The cumulative survival rates after bone metastasis from lung cancer were 59.9% at 6 months, 31.6% at 1 year, and 11.3% at 2 years. The mean survival was 9.7 months (median, 7.2 months; range, 0.1–74.5 months). A favorable prognosis was more likely in women and patients w...

  4. Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.

    Science.gov (United States)

    Faltermeier, Claire M; Drake, Justin M; Clark, Peter M; Smith, Bryan A; Zong, Yang; Volpe, Carmen; Mathis, Colleen; Morrissey, Colm; Castor, Brandon; Huang, Jiaoti; Witte, Owen N

    2016-01-12

    Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention. PMID:26621741

  5. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis

    Directory of Open Access Journals (Sweden)

    Sourik S Ganguly

    2014-12-01

    Full Text Available Prostate cancer (PCa is the second leading cause of cancer death in men worldwide. Most PCa patients die with osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. In this revew, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT to promote PCa progression, invasion, and metastasis. We discuss how the bone microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

  6. Survival in patients with breast cancer with bone metastasis

    DEFF Research Database (Denmark)

    Cetin, Karynsa; Christiansen, Christian Fynbo; Sværke, Claus;

    2015-01-01

    OBJECTIVES: Since population-based data on prognostic factors affecting survival in patients with breast cancer with bone metastasis (BM) are currently limited, we conducted this nationwide retrospective cohort study to examine the prognostic role of disease stage at breast cancer diagnosis and...... length of BM-free interval (BMFI). SETTING: Denmark. PARTICIPANTS: 2427 women with a breast cancer diagnosis between 1997 and 2011 in the Danish Cancer Registry and a concurrent or subsequent BM diagnosis in the Danish National Registry of Patients. PRIMARY AND SECONDARY OUTCOME MEASURES: Survival (crude......), following patients from BM diagnosis until death, emigration or until 31 December 2012, whichever came first. RESULTS: Survival decreased with more advanced stage of disease at the time of breast cancer diagnosis; risk of mortality during the first year following a BM diagnosis was over two times higher for...

  7. Establishment of Animal Model for Bone Metastasis of Walker 256 Breast Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    PANG; Fang-fang; SHEN; Hong-tao; HE; Ming; DONG; Ke-jun; WU; Shao-yong; DOU; Liang; SHI; Yan-jun; ZHANG; Shuang; WANG; Xiao-ming; ZHAO; Qin-zhang; YANG; Xu-ran; XU; Yong-ning; LAN; Xiao-xi; CAI; Li; JIANG; Shan

    2013-01-01

    Bone metastasis is a common complication of cancer.It often occurs in lung,breast and prostate cancer,and may cause osteolytic lesions,or cause few osteoblastic lesions.It has already advanced cancer When cancer metastasis to bone,which usually cannot be cured.It is one of the important factors leading to the death of cancer patients.Studying animal model of bone

  8. Preventive Effects of Zoledronic Acid on Bone Metastasis in Mice Injected with Human Breast Cancer Cells

    OpenAIRE

    Jeong, Joon; Lee, Kyung Sun; Choi, Yang-Kyu; Oh, Young Ju; Lee, Hy-De

    2011-01-01

    Bisphosphonates are used routinely to reduce bone-related events in breast cancer patients with bone metastasis. We evaluated the effects of zoledronic acid, a third generation, nitrogen-containing bisphosphonate, to prevent bone metastasis in breast cancer. Zoledronic acid or vehicle alone was administered to nude mice either simultaneously or after intracardiac injection of human breast cancer MDA-MB-231 cells. Nude mice treated with zoledronic acid at early time points showed a lower incid...

  9. Molecular mechanism of bone formation and regeneration

    Institute of Scientific and Technical Information of China (English)

    Akira Yamaguchi

    2008-01-01

    @@ Bone formation and regeneration are mediated by the coordinate action of various factors. Among these, bone morphogenetic protein (BMP) and runt-related gene 2 (Runx2) play crucial roles in bone formation.

  10. Internal targeted radiotherapy for bone metastasis: what about underlying physiopathology

    International Nuclear Information System (INIS)

    Once tumours metastasize to bone, they are usually incurable and responsible for several devastating consequences: severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression and other nerve-compression syndromes. Understanding of physiopathological mechanisms responsible for these symptoms is critical for therapeutic approach, especially pain treatments. Three types of pain occur in tumour bone involvement: tonic or background pain, which are deep non-specific ache rising in intensity as the disease progresses; incident pain on movement (allodynia); and spontaneous pain which can be severe. Bone metastases could be osteolytic or osteoblastic. However, this classification actually represents two extremes of a continuum characterized by dys-regulation of the normal bone remodeling process. Biochemical mediators production is crucial as a part of this process. The bone microenvironment plays a critical role in the formation of osteoclasts through the production of macrophage colony-stimulating factor, receptor activator of nuclear factor kB ligand (RANKL)... Many of these mediators of osteolysis also have been shown to activate nociceptors: prostaglandins A and E, IL-1, IL-6, TNF. Thus there is a link between osteolytic destruction, inflammation and pain. It explains that severe pain could occur independently from fractures and in absence of any bone structure alteration and nervous compression. Also, pain is often disproportionate to tumour size or degree of bone involvement. Inflammatory and osteolytic processes depend on number, localization and organization of tumour cells inside bone and bone marrow tissues. All these parameters are crucial to take into account for a good understanding of treatments mechanisms of action, especially anti-inflammatory drugs (corticosteroid and others), bi-phosphonates, internal radiotherapy (strontium 89 or radiolabelled bi-phosphonates), external radiotherapy and chemotherapy or hormonotherapy

  11. Future directions for bone metastasis research – highlights from the 2015 bone and the Oncologist new updates conference (BONUS

    Directory of Open Access Journals (Sweden)

    Ricardo Fernandes

    2016-06-01

    Full Text Available In an era of reduced peer-reviewed grant funding, performing academic bone oncology-related research has become increasingly challenging. Over the last 10 years we have held an annual meeting to bring together clinicians, clinician/scientists and basic biomedical researchers interested in the effects of cancer and its treatment on skeletal tissues. In the past these “Bone and the Oncologist New Updates Conference (BONUS” meetings have served as critical catalyst for initiating productive research collaborations between attendees. The 2015 BONUS meeting format focused on potential key research themes that could form the basis of a coordinated national research strategy to tackle unmet clinical and research needs related to complications associated with cancer metastasis to bone. The three themes planned for discussion were: Is bone metastases-related pain the main issue facing patients? Are there new therapeutic targets for patients with bone metastases? How do we more firmly link basic science with clinical practice? We present a summary of lectures and commentaries from the attendees to serve as an example that other similarly motivated groups can model and share their experiences. It is our hope that these presentations will result in comments, feedback and suggestions from all those researchers interested in this important area.

  12. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis.

    Science.gov (United States)

    Wang, Zhe; Xiong, Shanshan; Mao, Yubin; Chen, Mimi; Ma, Xiaohong; Zhou, Xueliang; Ma, Zhenling; Liu, Fan; Huang, Zhengjie; Luo, Qi; Ouyang, Gaoliang

    2016-08-01

    Periostin (POSTN) is a limiting factor in the metastatic colonization of disseminated tumour cells. However, the role of POSTN in regulating the immunosuppressive function of immature myeloid cells in tumour metastasis has not been documented. Here, we demonstrate that POSTN promotes the pulmonary accumulation of myeloid-derived suppressor cells (MDSCs) during the early stage of breast tumour metastasis. Postn deletion decreases neutrophil and monocytic cell populations in the bone marrow of mice and suppresses the accumulation of MDSCs to premetastatic sites. We also found that POSTN-deficient MDSCs display reduced activation of ERK, AKT and STAT3 and that POSTN deficiency decreases the immunosuppressive functions of MDSCs during tumour progression. Moreover, the pro-metastatic role of POSTN is largely limited to ER-negative breast cancer patients. Lysyl oxidase contributes to POSTN-promoted premetastatic niche formation and tumour metastasis. Our findings indicate that POSTN is essential for immunosuppressive premetastatic niche formation in the lungs during breast tumour metastasis and is a potential target for the prevention and treatment of breast tumour metastasis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27193093

  13. The Roles of Epithelial-to-Mesenchymal Transition (EMT and Mesenchymal-to-Epithelial Transition (MET in Breast Cancer Bone Metastasis: Potential Targets for Prevention and Treatment

    Directory of Open Access Journals (Sweden)

    Binnaz Demirkan

    2013-11-01

    Full Text Available Many studies have revealed molecular connections between breast and bone. Genes, important in the control of bone remodeling, such as receptor activator of nuclear kappa (RANK, receptor activator of nuclear kappa ligand (RANKL, vitamin D, bone sialoprotein (BSP, osteopontin (OPN, and calcitonin, are expressed in breast cancer and lactating breast. Epithelial-mesenchymal transition (EMT and mesenchymal-epithelial transition (MET effectors play critical roles during embryonic development, postnatal growth, and epithelial homeostasis, but also are involved in a number of pathological conditions, including wound repair, fibrosis, inflammation, as well as cancer progression and bone metastasis. Transforming growth factor β (TGFβ, insulin-like growth factor I & II (IGF I & II, platelet-derived growth factor (PDGF, parathyroid hormone-related protein (PTH(rP, vascular endothelial growth factor (VEGF, epithelial growth factors II/I (ErbB/EGF, interleukin 6 (IL-6, IL-8, IL-11, IL-1, integrin αvβ3, matrix metalloproteinases (MMPs, catepsin K, hypoxia, notch, Wnt, bone morphogenetic proteins (BMP, and hedgehog signaling pathways are important EMT and MET effectors identified in the bone microenviroment facilitating bone metastasis formation. Recently, Runx2, an essential transcription factor in the regulation of mesenchymal cell differentiation into the osteoblast lineage and proper bone development, is also well-recognized for its expression in breast cancer cells promoting osteolytic bone metastasis. Understanding the precise mechanisms of EMT and MET in the pathogenesis of breast cancer bone metastasis can inform the direction of therapeutic intervention and possibly prevention.

  14. RUNX2 promotes breast cancer bone metastasis by increasing integrin α5-mediated colonization.

    Science.gov (United States)

    Li, Xiao-Qing; Lu, Jun-Tao; Tan, Cong-Cong; Wang, Qing-Shan; Feng, Yu-Mei

    2016-09-28

    Runt-related transcription factor 2 (RUNX2) is regarded as an important contributor to breast cancer bone metastasis. However, previous studies did not provide direct clinical evidence for a role of RUNX2 in bone-specific metastasis in breast cancer, and the mechanism of RUNX2 in cancer cell recruitment and adhesion to the bone remains unclear. In this study, we showed that RUNX2 expression is positively correlated with the risk of bone-specific metastasis in lymph node-negative breast cancer patients. Then, we identified ITGA5 as a transcriptional target of RUNX2 from multiple candidate genes encoding adhesion molecules or chemokine receptors. We further provided experimental and clinical evidence that RUNX2, in an integrin α5-dependent manner, promotes the attraction and adhesion of breast cancer cells to the bone and confers cancer cell survival and bone colonization advantages. Overall, our findings clarify an adhesion-dependent mechanism of RUNX2 for the osteotropism and bone colonization of breast cancer cells and implicate RUNX2 and integrin α5 as potential molecular markers for the prediction of bone metastasis and therapeutic targets for the treatment of breast cancer bone metastasis. PMID:27317874

  15. Recombinant human bone morphogenetic protein induces bone formation

    International Nuclear Information System (INIS)

    The authors have purified and characterized active recombinant human bone morphogenetic protein (BMP) 2A. Implantation of the recombinant protein in rats showed that a single BMP can induce bone formation in vivo. A dose-response and time-course study using the rat ectopic bone formation assay revealed that implantation of 0.5-115 μg of partially purified recombinant human BMP-2A resulted in cartilage by day 7 and bone formation by day 14. The time at which bone formation occurred was dependent on the amount of BMP-2A implanted; at high doses bone formation could be observed at 5 days. The cartilage- and bone-inductive activity of the recombinant BMP-2A is histologically indistinguishable from that of bone extracts. Thus, recombinant BMP-2A has therapeutic potential to promote de novo bone formation in humans

  16. The impact of bone morphogenetic protein 4 (BMP4) on breast cancer metastasis in a mouse xenograft model.

    Science.gov (United States)

    Ampuja, M; Alarmo, E L; Owens, P; Havunen, R; Gorska, A E; Moses, H L; Kallioniemi, A

    2016-06-01

    Bone morphogenetic protein 4 (BMP4) is a key regulator of cell proliferation and differentiation. In breast cancer cells, BMP4 has been shown to reduce proliferation in vitro and interestingly, in some cases, also to induce migration and invasion. Here we investigated whether BMP4 influences breast cancer metastasis formation by using a xenograft mouse model. MDA-MB-231 breast cancer cells were injected intracardially into mice and metastasis formation was monitored using bioluminescence imaging. Mice treated with BMP4 developed metastases slightly earlier as compared to control animals but the overall number of metastases was similar in both groups (13 in the BMP4 group vs. 12 in controls). In BMP4-treated mice, bone metastases were more common (10 vs. 7) but adrenal gland metastases were less frequent (1 vs. 5) than in controls. Immunostaining revealed no differences in signaling activation, proliferation rate, blood vessel formation, EMT markers or the number of cancer-associated fibroblasts between the treatment groups. In conclusion, BMP4 caused a trend towards accelerated metastasis formation, especially in bone. More work is needed to uncover the long-term effects of BMP4 and the clinical relevance of these findings. PMID:26970275

  17. DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA

    OpenAIRE

    Rahman, M.; Veigas, Maria; Williams, Paul J.; Fernandes, Gabriel

    2013-01-01

    Breast cancer patients often develop bone metastasis evidenced by osteolytic lesions, leading to severe pain and bone fracture. Attenuation of breast cancer metastasis to bone and associated osteolysis by fish oil (FO), rich in EPA and DHA, has been demonstrated previously. However, it was not known whether EPA and DHA differentially or similarly affect breast cancer bone metastasis and associated osteolysis. In vitro culture of parental and luciferase gene encoded MDA-MB-231 human breast can...

  18. Study on 41Ca-AMS for diagnosis and assessment of cancer bone metastasis in rats

    Science.gov (United States)

    Shen, Hongtao; Pang, Fangfang; Jiang, Shan; He, Ming; Dong, Kejun; Dou, Liang; Pang, Yijun; Yang, Xianlin; Ruan, Xiangdong; Liu, Manjun; Xia, Chunbo

    2015-10-01

    The annual incidence of new cancer patients in China is about 2 million, 30-40% of which will end up with bone metastasis. Profound study on the preclinical model and early diagnosis of cancer bone metastasis in rats are very significant for the drug development, better understanding and treatment of bone metastases. In order to monitor the process of bone metabolism and early detection of bone metastasis of cancer cells, a technique of 41Ca isotope tracer combined with AMS has been developed and applied in the study on the bone metastasis of cancer cells by rat model. In this work, 3-month-old female Sprague-Dawley (SD) rats were randomly divided into different groups, and tumor cells injected respectively into the tail vein, femoral artery, femoral cavity and the thigh muscle to establish the rat models for bone metastases. The most appropriate model, i.e., the thigh muscle group, was finally adopted in our real metastases experiment. Each rat in this group was intramuscularly (i.m.) injected with 250 μl CaCl2 solution (containing 1.4 mg Ca and 5nCi 41Ca). About 40 days later, the rat mammary gland carcinoma cells (Walker 256) were injected into these rats following the established protocol. After bone metastasis, medicine interventions were performed. The sequential urine and blood samples were collected and analyzed for 41Ca (by AMS) and N-terminal telopeptide (Ntx), respectively. Bone Mineral Density (BMD) values in the femur and the tibia were measured by CT scan. The results of 41Ca/Ca in longitudinal urinary samples can sensitively reveal the skeletal perturbations caused by bone metastasis of rats, suggests that 41Ca might be similarly developed for human use and improve clinical management through the assessment of the curative effect and non-invasive detection of the earliest stages of cancer growth in bone.

  19. Searching early bone metastasis on plain radiography by using digital imaging processing

    Energy Technology Data Exchange (ETDEWEB)

    Jaramillo-Nunez, A.; Perez-Meza, M. [Instituto Nacional de Astrofisica, Optica y Electronica, Apdo. Postal 51 y 216, Pue. (Mexico); Universidad de la Sierra Sur, C. P. 70800, Miahuatlan, Oax. (Mexico)

    2012-10-23

    Some authors mention that it is not possible to detect early bone metastasis on plain radiography. In this work we use digital imaging processing to analyze three radiographs taken from a patient with bone metastasis discomfort on the right shoulder. The time period among the first and second radiography was approximately one month and between the first and the third one year. This procedure is a first approach in order to know if in this particular case it was possible to detect an early bone metastasis. The obtained results suggest that by carrying out a digital processing is possible to detect the metastasis since the radiography contains the information although visually it is not possible to observe it.

  20. Prognostic Evaluation of Nasopharyngeal Carcinoma with Bone-Only Metastasis after Therapy

    Science.gov (United States)

    Lu, Tianzhu; Guo, Qiaojuan; Cui, Xiaofei; Chen, Zhuhong; Lin, Shaojun; Xu, Luying; Lin, Jin; Zong, Jingfeng

    2016-01-01

    Purpose To evaluate the prognosis of nasopharyngeal carcinoma (NPC) patients who developed bone-only metastasis after primary treatment and the stratification of these patients into different risk groups based on independent prognostic factors. Materials and Methods Eighty NPC patients who developed bone-only metastasis after definitive radiotherapy from October 2005 to December 2010 were enrolled. All these patients received palliative treatment for bone metastasis, including chemotherapy and/or radiotherapy. Clinical features, treatment modality, and laboratory parameters were examined with univariate and multivariate analyses. Results The median follow-up time was 15.5 months (range, 2–67 months) for the whole cohort. The median overall metastatic survival (OMS) time and the 2-year estimate OMS rate were 26.5 months and 52%, respectively. Multivariate analysis indicated that patients with short metastases-free interval, multiple bone metastases sites, high serum lactic dehydrogenase levels, and treated with radiotherapy or chemotherapy alone had significantly worse outcomes. Patients were stratified into three different risk groups based on the number of adverse factors present. The OMS curves of the three groups were all significantly different (pnumber of adverse factors present, bone-only metastasis patients can be stratified into three risk groups with significantly different prognoses. Such grouping may help in improving the design of clinical trials and in guiding individualized treatment for NPC patients with bone-only metastasis. PMID:27189275

  1. Osteolytic bone metastasis is hampered by impinging on the interplay among autophagy, anoikis and ossification.

    Science.gov (United States)

    Maroni, P; Bendinelli, P; Matteucci, E; Locatelli, A; Nakamura, T; Scita, G; Desiderio, M A

    2014-01-01

    Here we show that the fate of osteolytic bone metastasis depends on the balance among autophagy, anoikis resistance and ossification, and that the hepatocyte growth factor (HGF) signaling pathway seems to have an important role in orchestrating bone colonization. These findings are consistent with the pathophysiology of bone metastasis that is influenced by the cross-talk of supportive and neoplastic cells through molecular signaling networks. We adopted the strategy to target metastasis and stroma with the use of adenovirally expressed NK4 (AdNK4) and Dasatinib to block HGF/Met axis and Src activity. In human bone metastatic 1833 cells, HGF conferred anoikis resistance via Akt and Src activities and HIF-1α induction, leading to Bim isoforms degradation. When Src and Met activities were inhibited with Dasatinib, the Bim isoforms accumulated conferring anoikis sensitivity. The proviability effect of HGF, under low-nutrient stress condition, was related to a faster autophagy deactivation with respect to HGF plus Dasatinib. In the 1833 xenograft model, AdNK4 switched metastasis vasculature to blood lacunae, increasing HIF-1α in metastasis. The combination of AdNK4 plus Dasatinib gave the most relevant results for mice survival, and the following molecular and cellular changes were found to be responsible. In bone metastasis, we observed a hypoxic condition - marked by HIF-1α - and an autophagy failure - marked by p62 without Beclin-1. Then, osteolytic bone metastases were largely prevented, because of autophagy failure in metastasis and ossification in bone marrow, with osteocalcin deposition. The abnormal repair process was triggered by the dysfunctional autophagy/anoikis interplay. In conclusion, the concomitant blockade of HGF/Met axis and Src activity seemed to induce HIF-1α in metastasis, whereas the bone marrow hypoxic response was reduced. As a consequence, anoikis resistance might be hampered favoring, instead, autophagy failure and neoformation of woven

  2. Bone metastasis in patients with para neoplastic myasthenic syndrome - Possible indication for bone scintigraphy

    International Nuclear Information System (INIS)

    Full text: Myasthenia gravis (MG) is a neuromuscular disorder caused by a decrease in the number of acetylcholine receptors at neuromuscular junctions and consequently characterized by weakness and fatigue. Paraneoplastic myasthenic syndrome (PMS) is a neurological disorder often difficult to diagnose in clinical practice, due to the lack, in most cases, of any sign of malignancy at the time when neurological impairment occurs. The connection between MG and pathological alterations of the thymus as well as between the presynaptic membrane alteration (Lambert-Eaton myasthenic syndrome) and the small-cell lung cancer is often demonstrated. Most researchers agree that myasthenic syndrome noticed in aged persons should be investigated as a possible paraneoplastic disorder. The aim of our study was to find if suspected PMS could be an indication to perform a bone scan, in presence of parameters suggesting malignancy (such as elevated serum levels of alkaline phosphatase, elevated tumor markers, unexplained bone pain etc.). Another question is whether bone metastases occur more frequently in malignancies associated with PMS than in the same diseases without neurological involvement, taking into account that neurological disorders are not produced by metastatic or direct invasion of the nervous system by the cancer. Our observations included 28 patients (13 men and 15 women), aged 42-80 years with myasthenic syndrome, who were referred by the neurology department for suspicion of bone metastasis. All patients had elevated serum levels of alkaline phosphatase, 18 patients had therapy-resistant bone and joints pain. Conventional imaging procedures (abdominal ultrasound, chest X-ray and computer tomography) were performed in all patients. Only in 6 patients the primary malignancy was diagnosed prior to bone scan (5 cases with thymoma and 1 case of digestive neoplasm). Bone scan was performed on a Diacam Siemens gamma camera and consisted of whole-body examination after

  3. Two cases of gastrointestinal stromal tumor of the small intestine with liver and bone metastasis.

    Science.gov (United States)

    Aktan, Meryem; Koc, Mehmet; Yavuz, Berrin Benli; Kanyilmaz, Gul

    2015-10-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors most commonly occur in the stomach (60%), jejunum and ileum (30%). Metastasis is characteristically the malignant behavior of the GISTs. GISTs most frequently metastasize to the liver and peritoneum, whereas bone and lung metastases are uncommon sites. Here, we described two cases of bone and liver metastases in patients with advanced GISTs. Both of them showed liver metastasis at disease presentation and bone metastasis in early time after the diagnosis. Bone metastases involved the lumber spine and right femur in first patient and L2 vertebral body in the second case. All of the lesions presented a lytic pattern. These cases are presented because of the rare incidence of bone metastasis to femur and vertebral bodies. More attention should be paid to the diagnosis of bone metastases from GISTs in clinical practice despite the shortage of available data on the sensitivity and specificity of bone scintigraphy and PET-CT. PMID:26605305

  4. The incidence of bone metastasis after early-stage breast cancer in Canada.

    Science.gov (United States)

    Liede, Alexander; Jerzak, Katarzyna J; Hernandez, Rohini K; Wade, Sally W; Sun, Ping; Narod, Steven A

    2016-04-01

    Current information on the incidence and prevalence of bone metastases in women with breast cancer is scarce. This study examined the occurrence and predictors of bone metastases, as well as post-metastasis survival in a prospective cohort of Canadian women with breast cancer. We included women treated for early-stage (stage I, II, or III) breast cancer at the Henrietta Banting Breast Centre (HBBC) in Toronto, Canada between 1987 and 2000. Data were abstracted from medical records and pathology reports in the HBBC database; follow-up extended to end of data availability or August 31, 2015. Actuarial survival analyses provided cumulative incidence of bone metastases at 5, 10, and 15 years after breast cancer diagnosis. Kaplan-Meier curves describe breast cancer mortality. Regression models assessed patient, tumor, and treatment characteristics as predictors of bone metastases with all-cause mortality as a competing risk. Among 2097 women studied, the 5-, 10-, and 15-year probability of bone metastasis was 6.5, 10.3, and 11.3 % for the first recurrence, and 8.4, 12.5, and 13.6 % for any bone recurrence. At median follow-up (12.5 years), 13.2 % of patients had bone metastases. Median survival was 1.6 years following bone metastasis, and shorter if both bone and visceral metastases occurred. Advanced age and adjuvant treatment with tamoxifen were protective against bone metastasis. In this representative cohort of women diagnosed with early-stage breast cancer in Ontario, Canada, with long follow-up, the incidence of bone metastases was consistent with longitudinal studies from the United Kingdom, Denmark, and the US. PMID:27083181

  5. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    OpenAIRE

    Ali Murat Tatlı; Seyda Gunduz; Sema Sezgin Göksu; Deniz Arslan; Mukremin Uysal; Cumhur İbrahim Başsorgun; Hasan Şenol Coşkun

    2013-01-01

    Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient’s history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we ...

  6. Bone formation following implantation of bone biomaterials into extraction sites

    OpenAIRE

    Molly, Liene; Vandromme, Heleen; Quirynen, Marc; Schepers, Evert; Adams, Jessica L; van Steenberghe, Daniel

    2008-01-01

    Background: Adequate bone volume is imperative for the osseointegration of endosseous implants, but post-extraction resorption and remodeling may challenge implant placement. The use of bone biomaterials has been advocated to fill extraction sites and to enhance primary implant stability during osseointegration. The objective of the case series was to evaluate bone formation histologically and biomechanically in extraction sites following implantation of three commercially available bone biom...

  7. Chronic Osteomyelitis in Sternum Mimicking Bone Metastasis of Lung Cancer Patient

    International Nuclear Information System (INIS)

    Primary sternal osteomyelitis without predisposing factors is a rare condition, and it is hardly differentiated from metastatic bone tumor especially in patient with the history of primary malignancy because osteomyelitis shares frequently common findings with metastatic bone lesion on 18F-FDG PET and bone scan. Although there have been several publications of primary osteomyelitis mimicking bone metastasis in the spine or extremities, we report a case of primary sternal osteomyelitis in the patient with lung cancer, which has, to our knowledge, not been reported before

  8. Chronic Osteomyelitis in Sternum Mimicking Bone Metastasis of Lung Cancer Patient

    Energy Technology Data Exchange (ETDEWEB)

    Im, Hyung Jun; Kim, Yu Keong; Lee, Sang Mi; Lee, Won Woo; Kim, Sang Eun [Seoul National University Bundang Hospital, Seoul (Korea, Republic of)

    2009-06-15

    Primary sternal osteomyelitis without predisposing factors is a rare condition, and it is hardly differentiated from metastatic bone tumor especially in patient with the history of primary malignancy because osteomyelitis shares frequently common findings with metastatic bone lesion on {sup 18}F-FDG PET and bone scan. Although there have been several publications of primary osteomyelitis mimicking bone metastasis in the spine or extremities, we report a case of primary sternal osteomyelitis in the patient with lung cancer, which has, to our knowledge, not been reported before.

  9. Spontaneous regression of bone metastasis from renal cell carcinoma; A case report

    International Nuclear Information System (INIS)

    Spontaneous regression of metastatic renal cell carcinoma is rarely observed. Metastatic renal cell carcinoma was identified in a 70-year-old male using computed tomography-guided percutaneous needle biopsy. Two months after the diagnosis, a partial resection of the sternal bone was performed. Pathological examination revealed granulated tissue with bleeding and necrosis but no carcinogenic cells. We report a pathologically identified case in which a sternal bone metastasis that was noticed two years after radical nephrectomy regressed completely and spontaneously

  10. Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation

    OpenAIRE

    ZHAN, JIE; Li, Yahong; Yu, Jing; ZHAO, YUANYAUN; CAO, WENMING; Ma, Jie; Sun, Xiaoxian; Sun, Li; QIAN, HUI; Zhu, Wei; Xu, Wenrong

    2015-01-01

    Human bone marrow mesenchymal stem cells (hBM-MSCs) favor tumor growth and metastasis in vivo and in vitro. Neovascularization is involved in several pathological conditions, including tumor growth and metastasis. Previous studies have demonstrated that human bone marrow MSC-derived conditioned medium (hBM-MSC-CM) can promote tumor growth by inducing the expression of vascular epidermal growth factor (VEGF) in tumor cells. However, the effect of BM-MSCs on tumor lymph vessel formation has yet...

  11. Analysis of bone metastasis in head and neck squamous cell carcinoma: Experience of a regional cancer center

    Directory of Open Access Journals (Sweden)

    Akhil Kapoor

    2015-01-01

    Full Text Available Background: Bone metastasis is a rare occurrence in head and neck squamous cell carcinoma (HNSCC. This retrospective study was performed to analyze the frequency and patterns of skeletal metastasis in HNSCC. Materials and Methods : We analyzed records of 8326 HNSCC patients attending our oncology outpatient department from January 2000 to December 2013. All statistical calculations were performed using MedCalc software for windows, version 12.5.0 (Osterd, Belgium. Results : Bone metastasis was found in 25 patients (0.3% of total HNSCC patients, nasopharynx excluded. 10 patients (0.66% of carcinoma tonsil had skeletal metastasis. The patients of younger age groups had higher frequency of bone metastasis; 1.56% patients of age group 20-29 years while 0.26% patients of 60-69 years age group had skeletal metastasis (P 70 years age was found to have bone metastasis. Most common site of metastasis was spine (56% followed by pelvis (32%. Isolated involvement of a single bony site was present in 64% of the metastatic cases. Conclusion: Bone metastasis though very rare, should be considered for evaluation in patients of HNSCC especially in younger patients.

  12. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis.

    Science.gov (United States)

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-Ichi; Gotoh, Noriko; Mukaida, Naofumi

    2016-08-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. PMID:27177471

  13. Sinonasal Schwannoma with New Bone Formation Expressing Bone Morphogenic Protein

    OpenAIRE

    Satoru Kodama; Tomoyo Okamoto; Masashi Suzuki

    2010-01-01

    Schwannoma is a benign tumor that arises from the sheath of myelinated nerve fibers and may occur in any part of the body. Osteogenesis in schwannoma is extremely rare and, to date, new bone formation in sinonasal schwannoma has not yet been reported. Here, we describe the first reported case of sinonasal schwannoma with new bone formation. The tumor was successfully treated by endoscopic sinus surgery, and the patient showed no evidence of recurrence 24 months postoperatively. Immunohistoche...

  14. Three-Dimensional Cancer-Bone Metastasis Model Using Ex-Vivo Co-Cultures of Live Calvarial Bones and Cancer Cells

    OpenAIRE

    Curtin, Paul; Youm, Helen; Salih, Erdjan

    2011-01-01

    One of the major limitations of studying cancer-bone metastasis has been the lack of an appropriate ex-vivo model which can be used under defined conditions that simulates closely the in vivo live bone microenvironment in response to cancer-bone interactions. We have developed and utilized a three-dimensional (3D) cancer-bone metastasis model using free floating live mouse calvarial bone organs in the presence of cancer cells in a roller-tube system. In such co-cultures under hypoxia and a sp...

  15. Preliminary clinical study of 99Tcm-HL91 imaging in bone metastasis

    International Nuclear Information System (INIS)

    Objective: 99Tcm-4, 9-diaza-3, 3, 10, 10-tetramethyldodecan-2, 11-dione dioxime (HL91), a new type of hypoxic agents, accumulates in tumor hypoxic tissue specifically. The aim of this study was to evaluate the value of 99Tcm-HL91 imaging in the diagnosis of bone metastasis. Methods: Nine- teen cases with bone metastasis (without any treatment) and 8 cases with benign lesions underwent SPECT imaging at 4 h after injection of 740 MBq of 99Tcm-HL91 along with 99Tcm-methylene diphosphonic acid (MDP) imaging. Regions of interest (ROIs) were drawn in tumor tissue and contralateral normal tissue respectively, and the radioactivity ratios of tumor-to-normal (T/N) were calculated. The t-test was used for data analysis with SPSS 11.0. Results: There were visible uptake of 99Tcm-HL91 in 79 out of 85 focuses in 19 patients of bone metastasis; however, there was no obvious uptake of 99Tcm-HL91 in 12 focuses of 8 patients of benign lesions. Significant difference existed between the T/N values of malignant (1.877 ± 0.288) and benign lesions [(0.735 ± 0.236); t=13.065, P0.05). Conclusion: The results indicated that 99Tcm-HL91 was useful in diagnosing the malignant and benign bone lesions. (authors)

  16. Molecular mechanisms of bone formation in spondyloarthritis.

    Science.gov (United States)

    González-Chávez, Susana Aideé; Quiñonez-Flores, Celia María; Pacheco-Tena, César

    2016-07-01

    Spondyloarthritis comprise a group of inflammatory rheumatic diseases characterized by its association to HLA-B27 and the presence of arthritis and enthesitis. The pathogenesis involves both an inflammatory process and new bone formation, which eventually lead to ankylosis of the spine. To date, the intrinsic mechanisms of the pathogenic process have not been fully elucidated, and our progress is remarkable in the identification of therapeutic targets to achieve the control of the inflammatory process, yet our ability to inhibit the excessive bone formation is still insufficient. The study of new bone formation in spondyloarthritis has been mostly conducted in animal models of the disease and only few experiments have been done using human biopsies. The deregulation and overexpression of molecules involved in the osteogenesis process have been observed in bone cells, mesenchymal cells, and fibroblasts. The signaling associated to the excessive bone formation is congruent with those involved in the physiological processes of bone remodeling. Bone morphogenetic proteins and Wnt pathways have been found deregulated in this disease; however, the cause for uncontrolled stimulation remains unknown. Mechanical stress appears to play an important role in the pathological osteogenesis process; nevertheless, the association of other important factors, such as the presence of HLA-B27 and environmental factors, remains uncertain. The present review summarizes the experimental findings that describe the signaling pathways involved in the new bone formation process in spondyloarthritis in animal models and in human biopsies. The role of mechanical stress as the trigger of these pathways is also reviewed. PMID:26838262

  17. Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis

    OpenAIRE

    Zheng Xin; Li Zhen; Cao Jie; Cai Dongqing; Yao Yao; Li Wanglin; Yuan Ziqiang

    2009-01-01

    Abstract Background Bone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic bre...

  18. BSP gene silencing inhibits migration, invasion, and bone metastasis of MDA-MB-231BO human breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Jie Wang

    Full Text Available Bone sialoprotein (BSP has been implicated in a variety of physiological and pathophysiological events, including tumor cell invasion, bone homing, adhesion, and matrix degradation. To explore the potential involvement of BSP in human breast cancer cell invasion and metastasis, we used retrovirus-mediated RNAi to deplete BSP levels in the human bone-seeking breast cancer cell line MDA-MB-231BO (231BO and established the 231BO-BSP27 and 231BO-BSP81 cell clones. Cell proliferation, colony formation, wound healing, and the ability to invade into matrigel of these BSP-depleted clones were all decreased. Both 231BO-BSP27 cells and 231BO-BSP81 cells showed a significant (15.4% and 28.6% respectively reduction of bone metastatic potential following intracardiac injection as determined by X-ray detection and by hematoxylin and eosin staining. Moreover, the expression of integrins αvβ3 and β3 was decreased in the BSP-silenced cells whereas ectopic BSP expression increased the integrins αvβ3 and β3 levels. These results together suggest that BSP silencing decreased the integrin αvβ3 and β3 levels, in turn inhibiting cell migration and invasion and decreasing the ability of the cells to metastasize to bone.

  19. Dynamic modeling of bone metastasis, microenvironment and therapy: Integrating parathyroid hormone (PTH) effect, anti-resorptive and anti-cancer therapy.

    Science.gov (United States)

    Coelho, Rui Moura; Lemos, João Miranda; Alho, Irina; Valério, Duarte; Ferreira, Arlindo R; Costa, Luís; Vinga, Susana

    2016-02-21

    Bone is a common site for the development of metastasis, as its microenvironment provides the necessary conditions for the growth and proliferation of cancer cells. Several mathematical models to describe the bone remodeling process and how osteoclasts and osteoblasts coupled action ensures bone homeostasis have been proposed and further extended to include the effect of cancer cells. The model proposed here includes the influence of the parathyroid hormone (PTH) as capable of triggering and regulating the bone remodeling cycle. It also considers the secretion of PTH-related protein (PTHrP) by cancer cells, which stimulates the production of receptor activator of nuclear factor kappa-B ligand (RANKL) by osteoblasts that activates osteoclasts, increasing bone resorption and the subsequent release of growth factors entrapped in the bone matrix, which induce tumor growth, giving rise to a self-perpetuating cycle known as the vicious cycle of bone metastases. The model additionally describes how the presence of metastases contributes to the decoupling between bone resorption and formation. Moreover, the effects of anti-cancer and anti-resorptive treatments, through chemotherapy and the administration of bisphosphonates or denosumab, are also included, along with their corresponding pharmacokinetics (PK) and pharmacodynamics (PD). The simulated models, available at http://sels.tecnico.ulisboa.pt/software/, are able to describe bone remodeling cycles, the growth of bone metastases and how treatment can effectively reduce tumor burden on bone and prevent loss of bone strength. PMID:26657065

  20. Understanding coupling between bone resorption and formation

    DEFF Research Database (Denmark)

    Andersen, Thomas Levin; Abdelgawad, Mohamed Essameldim; Kristensen, Helene Bjørg;

    2013-01-01

    Bone remodeling requires bone resorption by osteoclasts, bone formation by osteoblasts, and a poorly investigated reversal phase coupling resorption to formation. Likely players of the reversal phase are the cells recruited into the lacunae vacated by the osteoclasts and presumably preparing these...... lacunae for bone formation. These cells, called herein reversal cells, cover >80% of the eroded surfaces, but their nature is not identified, and it is not known whether malfunction of these cells may contribute to bone loss in diseases such as postmenopausal osteoporosis. Herein, we combined...... histomorphometry and IHC on human iliac biopsy specimens, and showed that reversal cells are immunoreactive for factors typically expressed by osteoblasts, but not for monocytic markers. Furthermore, a subpopulation of reversal cells showed several distinctive characteristics suggestive of an arrested...

  1. The use of palliative radiotherapy for bone metastasis

    International Nuclear Information System (INIS)

    Background: The value of palliative radiotherapy (PRT) for bone metastases is well established, but little is known about its use in the general population. Purpose: To describe the use of PRT for bone metastases in Ontario. Materials and methods: This was a retrospective cohort study. Treatment records from all Ontario RT departments were linked to a population-based cancer registry to describe the use of PRT. Results: 12.2% of the 434,241 patients, who died of cancer in Ontario between 1984 and 2004, received at least one course of PRT for bone metastases in the last 2 years of life. The rate of use of PRT varied across the province (inter-county range, 8.2-18.6%). Older patients and residents of poorer areas were less likely to receive PRT (p < 0.0001). Patients diagnosed with cancer in a hospital with a radiotherapy facility and those who lived closer to a radiotherapy centre were more likely to receive PRT (p < 0.0001). Over the study period, the use of PRT decreased in breast cancer and myeloma, but increased in prostate cancer (p < 0.0001). Conclusions: Access to PRT appears to be inequitable. More effort is required to make this useful treatment available to all those who would benefit from it.

  2. RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis

    International Nuclear Information System (INIS)

    Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the β3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment

  3. 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)

    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 18F fluorodeoxyglucose (18F 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 18F 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 18F 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 18F 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

  4. Fibrous dysplasia mimicking bone metastasis on both bone scintigraphy and {sup 18}F FDG PET CT: Diagnostic dilemma in a patient with breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    KC, Sud Hir Suman; Sharma, Punit; Singh, Har Man Deep; Bal, Chand Rasekhar; Kumar, Rake Sh [India Institute of Medical Sciences, New Delhi (India)

    2012-12-15

    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 {sup 18}F fluorodeoxyglucose ({sup 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 {sup 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 {sup 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 {sup 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.

  5. Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis.

    Science.gov (United States)

    Meng, X; Vander Ark, A; Lee, P; Hostetter, G; Bhowmick, N A; Matrisian, L M; Williams, B O; Miranti, C K; Li, X

    2016-05-01

    Breast cancer (BCa) bone metastases cause osteolytic bone lesions, which result from the interactions of metastatic BCa cells with osteoclasts and osteoblasts. Osteoclasts differentiate from myeloid lineage cells. To understand the cell-specific role of transforming growth factor beta (TGF-β) in the myeloid lineage, in BCa bone metastases, MDA-MB-231 BCa cells were intra-tibially or intra-cardially injected into LysM(Cre)/Tgfbr2(floxE2/floxE2) knockout (LysM(Cre)/Tgfbr2 KO) or Tgfbr2(floxE2/floxE2) mice. Metastatic bone lesion development was compared by analysis of both lesion number and area. We found that LysM(Cre)/Tgfbr2 knockout significantly decreased MDA-MB-231 bone lesion development in both the cardiac and tibial injection models. LysM(Cre)/Tgfbr2 knockout inhibited the tumor cell proliferation, angiogenesis and osteoclastogenesis of the metastatic bones. Cytokine array analysis showed that basic fibroblast growth factor (bFGF) was downregulated in MDA-MB-231-injected tibiae from the LysM(Cre)/Tgfbr2 KO group, and intravenous injection of the recombinant bFGF to LysM(Cre)/Tgfbr2 KO mice rescued the inhibited metastatic bone lesion development. The mechanism by which bFGF rescued the bone lesion development was by promotion of tumor cell proliferation through the downstream mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-cFos pathway after binding to the FGF receptor 1 (FGFR1). Consistent with animal studies, we found that in human BCa bone metastatic tissues, TGF-β type II receptor (TβRII) and p-Smad2 were expressed in osteoclasts and tumor cells, and were correlated with the expression of FGFR1. Our studies suggest that myeloid-specific TGF-β signaling-mediated bFGF in the bone promotes BCa bone metastasis. PMID:26279296

  6. 18F-fluoride PET imaging in a nude rat model of bone metastasis from breast cancer: Comparison with 18F-FDG and bioluminescence imaging

    International Nuclear Information System (INIS)

    Introduction: Clinically-relevant animal models and appropriate imaging diagnostic tools are essential to study cancer and develop novel therapeutics. We evaluated a model of bone metastasis in nude rats by micro-PET and bioluminescence imaging. Methods: A bone metastasis model was produced by intracardiac injection of osteotropic MDA-MB-231Bo-Luc human breast cancer cells into nude rats. Bioluminescence imaging and micro-PET scans using 18F-FDG and 18F-fluoride were acquired serially for 5 weeks. We correlated bioluminescence imaging, 18F-FDG and 18F-fluoride PET images, and histological slides. Results: Multiple bone metastases were successfully evaluated by bioluminescence imaging and 18F-FDG and 18F-fluoride PET scans. Bioluminescence photon flux increased exponentially on weekly follow-up. 18F-FDG PET revealed increased FDG uptake at the spine and bilaterally in the hind legs in week 2 images, and showed a progressive pattern up to 4 weeks that correlated with bioluminescence imaging. 18F-fluoride PET showed minimal abnormal findings in week 2 images, but it showed an irregular pattern at the spine from week 3 or 4 images. On quantitative analysis with standardized uptake values, a pattern of gradual increase was observed from week 2 to week 4 in both 18F-FDG PET and fluoride PET. Histopathological examination confirmed the formation of osteolytic metastasis and necrosis of the distal femur, which appeared as a photon defect on PET scans. Conclusion: Developing bone metastasis from breast cancer in a nude rat model was successfully evaluated with an animal PET imaging system and bioluminescence imaging. This nude rat model of bone metastasis, which can be evaluated by PET imaging, may be a valuable tool for evaluating early responses to novel therapeutics

  7. Extrinsic Mechanisms Involved in Age-Related Defective Bone Formation

    DEFF Research Database (Denmark)

    Trinquier, Anne Marie-Pierre Emilie; Kassem, Moustapha

    2011-01-01

    Context: Age-related bone loss is associated with progressive changes in bone remodeling characterized by decreased bone formation relative to bone resorption. Both trabecular and periosteal bone formation decline with age in both sexes, which contributes to bone fragility and increased risk of...

  8. cAMP-response-element-binding protein positively regulates breast cancer metastasis and subsequent bone destruction

    Energy Technology Data Exchange (ETDEWEB)

    Son, Jieun; Lee, Jong-Ho; Kim, Ha-Neui; Ha, Hyunil, E-mail: hyunil74@hotmail.com; Lee, Zang Hee, E-mail: zang1959@snu.ac.kr

    2010-07-23

    Research highlights: {yields} CREB is highly expressed in advanced breast cancer cells. {yields} Tumor-related factors such as TGF-{beta} further elevate CREB expression. {yields} CREB upregulation stimulates metastatic potential of breast cancer cells. {yields} CREB signaling is required for breast cancer-induced bone destruction. -- Abstract: cAMP-response-element-binding protein (CREB) signaling has been reported to be associated with cancer development and poor clinical outcome in various types of cancer. However, it remains to be elucidated whether CREB is involved in breast cancer development and osteotropism. Here, we found that metastatic MDA-MB-231 breast cancer cells exhibited higher CREB expression than did non-metastatic MCF-7 cells and that CREB expression was further increased by several soluble factors linked to cancer progression, such as IL-1, IGF-1, and TGF-{beta}. Using wild-type CREB and a dominant-negative form (K-CREB), we found that CREB signaling positively regulated the proliferation, migration, and invasion of MDA-MB-231 cells. In addition, K-CREB prevented MDA-MB-231 cell-induced osteolytic lesions in a mouse model of cancer metastasis. Furthermore, CREB signaling in cancer cells regulated the gene expression of PTHrP, MMPs, and OPG, which are closely involved in cancer metastasis and bone destruction. These results indicate that breast cancer cells acquire CREB overexpression during their development and that this CREB upregulation plays an important role in multiple steps of breast cancer bone metastasis.

  9. The Hedgehog signalling pathway in bone formation

    Institute of Scientific and Technical Information of China (English)

    Jing Yang; Philipp Andre; Ling Ye; Ying-Zi Yang

    2015-01-01

    The Hedgehog (Hh) signalling pathway plays many important roles in development, homeostasis and tumorigenesis. The critical function of Hh signalling in bone formation has been identified in the past two decades. Here, we review the evolutionarily conserved Hh signalling mechanisms with an emphasis on the functions of the Hh signalling pathway in bone development, homeostasis and diseases. In the early stages of embryonic limb development, Sonic Hedgehog (Shh) acts as a major morphogen in patterning the limb buds. Indian Hedgehog (Ihh) has an essential function in endochondral ossification and induces osteoblast differentiation in the perichondrium. Hh signalling is also involved intramembrane ossification. Interactions between Hh and Wnt signalling regulate cartilage development, endochondral bone formation and synovial joint formation. Hh also plays an important role in bone homeostasis, and reducing Hh signalling protects against age-related bone loss. Disruption of Hh signalling regulation leads to multiple bone diseases, such as progressive osseous heteroplasia. Therefore, understanding the signalling mechanisms and functions of Hh signalling in bone development, homeostasis and diseases will provide important insights into bone disease prevention, diagnoses and therapeutics.

  10. Post-operative breast cancer patients diagnosed with skeletal metastasis without bone pain had fewer skeletal-related events and deaths than those with bone pain

    Directory of Open Access Journals (Sweden)

    Koizumi Mitsuru

    2010-08-01

    Full Text Available Abstract Background Skeletal metastases are often accompanied by bone pain. To investigate the clinical meaning of bone pain associated with skeletal metastasis in breast cancer patients after surgery, we explored whether the presence of bone pain was due to skeletal-related events (SREs or survival (cause specific death, CSD, retrospectively. Methods Consecutive breast cancer patients undergoing surgery between 1988 and 1998 were examined for signs of skeletal metastasis until December 2006. Patients who were diagnosed as having skeletal metastasis were the subjects of this study. Bone scans were performed annually for 5, 7 or 10 years; they were also conducted if skeletal metastasis was suspected. Data concerning bone pain and tumor markers at the time of skeletal metastasis diagnosis, and data relating to various factors including tumors, lymph nodes and hormone receptors at the time of surgery, were investigated. The relationships between factors such as bone pain, SRE and CSD were analyzed using the Kaplan-Meier method and Cox's analysis. Results Skeletal metastasis occurred in 668 patients but the pain status of two patients was unknown, therefore 666 patients were included in the study. At the time of skeletal metastasis diagnosis 270 patients complained of pain; however, 396 patients did not. Analysis of data using Cox's and Kaplan-Meier methods demonstrated that patients without pain had fewer SREs and better survival rates than those with pain. Hazard ratios regarding SRE (base = patients without pain were 2.331 in univariate analysis and 2.243 in multivariate analysis. Hazard ratios regarding CSD (base = patients without pain were 1.441 in univariate analysis and 1.535 in multivariate analysis. Similar results were obtained when analyses were carried out using the date of surgery as the starting point. Conclusion Bone pain at diagnosis of skeletal metastasis was an indicator of increased SRE and CSD. However, these data did not

  11. The evaluation of Tracp5b as a marker for monitoring treatment results of bone metastasis in breast cancer patients

    Institute of Scientific and Technical Information of China (English)

    Xiaoyun Huang; Yan Si; Jia Zhao; Qiang Ding

    2008-01-01

    Objective:To evaluate the sensitivity of serum tartrate-resistant acid phosphatase 5b(Tracp5b) activity in monitoring bisphosphonate treatment results of bone metastasis in breast cancer(BC) patients. Methods:The serum activities of Tracp5b, CEA, CA153 were measured in 58 BC patients, including 26 without bone metastasis, 32 with bone metastasis. The serum activities of Tracp5b, CEA, CA153 were also measured in 19 patients with bone metastasis after 3 months of bisphosphonate treatment. Eighteen healthy women with age from 34 to 70 served as control. Results:Serum Tracp5b was significantly elevated in patients with bone metastasis compared with that in all any other groups(P< 0.05). The sensitivity of TracpSb was 78.13% and the specificity was 86.36%. The sensitivity of CA153 was 37.50% and the specificity was 77.27%. The sensitivity of CEA was 21.88% and the specificity was 84.09%. The serum activity of Tracp5b decreased significantly(P < 0.05) after 3 months of bisphosphonate treatment, while the levels of CA153 and CEA were unchanged. Conclusion:Serum TracpSb activity is a useful diagnostic marker for bone metastasis in BC patients and can be used to evaluate the treatment results of bisphosphonate.

  12. Predictive value of serum prostate specific antigen in detecting bone metastasis in prostate cancer patients using bone scintigraphy

    International Nuclear Information System (INIS)

    Radionuclide bone scan (BS) used to be the investigation of choice for detecting osseous metastases in prostate cancer. Now, with the availability serum prostate specific antigen (PSA) testing, clinicians do have a timely, cost-effective method to determine those patients who are highly unlikely to have osseous metastases. We determine the utility of PSA for predicting the presence of skeletal metastasis on BSs in prostate cancer patients. Retrospective analysis of medical records of 322 consecutive prostate cancers patients subjected to BS during the last 3 years was done. 52 cases were excluded due to following reasons: Serum PSA not available, hormonal or other therapy given prior to serum PSA measurement, and/or BS, and symptomatic for bone metastasis. In remaining 270 cases, PSA value and BS were evaluated. BS was performed with Tc99m methylene diphosphonate (MDP) as per the standard protocol. BS was found to be positive in 153/270 (56%) and negative in 117 (46%) patients. Of the 153 positive cases, 108 (70%) had serum PSA > 100 ng/ml, 42 (28%) had PSA of 20-100 ng/ml and only 3 (2%) had PSA < 20 ng/ml. All the patients with PSA > 100 ng/ml had multiple skeletal metastasis. Of the 117 negative cases, 110 (94%) had a PSA < 20 ng/ml, 5 had between 20 and 100 ng/ml and only 2 (1.8%) had PSA > 100 ng/ml. Of the 113 patients with serum PSA < 20 ng/ml, 110 (97.4%) did not show any bony metastasis. 150/157 (95.5%) patients with PSA > 20 ng/ml had bone metastasis. Using this criterion, 110 (40.7%) scans would have been omitted. Serum PSA < 20 ng/ml have high predictive value in ruling out skeletal metastasis. Our data are in corroboration with results from previous studies that BS should be performed only if PSA > 20 ng/ml. Using this cut-off, unnecessary investigation can be avoided. Avoiding BS in this group of patients would translate into a significant cost-saving and reduction in their psychological and physical burden

  13. Galectin-3 in bone tumor microenvironment: a beacon for individual skeletal metastasis management.

    Science.gov (United States)

    Nakajima, Kosei; Kho, Dong Hyo; Yanagawa, Takashi; Zimel, Melissa; Heath, Elisabeth; Hogan, Victor; Raz, Avraham

    2016-06-01

    The skeleton is frequently a secondary growth site of disseminated cancers, often leading to painful and devastating clinical outcomes. Metastatic cancer distorts bone marrow homeostasis through tumor-derived factors, which shapes different bone tumor microenvironments depending on the tumor cells' origin. Here, we propose a novel insight on tumor-secreted Galectin-3 (Gal-3) that controls the induction of an inflammatory cascade, differentiation of osteoblasts, osteoclasts, and bone marrow cells, resulting in bone destruction and therapeutic failure. In the approaching era of personalized medicine, the current treatment modalities targeting bone metastatic environments are provided to the patient with limited consideration of the cancer cells' origin. Our new outlook suggests delivering individual tumor microenvironment treatments based on the expression level/activity/functionality of tumor-derived factors, rather than utilizing a commonly shared therapeutic umbrella. The notion of "Gal-3-associated bone remodeling" could be the first step toward a specific personalized therapy for each cancer type generating a different bone niche in patients afflicted with non-curable bone metastasis. PMID:27067726

  14. Tumor-targeting Salmonella typhimurium A1-R prevents experimental human breast cancer bone metastasis in nude mice

    OpenAIRE

    Miwa, Shinji; Yano, Shuya; Zhang, Yong; Matsumoto, Yasunori; Uehara, Fuminari; Yamamoto, Mako; Hiroshima, Yukihiko; Kimura, Hiroaki; Hayashi, Katsuhiro; Yamamoto, Norio; Bouvet, Michael; Tsuchiya, Hiroyuki; Hoffman, Robert M.; Ming ZHAO

    2014-01-01

    Bone metastasis is a lethal and morbid late stage of breast cancer that is currently treatment resistant. More effective mouse models and treatment are necessary. High bone-metastatic variants of human breast cancer cells were selected in nude mice by cardiac injection. After cardiac injection of a high bone-metastatic variant of breast cancer, all untreated mice had bone metastases compared to only 20% with parental cells. Treatment with tumor-targeting Salmonella typhimurium A1-R completely...

  15. Short- term curative effects of Boning on relieving pain of bone metastasis of lung cancer%博宁缓解肺癌骨转移疼痛的近期疗效

    Institute of Scientific and Technical Information of China (English)

    岳莉; 吴红卫; 薛海鸥; 王新华

    2002-01-01

    @@ Background:23.8% patients with late stage lung cancer accompany bone metastasis, which bring about severe pain and make great influence on patients' living quality.Boning is the representation of domestic second generation Diphosphonate, which take good curative effects on bone pain caused by bone metastasis of malignant tumor.

  16. Heterotopic bone formation following total shoulder arthroplasty

    DEFF Research Database (Denmark)

    Kjaersgaard-Andersen, P.; Frich, Lars Henrik; Sjøbjerg, J.O.;

    1989-01-01

    the glenohumeral and/or the glenoacromial space. There was no correlation between shoulder pain and the development of ossification. Shoulders with grade III heterotopic bone formation had a limited range of active elevation compared with shoulders without or with only a milder lesion. Men and......The incidence and location of heterotopic bone formation following total shoulder arthroplasty were evaluated in 58 Neer Mark-II total shoulder replacements. One year after surgery, 45% had developed some ectopic ossification. In six shoulders (10%) the ossifications roentgenographically bridged...... patients with osteoarthritis of the shoulder joint were significantly disposed to the development of heterotopic bone. Heterotopic bone formation following total shoulder arthroplasty is frequent, but disabling heterotopic ossifications seem to be rare....

  17. The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches.

    Science.gov (United States)

    Özdemir, Berna C; Hensel, Janine; Secondini, Chiara; Wetterwald, Antoinette; Schwaninger, Ruth; Fleischmann, Achim; Raffelsberger, Wolfgang; Poch, Olivier; Delorenzi, Mauro; Temanni, Ramzi; Mills, Ian G; van der Pluijm, Gabri; Thalmann, George N; Cecchini, Marco G

    2014-01-01

    The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature ("Core" OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this

  18. Multi-modal imaging of angiogenesis in a nude rat model of breast cancer bone metastasis using magnetic resonance imaging, volumetric computed tomography and ultrasound.

    Science.gov (United States)

    Bäuerle, Tobias; Komljenovic, Dorde; Berger, Martin R; Semmler, Wolfhard

    2012-01-01

    Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques. For this purpose, we injected 10(5) MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US). MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated

  19. Differential expression of the RANKL/RANK/OPG system is associated with bone metastasis in human non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Xianbo Peng

    Full Text Available BACKGROUND: Human non-small cell lung cancer (NSCLC patients exhibit a high propensity to develop skeletal metastasis, resulting in excessive osteolytic activity. The RANKL/RANK/OPG system, which plays a pivotal role in bone remodeling by regulating osteoclast formation and activity, is of potential interest in this context. MATERIALS AND METHODS: Reverse transcriptase polymerase chain reaction, western blotting, and immunohistochemical analysis were used to examine the expression of RANKL, RANK, and OPG in human NSCLC cell lines with different metastatic potentials, as well as in 52 primary NSCLC samples and 75 NSCLC bone metastasis samples. In primary NSCLC patients, the expression of these proteins was correlated with clinicopathological parameters. Recombinant human RANKL and transfected RANKL cDNA were added to the PAa cell line to evaluate the promoter action of RANKL during the process of metastasis in vitro and in vivo. RESULTS: Up-regulated RANKL, RANK, and OPG expression and increased RANKL:OPG ratio were detected in NSCLC cell lines and in tumor tissues with bone metastasis, and were correlated with higher metastatic potential. The metastatic potential of NSCLC in vitro and in vivo, including migration and invasion ability, was significantly enhanced by recombinant human RANKL and the transfection of RANKL cDNA, and was impaired after OPG was added. The increased expression of RANKL and OPG correlated with tumor stage, lymph node metastasis, and distant metastasis. CONCLUSIONS: Differential expression of RANKL, RANK, and OPG is associated with the metastatic potential of human NSCLC to skeleton, raising the possibility that the RANKL/RANK/OPG system could be a therapeutic target for the treatment of metastatic NSCLC patients.

  20. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1

  1. XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Ting; Han, Shuai; Wu, Zhipeng; Han, Zhitao; Yan, Wangjun; Liu, Tielong; Wei, Haifeng; Song, Dianwen; Zhou, Wang, E-mail: brilliant212@163.com; Yang, Xinghai, E-mail: cnspineyang@163.com; Xiao, Jianru, E-mail: jianruxiao83@163.com

    2015-08-21

    Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer. In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.

  2. A case of synovial sarcoma with bone metastasis identified by bone marrow scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Otsuka, N.; Morita, R.; Yamamoto, T.; Muranaka, A.; Tomomitsu, T.; Yanagimoto, S.; Sone, T.; Fukunaga, M.

    1985-04-01

    In a patient with synovial sarcoma, routine bone survey showed no abnormality, while bone marrow scintigraphy with Tc-99m sulfur colloid revealed a defect in the fifth lumbar vertebra. At surgery, tumorous invasion was noted in the fifth lumbar vertebra and the surrounding tissues. It was suggested that the bone marrow scintigraphy was particularly useful in the detection of tumorous invasion into the bone marrow at the early stage before the destruction of skeletal tissue.

  3. A case of synovial sarcoma with bone metastasis identified by bone marrow scintigraphy

    International Nuclear Information System (INIS)

    In a patient with synovial sarcoma, routine bone survey showed no abnormality, while bone marrow scintigraphy with Tc-99m sulfur colloid revealed a defect in the fifth lumbar vertebra. At surgery, tumorous invasion was noted in the fifth lumbar vertebra and the surrounding tissues. It was suggested that the bone marrow scintigraphy was particularly useful in the detection of tumorous invasion into the bone marrow at the early stage before the destruction of skeletal tissue

  4. Brain metastasis from differentiated thyroid cancer in patients treated with radioiodine for bone and lung lesions

    International Nuclear Information System (INIS)

    Brain metastasis of differentiated thyroid cancer (DTC) often is detected during treatment of other remote lesions. We examined the prevalence, risk factors and treatment outcome of this disease encountered during nuclear medicine practice. Of the 167 patients with metastasis to lung or bone treated 1-14 times with radioactive iodine (RAI), 9 (5.4%) also had lesions in the brain. Five were males and 4 females, aged 49-84, out of the original population of 49 males and 118 females aged 10-84 (mean 54.7) years. Three of them underwent removal of their brain tumors, 5 received conventional external beam irradiation, and 2 had stereotactic radiosurgery with supervoltage X-ray. None of the brain lesions showed significant uptake of RAI despite demonstrable accumulation in most extracerebral lesions. Seven patients died 4-23 (mean 9.4) months after the discovery of cerebral metastasis, brain damage being the primary or at least a contributing cause. The 8th and 9th patients remained relatively well for more than 42 and 3 months, respectively, without any evidence of intracranial recurrence. Our results confirmed that the brain is a major site of secondary metastasis from DTC. No statistically significant demographic risk factor was detected. Any suspicious neurological symptoms in the course of RAI treatment warrant cerebral computed tomography. As for therapy, from out initial experience, radiosurgery seemed promising as an effective and less invasive alternative to surgical removal. (author)

  5. Microarrays bring new insights into understanding of breast cancer metastasis to bone

    International Nuclear Information System (INIS)

    Using a microarray approach, Kang and colleagues identified several genes involved in the generation of breast cancer metastasis in bone and demonstrated their roles in bone colonization in vivo. Their findings and interpretations are reviewed in the context of recent array studies that compared gene expression in primary tumors and metastases. RNA expression array results have already demonstrated value in predicting whether metastases will develop in patients. They have also shown that expression patterns are similar in primary tumors and metastases. The latter data have invited re-examination of long-held notions related to mechanisms of metastasis. While the arrays show promise for improving diagnostic capability in breast cancers, ascribing mechanistic interpretations to correlative data should be done with extreme caution. Kang and colleagues' paper in Cancer Cell elegantly reinforces the concepts that efficiency of the metastatic process is dependent on the coordinated expression of multiple genes and that the expression of metastasis-associated genes is sometimes dependent on the microenvironment in which cells find themselves

  6. Is retention of zoledronic acid onto bone different in multiple myeloma and breast cancer patients with bone metastasis?

    DEFF Research Database (Denmark)

    Søe, Kent; Plesner, Torben; Jakobsen, Erik H;

    2013-01-01

    Zoledronic acid (Zol) is used to treat bone disease in both multiple myeloma (MM) and breast cancer patients with bone metastasis (BC). However, bones of MM and BC patients show a difference in retention of the bisphosphonate used for bone scintigraphy. Therefore, we hypothesized that disease......-specific factors may differently influence Zol retention in MM and BC patients. We tested this hypothesis in an investigator initiated phase II clinical trial in which we compared the whole-body retention (WBrt) of Zol in a cohort of 30 multiple myeloma (MM) and 30 breast cancer (BC) (20 Zol naive and 40 with six...... of Zol correlated with bone-specific alkaline phosphatase (bALP) levels in BC (p = 0.001), and with CTX/bALP in Zol naive MM patients (p = 0.012). Especially in BC patients, WBrt correlated with age (p = 0.014) independently of kidney function. In MM patients WBrt was found to primarily correlate...

  7. Clinicopathological features and treatment of extremity bone metastasis in patients with endometrial carcinoma: a case report and review

    Institute of Scientific and Technical Information of China (English)

    JIANG Guo-qing; GAO Yu-nong; GAO Min; ZHENG Hong; YAN Xin; WANG Wen; AN Na; CAO Kun

    2011-01-01

    Unlike other non-gynecologic solid tumors, such as breast cancer, lung cancer, metastasis to bone from endometrial carcinoma is rare, metastasis to extremity is extremely rare. We report a 51-year-old multiparous woman with FIGO Stage IVb Grade 2 endometrial adenocarcinoma which metastasized to left lower extremity bone. She received an amputation of left lower extremity below the knees, and a total abdominal hysterectomy and bilateral salpingo-oophorectomy, and followed by systemic chemotherapy, radiation therapy to the pelvis and progestational agent. She had a complete response to above treatments, and disease-free survival for 10 months. After recurrence, she received chemotherapy, radiotherapy and progestational agent once again. She had lived 56 months and is still alive by the time of report. Metastasis of endometrial carcinoma to extremity bone can rarely occur and should be considered when the patient with endometrial carcinoma complained of unexplained pain and swelling associated with extremity bone.

  8. Effects of Sangu Decoction on Osteoclast Activity in a Rat Model of Breast Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Bo Deng

    2012-01-01

    Full Text Available Bone metastasis (BM is a major clinical problem for which current treatments lack full efficacy. The Traditional Chinese Medicine (TCM Sangu Decoction (SGD has been widely used to treat BM in China. However, no in vivo experiments to date have investigated the effects of TCM on osteoclast activity in BM. In this study, the protective effect and probable mechanism of SGD were evaluated. The model was established using the breast cancer MRMT-1 cells injected into the tibia of rat. SGD was administrated, compared with Zoledronic acid as a positive control. The development of the bone tumor and osteoclast activity was monitored by radiological analysis. TRAP stain was used to identify osteoclasts quantity and activity. TRAP-5b in serum or bone tumor and TRAP mRNA were also quantified. Radiological examination showed that SGD inhibited tumor proliferation and preserved the cortical and trabecular bone structure. In addition, a dramatic reduction of TRAP positive osteoclasts was observed and TRAP-5b levels in serum and bone tumor decreased significantly. It also reduced the mRNA expression of TRAP. The results indicated that SGD exerted potent antiosteoclast property that could be directly related to its TRAP inhibited activity. In addition it prevented bone tumor proliferation in BM model.

  9. Brief Review of Models of Ectopic Bone Formation

    OpenAIRE

    Scott, Michelle A.; Levi, Benjamin; Askarinam, Asal; Nguyen, Alan; Rackohn, Todd; Ting, Kang; Soo, Chia; James, Aaron W.

    2011-01-01

    Ectopic bone formation is a unique biologic entity—distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used f...

  10. Targeting of αv-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Geertje van der Horst

    2011-06-01

    Full Text Available Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT. Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide αv-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that αv-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking αv-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population, antiresorptive, and antiangiogenic mechanisms.

  11. Significance of CEA, CA15-3 and biochemical markers of bone turnover in the diagnosis of bone metastasis from breast cancer

    International Nuclear Information System (INIS)

    Objective: To evaluate the significance of tumor markers CEA and CA15-3, and biochemical markers of bone turnover (total procollagen type Ⅰ amino-terminal propeptide (TP Ⅰ NP), β-isomerized carboxyterminal propeptide (β-CTx), ALP and PTH) in the diagnosis of bone metastasis from breast cancer. Methods: A total of 78 patients (all females) with mean age (56.72 ± 10.76) years, who were diagnosed with breast cancer, were included in this study. The patients were divided into two groups based on radionuclide bone imaging: with bone metastasis (n=32) and without bone metastasis (n=46). The serum concentrations of CEA, CA15-3, TP Ⅰ NP, β-CTx, PTH, ALP were measured. Gleason scores were evaluated. The diagnostic value was evaluated by ROC curve.The two groups were compared using two-sample t test. The correlations between bone metastasis and tumor markers, bone metastasis and biochemical markers of bone turnover were analyzed with Pearson correlation and logistic analysis. Results: The serum levels of CEA, CA15-3, TP Ⅰ NP, β-CTx, PTH and ALP were significantly higher in the group with bone metastasis than those in the group without bone metastasis (t: 4.16-7.56, all P<0.05). For the diagnosis of bone metastasis from breast cancer, the AUC of CEA, CA15-3, TP Ⅰ NP, [β-CTx, PTH and ALP was 0.815, 0.887, 0.869, 0.852, 0.844, 0.731, respectively. Using the cut-off values of 4.18 μg/L for CEA, 0.04 U/L for CA15-3, 49.70 μg/L for TP Ⅰ NP, 0.47 pg/L for β-CTx,54.90 ng/L for PTH and 49.90 U/L for ALP, the sensitivities were 56.3% (18/32), 75.0% (24/32), 78.1% (25/32), 81.3% (26/32), 78.1% (25/32), 68.8% (22/32) and the specificities were 80.4% (37/46), 84.8% (39/46), 76.1% (35/46), 78.3% (36/46), 69.6% (32/46), 58.7% (27/46), respectively. CEA, CA15-3, TP Ⅰ NP, β-CTx, PTH, ALP and Gleason score were positively correlated with the presence of bone metastasis (r: 0.267-0.636, all P<0.05). CEA, CA15-3, TP Ⅰ NP, β-CTx, PTH and Gleason score were independent

  12. A solitary pleural metastasis of benign giant cell tumor of bone

    Science.gov (United States)

    Mitsui, Ai; Doi, Masatomo; Hoshikawa, Masahiro; Hayashi, Akinobu; Nakamura, Haruhiko

    2016-01-01

    Abstract Giant cell tumor of bone (GCTB) usually appears as a benign tumor. We describe an extremely rare case of a metastatic pleural tumor arising from a benign GCTB. The patient had undergone radial resection of a GCTB in his left wrist. After 6 years, he was sent to us for diagnosis of a large mass detected upon routine radiographic screening. We resected the tumor, which was found to be a solitary pleural metastasis of GCTB and had evidently spread arterially. To our knowledge, this is the first report of its kind.

  13. Skeletal-related events in urological cancer patients with bone metastasis. A multicenter study in Japan

    International Nuclear Information System (INIS)

    The objective of this study was to investigate the incidence of skeletal-related events (SRE) in urological cancer patients with bone metastases in Japan. Five hundred eleven patients with urological cancer and documented bone metastases treated from January 2003 to April 2008 in ten Japanese institutions were included in a retrospective analysis. Type and incidence of SRE (fracture, radiotherapy, spinal cord compression, surgery, hypercalcemia, and bone pain) were determined from patient medical records. The overall incidence of SRE, including 'pain', was 61%. The most common event was radiotherapy for bone metastases, with an incidence of 31%. The overall incidence of events seemed to be similar among Japanese and Western patients with prostate cancer and renal cell carcinoma when comparing data with previously published reports. Nevertheless, a much lower incidence of fracture (19.1%) was observed in Japanese renal cell carcinoma patients. The overall incidence of SRE in Japanese urological cancer patients with bone metastasis was similar to that in Western patients, but the incidence of fracture was lower in Japanese renal cancer patients. (author)

  14. Macrophage Polarization and Bone Formation: A review.

    Science.gov (United States)

    Horwood, Nicole J

    2016-08-01

    The contribution of inflammation to bone loss is well documented in arthritis and other diseases with an emphasis on how inflammatory cytokines promote osteoclastogenesis. Macrophages are the major producers of cytokines in inflammation, and the factors they produce depend upon their activation state or polarization. In recent years, it has become apparent that macrophages are also capable of interacting with osteoblasts and their mesenchymal precursors. This interaction provides growth and differentiation factors from one cell that act on the other and visa versa-a concept akin to the requirement for a feeder layer to grow hemopoietic cells or the coupling that occurs between osteoblasts and osteoclasts to maintain bone homeostasis. Alternatively, activated macrophages are the most likely candidates to promote bone formation and have also been implicated in the tissue repair process in other tissues. In bone, a number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo. This review discusses the different cell types involved, cellular mediators, and how this can be used to direct new bone anabolic approaches. PMID:26498771

  15. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    Directory of Open Access Journals (Sweden)

    Ali Murat Tatlı

    2013-01-01

    Full Text Available Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient’s history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we believed that the cutaneous dystrophic calcification could be associated with her long term bisphosphonate therapy. Adverse cutaneous events with bisphosphonates are very rare, and dystrophic calcification has not been reported previously. The dystrophic calcification and metaplastic bone formation in this patient are thought to be due to long term bisphosphonate usage.

  16. Dystrophic Cutaneous Calcification and Metaplastic Bone Formation due to Long Term Bisphosphonate Use in Breast Cancer

    Science.gov (United States)

    Tatlı, Ali Murat; Göksu, Sema Sezgin; Arslan, Deniz; Başsorgun, Cumhur İbrahim; Coşkun, Hasan Şenol

    2013-01-01

    Bisphosphonates are widely used in the treatment of breast cancer with bone metastases. We report a case of a female with breast cancer presented with a rash around a previous mastectomy site and a discharge lesion on her right chest wall in August 2010. Biopsy of the lesion showed dystrophic calcification and metaplastic bone formation. The patient's history revealed a long term use of zoledronic acid for the treatment of breast cancer with bone metastasis. We stopped the treatment since we believed that the cutaneous dystrophic calcification could be associated with her long term bisphosphonate therapy. Adverse cutaneous events with bisphosphonates are very rare, and dystrophic calcification has not been reported previously. The dystrophic calcification and metaplastic bone formation in this patient are thought to be due to long term bisphosphonate usage. PMID:23956898

  17. Clinical background and its relation to results of percutaneous needle biopsy of suspected bone metastasis under guidance with CT fluoroscopy

    International Nuclear Information System (INIS)

    The purpose of this study was to investigate the clinical background of needle biopsy of suspected bone metastasis under guidance with CT fluoroscopy. During a 3-year period (from April 2000 to March 2003), 103 needle biopsies on 101 lesions of 90 patients were performed for pathological evaluation of suspected bone metastasis. The clinical course of these patients prior to biopsy and its relation to the biopsy results were retrospectively reviewed. Sixty-two patients (69% of total cases) were referred for biopsy from orthopedic surgeons, and 51 of these patients consulted orthopedic surgeons on the initial presentation. Malignancy was pathologically proved in 47 (76%) of the 62 orthopedic patients, and in 19 (68%) of the 28 patients referred from other clinicians. Thirteen (21%) of the orthopedic patients had a history of malignancy, while 22 (78%) of the non-orthopedic patients were cancer patients. Metastasis was pathologically proved in 23 (66%) of the 35 patients with a history of malignancy, while malignancy was pathologically proved in 43 (78%) of the 55 patients without known malignancy. Diagnostic accuracy of the needle bone biopsy was 96%, and its complication rate was 0.7%. In the era of CT fluoroscopy, needle biopsy for suspected bone metastasis was most frequently requested for the patients who consulted orthopedic surgeons for the occurrence of local bone pain as the initial symptom of unknown malignancy. Frequency of malignancy proved by the biopsy in those patients was as high as that in the cancer patients referred from other clinicians. (author)

  18. Osteoclasts secrete non-bone derived signals that induce bone formation

    DEFF Research Database (Denmark)

    Karsdal, Morten A; Neutzsky-Wulff, Anita V; Dziegiel, Morten Hanefeld;

    2008-01-01

    Bone turnover is a highly regulated process, where bone resorption in the normal healthy individual always is followed by bone formation in a manner referred to as coupling. Patients with osteopetrosis caused by defective acidification of the resorption lacuna have severely decreased resorption, in...... face of normal or even increased bone formation. This suggests that osteoclasts, not their resorptive activity, are important for sustaining bone formation. To investigate whether osteoclasts mediate control of bone formation by production of bone anabolic signals, we collected conditioned media (CM......) from human osteoclasts cultured on either bone or plastic, and tested their effects on bone nodule formation by osteoblasts. Both types of CM were shown to dose-dependently induce bone nodule formation, whereas non-conditioned osteoclast culture medium had no effects. These data show that osteoclasts...

  19. Radiation therapy for metastatic lesions from breast cancer. Breast cancer metastasis to bone

    Energy Technology Data Exchange (ETDEWEB)

    Hayashi, Shinya; Hoshi, Hiroaki [Gifu Univ. (Japan). School of Medicine

    2000-10-01

    This paper summarizes radiation therapy in the treatment of bone metastases from breast cancer. Bone metastasis occurs in approximately 70% of breast cancer patients, and the goals of radiation therapy for bone metastasis are: palliation of pain, prevention and treatment of neuropathic symptoms, and prevention of pathologic fractures. The prognosis of bone metastasis from breast cancer is known to be better than that of bone metastasis from other solid tumors. Local-field radiation, hemibody (or wide-field) radiation, and systemic radionuclide treatment are the major methods of radiation therapy for pain palliation. Although many studies have shown that breast cancer is more responsive to radiation therapy for pain palliation than other solid tumors, some studies found no significant difference. Local-field radiation therapy, which includes multi-fraction irradiation and single-fraction irradiation, is currently the most generally used method of radiotherapy for pain palliation. Pain palliation has been reported to be achieved in approximately 80% to 90% of patients treated with local-field external beam irradiation. Three types of multi-fraction irradiation therapy are administered depending on the prognosis: high-dose fraction irradiation (36-50 Gy/12-25 Fr/2.4-5 wk), short-course irradiation (20-30 Gy/10-15 Fr/2-3 wk), and ultra-short-course irradiation (15-25 Gy/2-5 Fr/1 wk). The most common irradiation schedule is 30 Gy/10 Fr/2 wk. Although many reports indicate no significant difference in pain palliation according to the dose, the percentage of patients who show a complete cure is significantly higher in those treated with doses of 30 Gy or more, and thus the total irradiation dose should be at least 30 Gy. High-dose fraction irradiation is indicated for patients with an expected survival time of 6 months or more while short-course or single-fraction irradiation is indicated for those with an expected survival time of 3 months or more. Single

  20. [The new bone formation and bone metabolism in Forestier disease].

    Science.gov (United States)

    Kotrych, Daniel; Bohatyrewicz, Andrzej; Woźniak, Wojciech; Zietek, Paweł; Kołodziej, Łukasz; Karaczun, Maciej; Grzegorczyk, Wojciech; Antoniak, Krzysztof

    2008-01-01

    The study was performed on 36 male patients between 65 and 83 years who were either hospitalised or treated in the out-patients clinic due to Forestier's disease. The aim of the study was to evaluate the advance of ectopic bone formation process in cervical spine and bony metabolic changes in treated patients. The study showed reverse corelation between the degree of advance of cervical hyperostosis and the prevalence of osteoporosis and metabolic disorders in the tested group. The authors have emphasized the need of precise evaluation and differentiation of Forestier's disease and degenerative spine disease. PMID:18847002

  1. A Population-based Study of the Fractionation of Palliative Radiotherapy for Bone Metastasis in Ontario

    International Nuclear Information System (INIS)

    Purpose: To describe the use of palliative radiotherapy (PRT) for bone metastases in Ontario between 1984 and 2001 and identify factors associated with the choice of fractionation. Methods and Materials: Electronic RT records from the nine provincial RT centers in Ontario were linked to the Ontario Cancer Registry to identify all courses of PRT for bone metastases. Results: Between 1984 and 2001, 44,884 patients received 74,432 courses of PRT for bone metastases in Ontario. The mean number of courses per patient was 1.7, and 65% of patients received only a single course of PRT for bone metastasis. The mean number of fractions per course was 3.9. The proportion of patients treated with a single fraction increased from 27.2% in 1984-1986 to 40.3% in 1987-1992 and decreased thereafter. Single fractions were used more frequently in patients with a shorter life expectancy, in older patients, and in patients who lived further from an RT center. Single fractions were used more frequently when the prevailing waiting time for RT was longer. There were wide variations in the use of single fractions among the different RT centers (intercenter range, 11.8-62.3%). Intercenter variations persisted throughout the study period and were not explained by differences in case mix. Conclusions: Despite increasing evidence of the effectiveness of single-fraction PRT for bone metastases, most patients continued to receive fractionated PRT throughout the two decades of this study. Single fractions were used more frequently when waiting times were longer. There was persistent, unexplained variation in the fractionation of PRT among different centers

  2. Changes in Cytokines of the Bone Microenvironment during Breast Cancer Metastasis

    International Nuclear Information System (INIS)

    It is commonly accepted that cancer cells interact with host cells to create a microenvironment favoring malignant colonization. The complex bone microenvironment produces an ever changing array of cytokines and growth factors. In this study, we examined levels of MCP-1, IL-6, KC, MIP-2, VEGF, MIG, and eotaxin in femurs of athymic nude mice inoculated via intracardiac injection with MDA-MB-231GFP human metastatic breast cancer cells, MDA-MB-231 BRMS1GFP, a metastasis suppressed variant, or PBS. Animals were euthanized (day 3, 11, 19, 27 after injection) to examine femoral cytokine levels at various stages of cancer cell colonization. The epiphysis contained significantly more cytokines than the diaphysis except for MIG which was similar throughout the bone. Variation among femurs was evident within all groups. By day 27, MCP-1, MIG, VEGF and eotaxin levels were significantly greater in femurs of cancer cell-inoculated mice. These pro-osteoclastic and angiogenic cytokines may manipulate the bone microenvironment to enhance cancer cell colonization

  3. The Micro environmental Effect in the Progression, Metastasis, and Dormancy of Breast Cancer: A Model System within Bone Marrow

    International Nuclear Information System (INIS)

    Despite diagnostic advances, breast cancer remains the most prevalent cancer among women in the United States. The armamentarium of treatment options for metastatic disease is limited and mostly ineffective with regards to eradicating cancer. However, there have been novel findings in the recent literature that substantiate the function of the microenvironment in breast cancer progression and the support of metastasis to tertiary sites such as bone marrow. The uncovered significance of the microenvironment in the pathophysiology of breast cancer metastasis has served to challenge previously widespread theories and introduce new perspectives for the future research to eradicate breast cancer. This paper delineates the current understanding of the molecular mechanisms involved in the interactions between breast cancer cells and the microenvironment in progression, metastasis, and dormancy. The information, in addition to other mechanisms described in bone marrow, is discussed in the paper

  4. Is 18F-FDG PET/CT more reliable than 99mTc-MDP planar bone scintigraphy in detecting bone metastasis in nasopharyngeal carcinoma?

    International Nuclear Information System (INIS)

    Bone metastasis occurs frequently in naso-pharyngeal carcinoma (NPC) patients. The aim of this study was to compare the clinical value of 18F-FDG PET/CT with that of 99mTc-MDP planar bone scintigraphy (PBS) for detecting bone metastasis in NPC patients. Thirty-five histologically proven NPC patients were enrolled in this retrospective study. They underwent both 18F-FDG PET/CT and PBS within 7 days in our department. In a lesion-based analysis, the skeletal system, excluding the head, was divided into four regions: the spine, the pelvis, the thorax, and the appendix. Bone metastasis was considered to be present by either biopsy or clinical follow-up for at least 6 months. PET/CT and PBS were compared by McNemar's paired-sample test. A total of 50 lesions were confirmed to be malignant (spine 27, thorax 11, pelvis 8 and appendix 4). Although PET/CT was found to be more sensitive on lesion level than PBS (sensitivity 70.0 versus 42.0%; P=0.044), there were still 14 metastatic (28.0%) lesions that could be detected by PBS while negative in PET/CT imaging. In a patient-based analysis, fifteen (42.9%) of 35 eligible patients were found to have bone metastasis. The sensitivity, specificity and accuracy of PET/CT was 60.0% (9/15), 100% (20/20) and 82.9% (29/35); as for PBS, it was 66.7% (10/15), 85.0% (17/20) and 77.1% (27/35), respectively. There was no statistical difference between PET/CT and PBS (P > 0.05). PBS, as a conventional imaging, should be used as an important complement for detecting bone metastasis in NPC patients. (author)

  5. FEASIBILITY OF WHOLE BODY DIFFUSION WEIGHTED IMAGING IN DETECTING BONE METASTASIS ON 3.0T MR SCANNER

    Institute of Scientific and Technical Information of China (English)

    Xian Xu; Lin Ma; Jins-han Zhang; You-quan Cai; Bai-xuan Xu; Liu-quan Chen; Fei Sun; Xing-gao Guo

    2008-01-01

    Objective To evaluate the feasibility of whole body diffusion weighted imaging (DWI) in bone metastasis detection using bone scintigraphy as comparison.Methods Forty-five patients with malignancy history were enrolled in our study. All the patients received the whole body DWI and bone scintigraphy scan within 1 week. The magnetic resonance (MR) examination was performed on 3.0T MR scanner using embedded body coil. The images were reviewed separately by two radiologists and two nuclear medicine physicians, who were blinded to the results of the other imaging modality. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the two techniques for detecting bone metastasis were analyzed.Results A total of 181 metastatic lesions in 77 regions of 34 patients were detected by whole body DWI, and 167 metastatic lesions in 76 regions of 31 patients were identified by bone scintigraphy. The patient-based sensitivity and PPV of whole body DWI and bone scintigraphy were similar (89.5% vs. 81.6%, 97.1% vs. 91.2%), whereas, the patient-basod specificity and NPV of whole body DW1 were obviously higher than those of bone scintigraphy (85.7% vs. 57.1%, 60.0% vs. 36.4%). Ten regions negative in scintigraphy but positive in whole body DWI, mainly located in spine, pelvis, and femur; nine regions only detected by scintigraphy, mainly located in skull, sternum, clavicle, and scapula. The region-based sensitivity and specificity of whole body DWI were slightly higher than those of bone scintigraphy (89.5% vs. 88.4%, 95.6% vs. 87.6%). Conclusion Whole body DWI reveals excellent concordance with bone scintigraphy regarding detection of bone metastasis, and the two techniques are complementary for each other.

  6. Development of a Patient-Derived Xenograft (PDX of Breast Cancer Bone Metastasis in a Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Laura Mercatali

    2016-08-01

    Full Text Available Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231. The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT, revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model.

  7. Development of a Patient-Derived Xenograft (PDX) of Breast Cancer Bone Metastasis in a Zebrafish Model

    Science.gov (United States)

    Mercatali, Laura; La Manna, Federico; Groenewoud, Arwin; Casadei, Roberto; Recine, Federica; Miserocchi, Giacomo; Pieri, Federica; Liverani, Chiara; Bongiovanni, Alberto; Spadazzi, Chiara; de Vita, Alessandro; van der Pluijm, Gabri; Giorgini, Andrea; Biagini, Roberto; Amadori, Dino; Ibrahim, Toni; Snaar-Jagalska, Ewa

    2016-01-01

    Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231). The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT), revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model. PMID:27556456

  8. Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies

    International Nuclear Information System (INIS)

    Metastatic events to the bone occur frequently in numerous cancer types such as breast, prostate, lung, and renal carcinomas, melanoma, neuroblastoma, and multiple myeloma. Accumulating evidence suggests that the inflammatory cytokine interleukin (IL)-6 is frequently upregulated and is implicated in the ability of cancer cells to metastasize to bone. IL-6 is able to activate various cell signaling cascades that include the STAT (signal transducer and activator of transcription) pathway, the PI3K (phosphatidylinositol-3 kinase) pathway, and the MAPK (mitogen-activated protein kinase) pathway. Activation of these pathways may explain the ability of IL-6 to mediate various aspects of normal and pathogenic bone remodeling, inflammation, cell survival, proliferation, and pro-tumorigenic effects. This review article will discuss the role of IL-6: 1) in bone metabolism, 2) in cancer metastasis to bone, 3) in cancer prognosis, and 4) as potential therapies for metastatic bone cancer

  9. Diagnostic value of urinary pyridinoline for determining bone metastasis in patients with non-metastatic breast cancer

    Directory of Open Access Journals (Sweden)

    Fatma Uçar

    2011-12-01

    Full Text Available Objective: In this study, urinary pyridinoline (uPYR, urinary deoxypyridinoline (uDPD and serum alkaline phosphatase (sALP levels were measured in patients without metastatic breast cancer and the role of uPYR and uDPD as biochemical markers of bone metastases were examined during a six years follow-up.Materials and methods: Totally, 34 patients without bone metastasis and 40 healthy individuals as a control group were included in the study.Results: Urinary pyridinoline and uDPD levels were significantly higher in patients without bone metastasis than in normal controls (p<0,05, except sALP levels. As a result of a 6-year follow-up of patients, 20.5% had metastasis. The distribution of metastasis types was as follows: 2.9% of those patients had local, 2.9% had liver, 5.9% had lung and 8.8% had bone metastasis. The cut off value, sensitivity and specifity of uPYR was established as 47,3 pmol/μmol creatinin, 82% and 80% respectively. The cut off value, sensitivity and specifity of uDPD were determined as 9.53 pmol/μmol creatinin, 76%, 72% respectively.Conclusions: This study demonstrated that measurement of urinary collagen cross-links assay may contribute to the early detection of metastatic spread to bone in breast cancer. However further studies with larger scaled groups should be performed. J Clin Exp Invest 2011; 2 (4: 420-424

  10. Receptor Activator of NF-kB (RANK) Expression in Primary Tumors Associates with Bone Metastasis Occurrence in Breast Cancer Patients

    Science.gov (United States)

    Vincenzi, Bruno; Gaeta, Laura; Pantano, Francesco; Russo, Antonio; Ortega, Cinzia; Porta, Camillo; Galluzzo, Sara; Armento, Grazia; La Verde, Nicla; Caroti, Cinzia; Treilleux, Isabelle; Ruggiero, Alessandro; Perrone, Giuseppe; Addeo, Raffaele; Clezardin, Philippe; Muda, Andrea Onetti; Tonini, Giuseppe

    2011-01-01

    Background Receptor activator of NFkB (RANK), its ligand (RANKL) and the decoy receptor of RANKL (osteoprotegerin, OPG) play a pivotal role in bone remodeling by regulating osteoclasts formation and activity. RANKL stimulates migration of RANK-expressing tumor cells in vitro, conversely inhibited by OPG. Materials and Methods We examined mRNA expression levels of RANKL/RANK/OPG in a publicly available microarray dataset of 295 primary breast cancer patients. We next analyzed RANK expression by immunohistochemistry in an independent series of 93 primary breast cancer specimens and investigated a possible association with clinicopathological parameters, bone recurrence and survival. Results Microarray analysis showed that lower RANK and high OPG mRNA levels correlate with longer overall survival (P = 0.0078 and 0.0335, respectively) and disease-free survival (P = 0.059 and 0.0402, respectively). Immunohistochemical analysis of RANK showed a positive correlation with the development of bone metastases (P = 0.023) and a shorter skeletal disease-free survival (SDFS, P = 0.037). Specifically, univariate analysis of survival showed that “RANK-negative” and “RANK-positive” patients had a SDFS of 105.7 months (95% CI: 73.9–124.4) and 58.9 months (95% CI: 34.7–68.5), respectively. RANK protein expression was also associated with accelerated bone metastasis formation in a multivariate analysis (P = 0.029). Conclusions This is the first demonstration of the role of RANK expression in primary tumors as a predictive marker of bone metastasis occurrence and SDFS in a large population of breast cancer patients. PMID:21559440

  11. Therapeutic inhibition of cathepsin K—reducing bone resorption while maintaining bone formation

    OpenAIRE

    Duong, Le T.

    2012-01-01

    Osteoporosis is a disease of high bone remodeling with an imbalance of bone resorption over bone formation, resulting in decreased bone mineral density and deterioration of bone microarchitecture. From the emerging understandings of the molecular and cellular regulators of bone remodeling, potential new targets for therapeutic intervention for this disease have been identified. Cathepsin K (CatK), a cysteine protease produced by osteoclasts, is the primary enzyme mediating the degradation of ...

  12. Establishing the Nude Mice Bone Metastasis Model of Lung Adenocarcinoma and Applying MicroCT into the Observation

    OpenAIRE

    Yongqi CUI; Geng, Qin; Gu, Aiqin; Miaoxin ZHU; Hanwei KONG; Sun, Lei; Liu, Lei; Yan, Mingxia; Yao, Ming

    2013-01-01

    Background and objective 50%-70% of patients with advanced lung cancer will develop bone metastases. The aim of this study is to establish the nude mice bone metastasis model of lung adenocarcinoma using A549, H1299, SPC-A-1 and XL-2, all of which own different invasion and migration abilities in vitro and supervise the bone metastases by MicroCT. Methods fifty BALB/C-nu/nu nude mice were grouped into five groups on average randomly. Cells of the four cell lines were injected into the left ca...

  13. Establishing the Nude Mice Bone Metastasis Model of Lung Adenocarcinoma and Applying MicroCT into the Observation

    Directory of Open Access Journals (Sweden)

    Yongqi CUI

    2013-09-01

    Full Text Available Background and objective 50%-70% of patients with advanced lung cancer will develop bone metastases. The aim of this study is to establish the nude mice bone metastasis model of lung adenocarcinoma using A549, H1299, SPC-A-1 and XL-2, all of which own different invasion and migration abilities in vitro and supervise the bone metastases by MicroCT. Methods fifty BALB/C-nu/nu nude mice were grouped into five groups on average randomly. Cells of the four cell lines were injected into the left cardiac ventricle of mice in the four experimental groups (0.2 mL/mouse respectively; meanwhile, mice in the control group were injected with normal saline (0.2 mL/mouse in the same manner. Periodical radiological examination was carried out to supervise the variation of the mice since the second week after injection. When mice in each group became thin obviously, end the experiment of this group. Before the end, pathological sections of bone tissues were made. We classified the bone metastatic sites into axial skeleton and limb bone, in order to compare the metastatic rates of these two different parts. The bone metastatic abilities of the four cell lines was statistically analyzed by comparing the average time cost in the appearance of bone metastases and the percentage of bone metastases among the experimental groups. Results Different metastatic sites which had been identified both by MicroCT and pathological sections appeared in each group of the four experimental groups. By contrast, no metastasis was observed in the control group. The percentage of cancer metastasizing to axial skeleton was remarkably higher than the percentage of tumor metastasizing to the limb bone in each experimental group, which was consistent with the clinical regularity and characteristics of skeletal metastases with lung cancer. Thus, the model has been established triumphantly. However, there were no statistical differences in the average time consumed and skeletal metastatic

  14. Brain Metastasis in Bone and Soft Tissue Cancers: A Review of Incidence, Interventions, and Outcomes

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    Faris Shweikeh

    2014-01-01

    Full Text Available Bone and soft tissue malignancies account for a small portion of brain metastases. In this review, we characterize their incidence, treatments, and prognosis. Most of the data in the literature is based on case reports and small case series. Less than 5% of brain metastases are from bone and soft tissue sarcomas, occurring most commonly in Ewing’s sarcoma, malignant fibrous tumors, and osteosarcoma. Mean interval from initial cancer diagnosis to brain metastasis is in the range of 20–30 months, with most being detected before 24 months (osteosarcoma, Ewing sarcoma, chordoma, angiosarcoma, and rhabdomyosarcoma, some at 24–36 months (malignant fibrous tumors, malignant peripheral nerve sheath tumors, and alveolar soft part sarcoma, and a few after 36 months (chondrosarcoma and liposarcoma. Overall mean survival ranges between 7 and 16 months, with the majority surviving < 12 months (Ewing’s sarcoma, liposarcoma, malignant fibrous tumors, malignant peripheral nerve sheath tumors, angiosarcoma and chordomas. Management is heterogeneous involving surgery, radiosurgery, radiotherapy, and chemotherapy. While a survival advantage may exist for those given aggressive treatment involving surgical resection, such patients tended to have a favorable preoperative performance status and minimal systemic disease.

  15. Survey for primary tumor site in patients with initial clinical presentation of bone metastasis

    International Nuclear Information System (INIS)

    Among the patients who were examined with bone scintigraphy between April 1985 and March 1991, there were 27 patients whose initial clinical manifestation was bone metastasis and who were surveyed for the primary tumor site. The primary tumor site could be identified in 20 patients (74%), consisting of 9 patients with lung cancer, 3 with prostate cancer, 3 with hepatoma, 2 with renal cancer, and one each with thyroid cancer, adrenal cancer, and pleural malignant mesothelioma. In 17 of the 20 patients, the primary site had been detected within two months after presentation. Examinations which were helpful in identifying the primary site included chest radiography, sputum cytology, abdominal sonography, serum prostatic acid phosphatase level and pathologic examination of biopsy specimens. 99mTc-pyridoxylenemethyl tryptophan (99mTc-PMT) scintigraphy was useful in the diagnosis of the hepatoma when accumulation was observed at the metastatic sites. In 2 patients, lung cancer had been recognized using follow-up chest, radiography 3 and 6 months after presentation, respectively. One patient was diagnosed at autopsy as having adrenal cancer. In 7 patients the primary site remains unknown. Histology examination of the biopsy specimen performed in 6 of these patients revealed 4 to be adenocarcinoma and 2 undifferentiated carcinoma. The average survival period of the 17 patients who died was 9.5 months. Four patients are alive, and the outcome in the remaining 6 could not be determined. (author)

  16. A Bone Metastasis Nude Mouse Model Created by Ultrasound Guided Intracardiac Injection of Breast Cancer Cells: the Micro-CT, MRI and Bioluminescence Imaging Analysis

    International Nuclear Information System (INIS)

    The purpose of this study was to develop a nude mouse model of bone metastasis by performing intracardiac injection of breast cancer cells under ultrasonography guidance and we wanted to evaluate the development and the distribution of metastasis in vivo using micro-CT, MRI and bioluminescence imaging. Animal experiments were performed in 6-week-old female nude mice. The animals underwent left ventricular injection of 2x105 MDA-MB-231Bo-Luc cells. After injection of the tumor cells, serial bioluminescence imaging was performed for 7 weeks. The findings of micro-CT, MRI and the histology were correlated with the 'hot' lesions seen on the bioluminescence imaging. Metastasis was found in 62.3% of the animals. Two weeks after intracardiac injection, metastasis to the brain, spine and femur was detected with bioluminescence imaging with an increasing intensity by week 7. Micro-CT scan confirmed multiple osteolytic lesions at the femur, spine and skull. MRI and the histology were able to show metastasis in the brain and extraskeletal metastasis around the femur. The intracardiac injection of cancer cells under ultrasonography guidance is a safe and highly reproducible method to produce bone metastasis in nude mice. This bone metastasis nude mouse model will be useful to study the mechanism of bone metastasis and to validate new therapeutics

  17. A Bone Metastasis Nude Mouse Model Created by Ultrasound Guided Intracardiac Injection of Breast Cancer Cells: the Micro-CT, MRI and Bioluminescence Imaging Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Park, Young Jin; Song, Eun Hye; Kim, Seol Hwa; Song, Ho Taek; Suh, Jin Suck [Yonsei University College of Medicine, Seoul (Korea, Republic of); Choi, Sang Hyun [Korean Minjok Leadership Academy, Heongsung (Korea, Republic of)

    2011-01-15

    The purpose of this study was to develop a nude mouse model of bone metastasis by performing intracardiac injection of breast cancer cells under ultrasonography guidance and we wanted to evaluate the development and the distribution of metastasis in vivo using micro-CT, MRI and bioluminescence imaging. Animal experiments were performed in 6-week-old female nude mice. The animals underwent left ventricular injection of 2x105 MDA-MB-231Bo-Luc cells. After injection of the tumor cells, serial bioluminescence imaging was performed for 7 weeks. The findings of micro-CT, MRI and the histology were correlated with the 'hot' lesions seen on the bioluminescence imaging. Metastasis was found in 62.3% of the animals. Two weeks after intracardiac injection, metastasis to the brain, spine and femur was detected with bioluminescence imaging with an increasing intensity by week 7. Micro-CT scan confirmed multiple osteolytic lesions at the femur, spine and skull. MRI and the histology were able to show metastasis in the brain and extraskeletal metastasis around the femur. The intracardiac injection of cancer cells under ultrasonography guidance is a safe and highly reproducible method to produce bone metastasis in nude mice. This bone metastasis nude mouse model will be useful to study the mechanism of bone metastasis and to validate new therapeutics

  18. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

    Directory of Open Access Journals (Sweden)

    Paola Maroni

    2016-03-01

    Full Text Available Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination.

  19. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages.

    Science.gov (United States)

    Maroni, Paola; Bendinelli, Paola; Resnati, Massimo; Matteucci, Emanuela; Milan, Enrico; Desiderio, Maria Alfonsina

    2016-01-01

    Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. PMID:27023526

  20. Gene expression markers in circulating tumor cells may predict bone metastasis and response to hormonal treatment in breast cancer

    Science.gov (United States)

    WANG, HAIYING; MOLINA, JULIAN; JIANG, JOHN; FERBER, MATTHEW; PRUTHI, SANDHYA; JATKOE, TIMOTHY; DERECHO, CARLO; RAJPUROHIT, YASHODA; ZHENG, JIAN; WANG, YIXIN

    2013-01-01

    Circulating tumor cells (CTCs) have recently attracted attention due to their potential as prognostic and predictive markers for the clinical management of metastatic breast cancer patients. The isolation of CTCs from patients may enable the molecular characterization of these cells, which may help establish a minimally invasive assay for the prediction of metastasis and further optimization of treatment. Molecular markers of proven clinical value may therefore be useful in predicting disease aggressiveness and response to treatment. In our earlier study, we identified a gene signature in breast cancer that appears to be significantly associated with bone metastasis. Among the genes that constitute this signature, trefoil factor 1 (TFF1) was identified as the most differentially expressed gene associated with bone metastasis. In this study, we investigated 25 candidate gene markers in the CTCs of metastatic breast cancer patients with different metastatic sites. The panel of the 25 markers was investigated in 80 baseline samples (first blood draw of CTCs) and 30 follow-up samples. In addition, 40 healthy blood donors (HBDs) were analyzed as controls. The assay was performed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) with RNA extracted from CTCs captured by the CellSearch system. Our study indicated that 12 of the genes were uniquely expressed in CTCs and 10 were highly expressed in the CTCs obtained from patients compared to those obtained from HBDs. Among these genes, the expression of keratin 19 was highly correlated with the CTC count. The TFF1 expression in CTCs was a strong predictor of bone metastasis and the patients with a high expression of estrogen receptor β in CTCs exhibited a better response to hormonal treatment. Molecular characterization of these genes in CTCs may provide a better understanding of the mechanism underlying tumor metastasis and identify gene markers in CTCs for predicting disease progression and

  1. Effect of spaceflight on periosteal bone formation in rats

    Science.gov (United States)

    Wronski, T. J.; Morey, E. R.

    1983-01-01

    Male Wistar rats were placed in orbit for 18.5 days aboard the Soviet COSMOS 1129 biological satellite. Tetracycline was administered before and after spaceflight to label areas of bone formation. An inhibition of periosteal bone formation occurred during spaceflight in the tibial and humeral diaphyses, but this defect was corrected during the postflight period. The increased extent of arrest lines at these skeletal sites suggested that periosteal bone formation may have even ceased during spaceflight. The rib exhibited a small but nonsignificant decrease in periosteal bone formation. Endosteal bone resorption was not affected markedly by spaceflight conditions. The observed inhibition of periosteal bone formation may be a result of mechanical unloading, but endocrine factors cannot be ruled out.

  2. The content of 153Sm-oxabifor in cancer patients blood in the treatment of bone metastasis

    International Nuclear Information System (INIS)

    Concentration 153Sm in the blood of patients with bone metastasis after radionuclide therapy was determined. Considerable variation of the content of 153Sm in blood of patients with various primary cancers from 10 to 65 Bq/ml is found. The effective half-life of 153Sm in the blood of patients was estimated at more than 10 days during the course of the therapy in time interval more than 7 days

  3. Kinetics of 153Sm oxabiphor in the blood of cancer patients undergoing complex therapy for bone metastasis

    International Nuclear Information System (INIS)

    Concentration 153Sm in the blood of patients with bone metastasis after radionuclide therapy was determined. Considerable variation of the content of 153Sm in blood of patients with various primary cancers from 10 to 65 Bq/ml is found. The effective half-life of 153Sm in the blood of patients was estimated at more than 10 days during the course of the therapy.

  4. 177Lu-DOTMP: a viable agent for palliative radiotherapy of painful bone metastasis

    International Nuclear Information System (INIS)

    The suitable nuclear decay characteristics [T1/2 = 6.73 d, Eβ(max) = 497 keV, Eγ = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production with adequate specific activity and radionuclidic purity using a moderate flux reactor are important attributes towards 177Lu to be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study describes the preparation of 177Lu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and its preliminary biological evaluation in animal models with an aim to proposing it as a viable radiopharmaceutical for bone pain palliation. The choice DOTMP as the polyaminophosphonic acid carrier ligand is based on the enhanced thermodynamic stability and kinetic inertness of the metal-ligand complexes with macrocyclic chelators. 177Lu was produced with a specific activity of ∝ 12 GBq/mg (∝ 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu2O3 target at a thermal neutron flux of ∝ 6 x 1013 n/cm2 s for 21 d. 177Lu-DOTMP complex was prepared in high yield and excellent radiochemical purity (> 99%) using DOTMP synthesized and characterized in-house. The complex exhibited excellent in-vitro stability at room temperature. Biodistribution studies in Wistar rats showed rapid skeletal accumulation of the injected activity [(1.60±0.19)% per gram in femur at 3 h post-injection] with fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated significant accumulation of the agent in skeleton and almost no retention in any other vital organs. (orig.)

  5. Cytogenetic analysis of 153 Sm-EDTMP in peripheral lymphocytes from patients with bone cancer metastasis

    International Nuclear Information System (INIS)

    The 153 Sm-EDTMP is a radiopharmaceutical used in nuclear medicine with promising results for the relief of metastatic pain. Therefore, there are few knowledge about the effects of 153 Sm-EDTMP at cellular level. The present study was conducted with the aim of evaluating the cytogenetic effects of 153 Sm-EDTMP in peripheral lymphocytes from patients with bone metastasis (with and without previous radio and/or chemotherapy) by the chromosome aberration technique. For that, the blood samples were collected before and one hour after the endovenous administrations of 153 Sm-EDTMP (mean activity of 42.53 ± 5.31 MBq/kg body weight), taking into account the rapid blood clearance. The principal types of structural chromosome aberrations found gaps and breaks, acentric fragments centric rings, double minutes and dicentrics. The statistical analysis showed that the group submitted to previous radio and chemotherapy before153 Sm-EDTMP administration showed significant difference in chromosome aberrations frequency one hour after the treatment. The analysis of the chromosome modal number and the kinetics of cellular cycle showed no statistical difference among the groups, suggesting that the treatment with 153 Sm-EDTMP, did not influence these parameters. The obtained data showed that the therapy with 153 Sm-EDTMP induced a few quantity of cytogenetic damages in peripheral lymphocytes one hour after its administration in patients, although, theoretically, a long term stochastic effect cannot be disregarded. (author)

  6. Lung Metastasis From Prostate Cancer Revealed by 18F-FDG PET/CT Without Osseous Metastasis on Bone Scan.

    Science.gov (United States)

    Su, Hung-Yi; Chen, Meng-Lin; Hsieh, Ping-Ju; Hsieh, Teh-Sheng; Chao, Ing-Ming

    2016-05-01

    A 54-year-old man, a case of prostate cancer, underwent radical prostatectomy and hormone therapy. Elevated prostate-specific antigen level developed 7 years later, but pelvic MRI and bone scan revealed negative results. Radiotherapy was performed under the suspicion of local recurrence but in vain. F-FDG PET/CT performed 1 more year later showed 3 FDG-avid lesions in the right lung and mediastinum. Lung and lymph node metastases were proved with video-assisted thoracoscopic surgery. Bone scan remained negative at that time. PMID:26859201

  7. Primary neuroendocrine carcinoma of breast with liver and bone metastasis detected with fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography

    International Nuclear Information System (INIS)

    Cases of primary neuroendocrine carcinoma (NEC) of the breast have been reported, though rare. We report the case of a 45-year-old woman presented with jaundice and evaluated to have liver metastasis from neuroendocrine origin. She underwent whole body positron emission tomography/computed tomography, which showed left breast lesion and bone metastasis. Fine-needle aspiration (FNA) of breast revealed a NEC. A diagnosis of a primary NEC of the breast was rendered with hepatic and bone metastasis. She was treated with peptide receptor radionuclide therapy and is on follow-up

  8. Development of the method for treatment for bone metastasis by using disequilibrium-type alpha particle emitting in vivo generator: 227Th-EDTMP

    International Nuclear Information System (INIS)

    To evaluate the efficacy of an alpha emitting radiopharmaceutical, 227Th-EDTMP for treatment of bone metastasis, 1) the process of bone metastasis on rats were monitored by radiography and gamma scintigraphy, and 2) 227Th-EDTMP were administered to bone metastasis model rats and assessed its palliation effect by von Frey filament test and measured tumor size. Two weeks after tumor cell inoculation, rats showed osteolytic change on cell inoculated site and bone lesion was detected by scintigraphy. In the therapy study, the rats showed no toxic effect by 227Th-EDTMP. However, the tumor volume size was increased with time and the bone pain palliation was comparable to control groups. Further experiment was necessary. (author)

  9. Impact of bone graft harvesting techniques on bone formation and graft resorption

    DEFF Research Database (Denmark)

    Saulacic, Nikola; Bosshardt, Dieter D; Jensen, Simon S;

    2015-01-01

    BACKGROUND: Harvesting techniques can affect cellular parameters of autogenous bone grafts in vitro. Whether these differences translate to in vivo bone formation, however, remains unknown. OBJECTIVE: The purpose of this study was to assess the impact of different harvesting techniques on bone fo...

  10. Comparison of 18F-FDG PET/CT with bone scintigraphy for detection of bone metastasis: a meta-analysis

    International Nuclear Information System (INIS)

    Background. The skeleton is one of the favorable sites for the metastasis of almost all human malignant neoplasms. An accurate diagnosis of bone metastasis is crucial for the patient's staging and management. Purpose. To investigate and compare diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BS) for detection of bone metastasis in malignancies using meta-analysis. Material and Methods. PubMed (Medline included) was searched for relevant articles. We assessed the methodological quality with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used statistical software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve. Results. Six studies met inclusion criteria. For 18F-FDG PET/CT, the pooled sensitivity and specificity were 0.934 and 0.975, respectively. The pooled positive likelihood ratio (LR+), negative likelihood ratio (LR-) and diagnostic odds ratio (DOR) were 34.990, 0.068 and 559.02, respectively. The area under the SROC curve was 0.9854. For BS, the pooled sensitivity, specificity, LR+ , LR- and DOR were 0.706 (0.642-0.764), 0.911 (0.896-0.926), 13.982 (2.419-80.817), 0.319 (0.143-0.712), and 60.420 (21.393-170.64), respectively. The area under the SROC curve was 0.9386. Conclusion. The results indicate that 18F-FDG PET/CT do have both higher sensitivity and specificity than bone scintigraphy for detecting metastatic bone tumor. However, further research is needed to evaluate the diagnostic performance of 18F-FDG PET/CT and BS in each common malignancy

  11. The impact of skeletal unloading on bone formation

    Science.gov (United States)

    Bikle, Daniel D.; Sakata, Takeshi; Halloran, Bernard P.

    2003-01-01

    Skeletal unloading leads to decreased bone formation and decreased bone mass. Bone resorption is uncoupled from bone formation, contributing to the bone loss. During space flight bone is lost principally from the bones most loaded in the 1 g environment. Determining the mechanism(s) by which loading of bone is sensed and translated into a signal(s) controlling bone formation remains the holy grail in this field. It seems likely that matrix/cell interactions will underlie much of the mechanocoupling. Integrins are a prime mediator of such interactions. The role for systemic hormones such as PTH, GH and 1,25(OH)2D compared to locally produced factors such as IGF-I, PTHrP, BMPs and TGF beta in modulating the cellular response to load remains unclear. Our studies demonstrate that skeletal unloading leads to resistance to the anabolic actions of IGF-I on bone as a result of failure of IGF-I to activate its own signaling pathways. This is associated with a reduction in integrin expression, suggesting crosstalk between these two pathways. As the mechanism(s) by which bone responds to changes in mechanical load with changes in bone formation is further elucidated, applications of this knowledge to other etiologies of osteoporosis are likely to develop. Skeletal unloading provides a perturbation in bone mineral homeostasis that can be used to understand the mechanisms by which bone mineral homeostasis is maintained, and that such understanding will lead to effective treatment for disuse osteoporosis in addition to preventive measures for the bone loss that accompanies space travel.

  12. High-dose therapy improved the bone remodelling compartment canopy and bone formation in multiple myeloma

    DEFF Research Database (Denmark)

    Hinge, Maja; Delaissé, Jean-Marie; Plesner, Torben; Clasen-Linde, Erik; Salomo, Morten; Levin Andersen, Thomas

    2015-01-01

    . Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell......Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling...... transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a...

  13. Clinical features of bone metastasis for differentiated thyroid carcinoma: A study of 21 patients from a Tunisian center

    Directory of Open Access Journals (Sweden)

    Faouzi Kallel

    2014-01-01

    Full Text Available Introduction: The differentiated thyroid cancers have a good prognosis unless the presence of metastasis. These distant metastases, especially in bone, are a major cause of impaired quality of life and death requiring intensive management. The aim of our work was to study the patients′ data, the disease characteristics and to analyze the therapeutic management of these patients. Results: This study concerned a cohort of 21 patients treated for differentiated thyroid cancer during the period from 1995 to 2011. Eighteen of our patients were aged over 45 years. A majority of them had follicular carcinoma. Bone metastases were often multiple and located at the axial skeleton. They were associated with other types of metastases, especially lung metastasis. A majority of patients received 131I treatment, following surgery or external beam radiotherapy for a palliative purpose. Overall survival was 65% at 5 years and 49% at 10 years. A long-term survival was achieved in 10% of the patients benefiting from a multidisciplinary care adapted to each case. Conclusion: Bone metastases often have a pejorative turning in the natural history of differentiated thyroid cancers. The right selection of individuals with better prognosis, for whom more aggressive curative treatment was indicated, requires a better understanding of the features of bone involvement.

  14. Demineralized Bone Matrix Injection in Consolidation Phase Enhances Bone Regeneration in Distraction Osteogenesis via Endochondral Bone Formation

    OpenAIRE

    Kim, Ji-Beom; Lee, Dong Yeon; Seo, Sang Gyo; Kim, Eo Jin; Kim, Ji Hye; Yoo, Won Joon; Cho, Tae-Joon; Choi, In Ho

    2015-01-01

    Background Distraction osteogenesis (DO) is a promising tool for bone and tissue regeneration. However, prolonged healing time remains a major problem. Various materials including cells, cytokines, and growth factors have been used in an attempt to enhance bone formation. We examined the effect of percutaneous injection of demineralized bone matrix (DBM) during the consolidation phase on bone regeneration after distraction. Methods The immature rabbit tibial DO model (20 mm length-gain) was u...

  15. Brief review of models of ectopic bone formation.

    Science.gov (United States)

    Scott, Michelle A; Levi, Benjamin; Askarinam, Asal; Nguyen, Alan; Rackohn, Todd; Ting, Kang; Soo, Chia; James, Aaron W

    2012-03-20

    Ectopic bone formation is a unique biologic entity--distinct from other areas of skeletal biology. Animal research models of ectopic bone formation most often employ rodent models and have unique advantages over orthotopic (bone) environments, including a relative lack of bone cytokine stimulation and cell-to-cell interaction with endogenous (host) bone-forming cells. This allows for relatively controlled in vivo experimental bone formation. A wide variety of ectopic locations have been used for experimentation, including subcutaneous, intramuscular, and kidney capsule transplantation. The method, benefits and detractions of each method are summarized in the following review. Briefly, subcutaneous implantation is the simplest method. However, the most pertinent concern is the relative paucity of bone formation in comparison to other models. Intramuscular implantation is also widely used and relatively simple, however intramuscular implants are exposed to skeletal muscle satellite progenitor cells. Thus, distinguishing host from donor osteogenesis becomes challenging without cell-tracking studies. The kidney capsule (perirenal or renal capsule) method is less widely used and more technically challenging. It allows for supraphysiologic blood and nutrient resource, promoting robust bone growth. In summary, ectopic bone models are extremely useful in the evaluation of bone-forming stem cells, new osteoinductive biomaterials, and growth factors; an appropriate choice of model, however, will greatly increase experimental success. PMID:22085228

  16. Leptin regulates bone formation via the sympathetic nervous system

    Science.gov (United States)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  17. [Bone formation and corticotomy-induced accelerated bone remodeling: can alveolar corticotomy induce bone formation?].

    Science.gov (United States)

    Moreau, Nathan; Charrier, Jean-Baptiste

    2015-03-01

    Current orthodontic treatments must answer an increasing demand for faster yet as efficient treatments, especially in adult patients. These past years, the amelioration of orthodontic, anesthetic and orthognathic surgery techniques have allowed considerable improvement of orthodontico-surgical treatments and of adult orthodontic treatments. Alveolar corticotomy (an example of such techniques) accelerates orthodontic tooth movements by local modifications of bone metabolism, inducing a transient osteopenia. This osteopenia allows greater tooth movements than conventional techniques. Whereas there is a growing understanding of the underlying biological mechanisms of alveolar corticotomies, there is little data regarding the osteogenic potential of such technique. In the present article, we review the literature pertaining to alveolar corticotomies and their underlying biological mechanisms and present a clinical case underlining the osteogenic potential of the technique. PMID:25888047

  18. {sup 177}Lu-DOTMP: a viable agent for palliative radiotherapy of painful bone metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Das, T.; Chakraborty, S.; Banerjee, S. [Radiopharmaceuticals Div., Bhabha Atomic Research Centre, Mumbai (India); Sarma, H.D. [Radiation Biology and Health Sciences Div., Bhabha Atomic Research Centre, Mumbai (India)

    2008-07-01

    The suitable nuclear decay characteristics [T{sub 1/2} = 6.73 d, E{sub {beta}}{sub (max)} = 497 keV, E{sub {gamma}} = 113 keV (6.4%), 208 keV (11%)] as well as the feasibility of large-scale production with adequate specific activity and radionuclidic purity using a moderate flux reactor are important attributes towards {sup 177}Lu to be considered as a promising radionuclide for palliative care in painful bone metastasis. The present study describes the preparation of {sup 177}Lu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP) and its preliminary biological evaluation in animal models with an aim to proposing it as a viable radiopharmaceutical for bone pain palliation. The choice DOTMP as the polyaminophosphonic acid carrier ligand is based on the enhanced thermodynamic stability and kinetic inertness of the metal-ligand complexes with macrocyclic chelators. {sup 177}Lu was produced with a specific activity of {proportional_to} 12 GBq/mg ({proportional_to} 324 mCi/mg) and radionuclidic purity of 99.98% by irradiation of natural Lu{sub 2}O{sub 3} target at a thermal neutron flux of {proportional_to} 6 x 10{sup 13} n/cm{sup 2} s for 21 d. {sup 177}Lu-DOTMP complex was prepared in high yield and excellent radiochemical purity (> 99%) using DOTMP synthesized and characterized in-house. The complex exhibited excellent in-vitro stability at room temperature. Biodistribution studies in Wistar rats showed rapid skeletal accumulation of the injected activity [(1.60{+-}0.19)% per gram in femur at 3 h post-injection] with fast clearance from blood and minimal uptake in any of the major organs. Scintigraphic studies carried out in normal Wistar rats and New Zealand white rabbits also demonstrated significant accumulation of the agent in skeleton and almost no retention in any other vital organs. (orig.)

  19. Radiation therapy for bone metastasis from hepatocellular carcinoma. Evaluation of pain relief and tumor regression

    Energy Technology Data Exchange (ETDEWEB)

    Wakisaka, Masaki; Mori, Hiromu; Matsumoto, Akira; Ochotorena, I. J.; Funakoshi, Takeshi [Oita Medical Univ. (Japan)

    1999-01-01

    The purpose of this retrospective study is to analyze the effectiveness of radiation therapy (RT) for the patients with bone metastasis from HCC with regard to tumor regression and pain relief. Twenty-five patients (42-78 years old) with 32 bone metastases (7 ribs, 13 vertebras, 6 iliums, 3 humeruses, 2 femurs and 1 scapula) from HCC received RT (10-60 Gy, mean 35.9 Gy). RT was performed using 5-10 MV x-rays or 12-18 MeV electron beams from a linear accelerator. Additional transcatheter arterial injection of anti-cancer drugs (TAI) and/or arterial embolization (TAE) were carried out for five lesions. Pain relief was obtained in 22 patients with 26 lesions (81%). Pain relief appeared at a dose of 12-30 Gy with a mean of 18.5 Gy. In 9 patients (82%) with 12 lesions out of 11 patients with 15 lesions who could be evaluated for duration of pain relief, recurrence of pain was not noted up to the last follow-up day or to the death of the patients (1-36 months). In 13 lesions, tumor regression was evaluated by CT and/or MRI; Complete regression (CR) was noted in 1 lesion, partial regression (PR) in 6 lesions, no change (NC) in 2 lesions, and progressive disease (PD) in 4 lesions. The tumor regression (CR+PR) rate was 53.8%. In 8 lesions treated with RT alone, there was PR in 2 lesions, NC in 2 lesions, PD in 4 lesions, and CR was not seen. In 5 lesions treated with a combination of RT and TAI and/or TAE, CR was noted in 1 lesion, PR in 4 lesions and no NC or PD. There was a correlation between the initial tumor volume and the degree of pain before RT, but there was no correlation between tumor regression and pain relief after RT. The one-year survival rate was 17%, and the two-year rate was 8%. (K.H.)

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

    International Nuclear Information System (INIS)

    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.

  1. 消化道肿瘤骨转移患者297例放射性骨显像分析%An Analysis on Radioactive Bone Imaging in 297 Patients with Bone Metastasis from Gastrointestinal Cancer

    Institute of Scientific and Technical Information of China (English)

    任媛; 张茜; 庄坤

    2013-01-01

    [Purpose] To investigate the role of radioactive bone imaging in the diagnosis for gastrointestinal cancer with bone metastasis.[Methods] Radioactive bone imaging in 605 cases with gastrointestinal cancer was analyzed.[Results] Among the 605 patients,297(49.09%) occurred bone metastasis.The frequency of multiple bone metastases(88.22%) was obviously more than that of single bone metastasis (11.78%).Cancer adjacent bone metastases were the major modality.The trunk bone metastasis was more than that of limbs and skull bone.There were 69.36% patients with bone pain symptom.[Conclusion] Radionuclide bone imaging is valuable for diagnosis gastrointestinal cancer with bone metastasis.Patients with gastrointestinal cancer should receive routinely radionuclide bone imaging during the follow-up.%[目的]探讨核素骨显像对消化道肿瘤骨转移的临床诊断价值.[方法]分析605例消化道肿瘤患者中骨转移患者的全身骨显像结果.[结果] 605例肿瘤患者中,297例(49.09%)发生骨转移.多发骨转移(88.22%)多于单发骨转移(11.78%).转移灶的分布多为邻近转移,且躯干骨多于四肢骨和颅骨.69.36%患者有骨痛症状.[结论]核素骨显像对消化道肿瘤骨转移诊断具有诊断价值.消化道肿瘤患者在随访中应常规行核素骨显像.

  2. Osteoblast-derived sphingosine 1-phosphate to induce proliferation and confer resistance to therapeutics to bone metastasis-derived prostate cancer cells.

    Science.gov (United States)

    Brizuela, Leyre; Martin, Claire; Jeannot, Pauline; Ader, Isabelle; Gstalder, Cécile; Andrieu, Guillaume; Bocquet, Magalie; Laffosse, Jean-Michel; Gomez-Brouchet, Anne; Malavaud, Bernard; Sabbadini, Roger A; Cuvillier, Olivier

    2014-10-01

    Sphingosine 1-phosphate (S1P) plays important roles in cell proliferation, differentiation or survival mainly through its surface G-protein-coupled receptors S1P1-5. Bone represents the major site of metastasis for prostate cancer (CaP) cells, which rely on bone-derived factors to support their proliferation and resistance to therapeutics. In the present work we have found that conditioned medium (CM) from the MC3T3 osteoblastic cell line or primary murine and human osteoblast-like cells, as well as co-culture with MC3T3 stimulate proliferation of CaP lines in S1P-dependent manner. In addition, osteoblastic-derived S1P induces resistance of CaP cells to therapeutics including chemotherapy and radiotherapy. When S1P release from osteoblastic cells is decreased (inhibition of SphK1, knock-down of SphK1 or the S1P transporter, Spns2 by siRNA) or secreted S1P neutralized with anti-S1P antibody, the proliferative and survival effects of osteoblasts on CaP cells are abolished. Because of the paracrine nature of the signaling, we studied the role of the S1P receptors expressed on CaP cells in the communication with S1P secreted by osteoblasts. Strategies aimed at down-regulating S1P1, S1P2 or S1P3 (siRNA, antagonists), established the exclusive role of the S1P/S1P1 signaling between osteoblasts and CaP cells. Bone metastases from CaP are associated with osteoblastic differentiation resulting in abnormal bone formation. We show that the autocrine S1P/S1P3 signaling is central during differentiation to mature osteoblasts by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation. Importantly, differentiated osteoblasts exhibited enhanced secretion of S1P and further stimulated CaP cell proliferation in a S1P-dependent manner. By establishing the dual role of osteoblast-borne S1P on both osteoblastic differentiation and CaP cell proliferation and survival, we uncover the importance of S1P in the bone metastatic microenvironment, which may open

  3. Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats.

    OpenAIRE

    Belfrage Ola; Isaksson Hanna; Tägil Magnus

    2012-01-01

    ABSTRACT: BACKGROUND: Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone...

  4. Vascular biology and bone formation: hints from HIF

    OpenAIRE

    Towler, Dwight A.

    2007-01-01

    In this issue of the JCI, Wang, Clemens, and colleagues demonstrate that hypoxia-inducible factor α (HIFα) signaling in bone-building osteoblasts is central to the coupling of angiogenesis and long bone development in mice (see the related article beginning on page 1616). They show that bone formation controlled by osteoblast HIFα signaling is not cell autonomous but is coupled to skeletal angiogenesis dependent upon VEGF signaling. Thus, strategies that promote HIFα signaling in osteoblasts ...

  5. Non-ossifying fibroma mimicking distant metastasis of osteosarcoma on 99mTc-methylene diphosphonate bone scintigraphy: Diagnosis with single photon emission tomography/computed tomography

    International Nuclear Information System (INIS)

    Non-ossifying fibromas (NOFs) are benign bone lesions with variable appearance on bone scintigraphy. Single photon emission tomography/computed tomography (SPECT/CT) can help in accurate characterization of these lesions. We present a case of 14-year-old boy with recurrent osteosarcoma where NOF was mimicking distant metastasis on 99mTc-methylene diphosphonate bone scintigraphy. SPECT/CT was able to correctly characterize the lesion as NOF, thereby altering the management

  6. A supra-cellular model for coupling of bone resorption to formation during remodeling: lessons from two bone resorption inhibitors affecting bone formation differently.

    Science.gov (United States)

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Pennypacker, Brenda L; Duong, Le T; Engelholm, Lars H; Delaissé, Jean-Marie

    2014-01-10

    The bone matrix is maintained functional through the combined action of bone resorbing osteoclasts and bone forming osteoblasts, in so-called bone remodeling units. The coupling of these two activities is critical for securing bone replenishment and involves osteogenic factors released by the osteoclasts. However, the osteoclasts are separated from the mature bone forming osteoblasts in time and space. Therefore the target cell of these osteoclastic factors has remained unknown. Recent explorations of the physical microenvironment of osteoclasts revealed a cell layer lining the bone marrow and forming a canopy over the whole remodeling surface, spanning from the osteoclasts to the bone forming osteoblasts. Several observations show that these canopy cells are a source of osteoblast progenitors, and we hypothesized therefore that they are the likely cells targeted by the osteogenic factors of the osteoclasts. Here we provide evidence supporting this hypothesis, by comparing the osteoclast-canopy interface in response to two types of bone resorption inhibitors in rabbit lumbar vertebrae. The bisphosphonate alendronate, an inhibitor leading to low bone formation levels, reduces the extent of canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone formation follows resorption during these respective treatments. Furthermore, canopy cells exhibit uPARAP/Endo180, a receptor able to bind the collagen made available by osteoclasts, and reported to mediate osteoblast recruitment. Overall these observations support a mechanism where the recruitment of bone forming osteoblasts from the canopy is induced by osteoclastic factors, thereby favoring initiation of bone formation. They lead to a model where the osteoclast-canopy interface is

  7. Tumor-environment biomimetics delay peritoneal metastasis formation by deceiving and redirecting disseminated cancer cells.

    Science.gov (United States)

    De Vlieghere, Elly; Gremonprez, Félix; Verset, Laurine; Mariën, Lore; Jones, Christopher J; De Craene, Bram; Berx, Geert; Descamps, Benedicte; Vanhove, Christian; Remon, Jean-Paul; Ceelen, Wim; Demetter, Pieter; Bracke, Marc; De Geest, Bruno G; De Wever, Olivier

    2015-06-01

    Peritoneal metastasis is life threatening and is the result of an extensive communication between disseminated cancer cells, mesothelial cells and cancer-associated fibroblasts (CAF). CAFs secrete extracellular matrix (ECM) proteins creating a receptive environment for peritoneal implantation. Considering cancer as an ecosystem may provide opportunities to exploit CAFs to create biomimetic traps to deceive and redirect cancer cells. We have designed microparticles (MP) containing a CAF-derived ECM-surface that is intended to compete with natural niches. CAFs were encapsulated in alginate/gelatine beads (500-750 μm in diameter) functionalised with a polyelectrolyte coating (MP[CAF]). The encapsulated CAFs remain viable and metabolically active (≥35 days), when permanently encapsulated. CAF-derived ECM proteins are retained by the non-biodegradable coating. Adhesion experiments mimicking the environment of the peritoneal cavity show the selective capture of floating cancer cells from different tumor origins by MP[CAF] compared to control MP. MP[CAF] are distributed throughout the abdominal cavity without attachment to intestinal organs and without signs of inflammatory reaction. Intraperitoneal delivery of MP[CAF] and sequential removal redirects cancer cell adhesion from the surgical wound to the MP[CAF], delays peritoneal metastasis formation and prolongs animal survival. Our experiments suggest the use of a biomimetic trap based on tumor-environment interactions to delay peritoneal metastasis. PMID:25907048

  8. Extraskeletal and intraskeletal new bone formation induced by demineralized bone matrix combined with bone marrow cells

    International Nuclear Information System (INIS)

    Dilutions of fresh autogenous bone marrow cells in combination with allogeneic demineralized cortical bone matrix were tested extraskeletally in rats using roentgenographic, histologic, and 45Ca techniques. Suspensions of bone marrow cells (especially diluted 1:2 with culture media) combined with demineralized cortical bone seemed to induce significantly more new bone than did demineralized bone, bone marrow, or composite grafts with whole bone marrow, respectively. In a short-term spinal fusion experiment, demineralized cortical bone combined with fresh bone marrow produced new bone and bridged the interspace between the spinous processes faster than other transplantation procedures. The induction of undifferentiated host cells by demineralized bone matrix is further complemented by addition of autogenous, especially slightly diluted, bone marrow cells

  9. Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice.

    Science.gov (United States)

    Zong, Jian-Chun; Wang, Xing; Zhou, Xiang; Wang, Chen; Chen, Liang; Yin, Liang-Jun; He, Bai-Cheng; Deng, Zhong-Liang

    2016-02-01

    Breast cancer metastasizes to the bone in a majority of patients with advanced disease resulting in bone destruction. The underlying mechanisms are complex, and both processes are controlled by an interaction between locally and systemically derived signals. Clinically, breast cancer patients with depression have a higher risk of bone metastasis, yet the etiology and mechanisms are yet to be elucidated. MDA‑MB‑231 breast cancer cells were used to establish a bone metastasis model by using intracardiac injection in nude mice. Chronic mild stress (CMS) was chosen as a model of depression in mice before and after inoculation of the cells. Knockdown of the RUNX‑2 gene was performed by transfection of the cells with shRNA silencing vectors against human RUNX‑2. A co‑culture system was used to test the effect of the MDA‑MB‑231 cells on osteoclasts and osteoblasts. RT‑PCR and western blotting were used to test gene and protein expression, respectively. We confirmed that depression induced bone metastasis by promoting osteoclast activity while inhibiting osteoblast differentiation. Free serotonin led to an increase in the expression of RUNX2 in breast cancer cells (MDA‑MB‑231), which directly inhibited osteoblast differentiation and stimulated osteoclast differentiation by the PTHrP/RANKL pathway, which caused bone destruction and formed osteolytic bone lesions. Additionally, the interaction between depression and breast cancer cells was interrupted by LP533401 or RUNX2 knockdown. In conclusion, depression promotes breast cancer bone metastasis partly through increasing levels of gut‑derived serotonin. Activation of RUNX2 in breast cancer cells by circulating serotonin appears to dissociate coupling between osteoblasts and osteoclasts, suggesting that the suppression of gut‑derived serotonin decreases the rate of breast cancer bone metastasis induced by depression. PMID:26573960

  10. Stimulation of bone marrow cells and bone formation by nacre: in vivo and in vitro studies.

    Science.gov (United States)

    Lamghari, M; Almeida, M J; Berland, S; Huet, H; Laurent, A; Milet, C; Lopez, E

    1999-08-01

    There is frequently a loss of vertebral bone due to disease or aging. Nacre (mother of pearl from the oyster Pinctada maxima) stimulates bone cell differentiation and bone formation in vitro and in vivo. Experimental bone defects were prepared in the vertebrae of sheep and used to test the suitability of nacre as an injectable osteogenic biomaterial for treating vertebral bone loss. Twenty-one cavities were prepared in the first four upper lumbar vertebrae of 11 sheep and filled with nacre powder. The lumbar vertebrae were removed after 1 to 12 weeks, embedded undecalcified in methacrylate, and processed for histological studies. The nacre slowly dissolved and the experimental cavities contained a large active cell population. By 12 weeks, the experimental cavity was occupied by newly matured bone trabeculae in contact with or adjacent to the dissolving nacre. The functional new bone trabeculae were covered with osteoid lined with osteoblasts, indicating continuing bone formation. The in vitro study on rat bone marrow explants cultured with a water-soluble extract of the nacre organic matrix also resulted in the stimulation of osteogenic bone marrow cells with enhanced alkaline phosphatase activity. Thus, both the in vivo and in vitro findings suggest that nacre contains one or more signal molecules capable of activating osteogenic bone marrow cells. PMID:10458284

  11. Cellulitis-like symptoms manifested by bone metastasis of lung cancer in a patient living with human immunodeficiency virus.

    Science.gov (United States)

    Kashima, Jumpei; Okuma, Yusuke; Watanabe, Kageaki; Ajisawa, Atushi; Hishima, Tsunekazu

    2016-09-01

    Human immunodeficiency virus (HIV)-infected patients are at a high risk of cancer compared with the general population. As the use of antiretroviral therapy (ART) has increased, non-AIDS-defining cancers have also increased in the past decade. A 61-year-old man with HIV infection on ART developed a painful, erythematous and oedematous lower left leg and an associated fever. He was initially treated with antibiotics for cellulitis but there was no improvement, which warranted further investigation. A translucent lesion was found by X-ray imaging and bone scintigraphy showed bone metastasis from a primary adenocarcinoma of the lung, documented by chest computed tomography and an axillary lymph node biopsy. The patient died three months after the diagnosis despite undergoing chemotherapy. This case demonstrates that physicians should consider metastatic malignancies as a differential diagnoses for diverse skin changes in HIV-infected patients. PMID:26404113

  12. Iron deficiency anemia's effect on bone formation in zebrafish mutant.

    Science.gov (United States)

    Bo, Lin; Liu, Zhichun; Zhong, Yingbin; Huang, Jian; Chen, Bin; Wang, Han; Xu, Youjia

    2016-07-01

    Iron is one of the essential elements of life. Iron metabolism is related to bone metabolism. Previous studies have confirmed that iron overload is a risk factor for osteoporosis. But the correlation between iron deficiency and bone metabolism remains unclear. Ferroportin 1 is identified as a cellular iron exporter and required for normal iron cycling. In zebrafish, the mutant of ferroportin 1 gene (fpn1), weh(tp85c) exhibited the defective iron transport, leading to developing severe hypochromic anemia. We used weh(tp85c) as a model for investigating iron deficiency and bone metabolism. In this study, we examined the morphology of the developing cartilage and vertebrae of the Weh(tp85) compared to the wild type siblings by staining the larvae with alcian blue for cartilage and alizarin red for the bone. In addition, we evaluated the expression patterns of the marker genes of bone development and cell signaling in bone formation. Our results showed that weh(tp85c) mutant larvae exhibited the defects in bone formation, revealing by decreases in the number of calcified vertebrae along with decreased expression of osteoblast novel genes: alpl, runx2a and col1a1a and BMPs signaling genes in osteoblast differentiation: bmp2a and bmp2b. Our data suggest that iron deficiency anemia affects bone formation, potentially through the BMPs signaling pathway in zebrafish. PMID:27184405

  13. Rethinking the nature of fibrolamellar bone: an integrative biological revision of sauropod plexiform bone formation.

    Science.gov (United States)

    Stein, Koen; Prondvai, Edina

    2014-02-01

    We present novel findings on sauropod bone histology that cast doubt on general palaeohistological concepts concerning the true nature of woven bone in primary cortical bone and its role in the rapid growth and giant body sizes of sauropod dinosaurs. By preparing and investigating longitudinal thin sections of sauropod long bones, of which transverse thin sections were published previously, we found that the amount of woven bone in the primary complex has been largely overestimated. Using comparative cellular and light-extinction characteristics in the two section planes, we revealed that the majority of the bony lamina consists of longitudinally organized primary bone, whereas woven bone is usually represented only by a layer a few cells thin in the laminae. Previous arguments on sauropod biology, which have been based on the overestimated amount, misinterpreted formation process and misjudged role of woven bone in the plexiform bone formation of sauropod dinosaurs, are thereby rejected. To explain the observed pattern in fossil bones, we review the most recent advances in bone biology concerning bone formation processes at the cellular and tissue levels. Differentiation between static and dynamic osteogenesis (SO and DO) and the revealed characteristics of SO- versus DO-derived bone tissues shed light on several questions raised by our palaeohistological results and permit identification of these bone tissues in fossils with high confidence. By presenting the methods generally used for investigating fossil bones, we show that the major cause of overestimation of the amount of woven bone in previous palaeohistological studies is the almost exclusive usage of transverse sections. In these sections, cells and crystallites of the longitudinally organized primary bone are cut transversely, thus cells appear rounded and crystallites remain dark under crossed plane polarizers, thereby giving the false impression of woven bone. In order to avoid further confusion in

  14. Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations

    Energy Technology Data Exchange (ETDEWEB)

    Katharina, Pachmann [Department of Experimental Hematology and Oncology, Clinic for Internal Medicine II, Friedrich Schiller University, Jena D-07747 (Germany)

    2011-06-08

    In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may add to the risk of metastasis formation. The change in circulating epithelial tumor cells (CETC) was monitored in 66 breast cancer patients operated on with breast conserving surgery or mastectomy and during the further course of the disease, analyzing CETC from unseparated white blood cells stained with FITC-anti-EpCAM. An increase in cell numbers lasting until the start of chemotherapy was observed in about one third of patients. It was more preeminent in patients with low numbers of CETC before surgery and, surprisingly, in patients without involved lymph nodes. Patients with the previously reported behavior—Reincrease in cell numbers during adjuvant chemotherapy and subsequent further increase during maintenance therapy—were at increased risk of relapse. In addition to tumor cells already released during growth of the tumor, cell seeding during surgery may contribute to the early peak of relapses observed after removal of the primary tumor and chemotherapy may only marginally postpone relapse in patients with aggressively growing tumors.

  15. Tumor Cell Seeding During Surgery—Possible Contribution to Metastasis Formations

    International Nuclear Information System (INIS)

    In spite of optimal local control in breast cancer, distant metastases can develop as a systemic part of this disease. Surgery is suspected to contribute to metastasis formation activating dormant tumor cells. Here we add data that seeding of cells during surgery may add to the risk of metastasis formation. The change in circulating epithelial tumor cells (CETC) was monitored in 66 breast cancer patients operated on with breast conserving surgery or mastectomy and during the further course of the disease, analyzing CETC from unseparated white blood cells stained with FITC-anti-EpCAM. An increase in cell numbers lasting until the start of chemotherapy was observed in about one third of patients. It was more preeminent in patients with low numbers of CETC before surgery and, surprisingly, in patients without involved lymph nodes. Patients with the previously reported behavior—Reincrease in cell numbers during adjuvant chemotherapy and subsequent further increase during maintenance therapy—were at increased risk of relapse. In addition to tumor cells already released during growth of the tumor, cell seeding during surgery may contribute to the early peak of relapses observed after removal of the primary tumor and chemotherapy may only marginally postpone relapse in patients with aggressively growing tumors

  16. The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation

    NARCIS (Netherlands)

    E. Maronde (Erik); A.F. Schilling (Arndt); S. Seitz (Sebastian); T. Schinke (Thorsten); I. Schmutz (Isabelle); G.T.J. van der Horst (Gijsbertus); M. Amling (Michael); U. Albrecht (Urs)

    2010-01-01

    textabstractBackground: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To

  17. The Effect of Aloe, Gelfoam, Plaster on Bone Formation in applying to the bone defect

    International Nuclear Information System (INIS)

    This study was to evaluate the effects of Aloe, Gelfoam, and Plaster of Paris on bone healing. Four experimental defects were created for placement of the three materials in the right femur of dogs. One defect served as an empty control site. The evaluation was performed at 1-, 6-, and 12-weeks by light microscopy and NIH image program. Radiographic and Histologic examinations showed new bone formation in the presence of Aloe, Gelfoam, and Plaster of Paris and similar bone healing reactions. On the basis of these findings, it was concluded that Aloe, Gelfoam, and Plaster of Paris may be adequate agents for use in bone procurement.

  18. RGD peptide conjugated liposomal drug delivery system for enhance therapeutic efficacy in treating bone metastasis from prostate cancer.

    Science.gov (United States)

    Wang, Fangfang; Chen, Lei; Zhang, Rui; Chen, Zhongping; Zhu, Li

    2014-12-28

    Targeting αvβ3 integrin is particularly promising for the treatment of bone metastases by targeting integrin-rich tumor cells and by inhibiting integrin-involved bone metastases. In this work, a liposomal drug delivery system conjugated with cyclic arginine-glycine-aspartic acid-tyrosine-lysine peptide (cRGDyk) as αvβ3 integrin ligand was thus developed to improve therapeutic efficacy in a mice model of bone metastasis from prostate cancer. The resultant liposomes were characterized in terms of size, morphology, zeta potential, stability, drug encapsulation percentage and loading efficiency, and drug release. Compared with free cisplatin and cRGDyk-free liposomes, cRGDyk conjugated liposomes showed significantly higher cellular uptake and higher cytotoxicity of loaded cisplatin, as evidenced by in vitro cell experiments. In vivo results revealed that free cisplatin and free cRGDyk could relieve tumor-induced pain but had no contributions to tumor regression and overall survival improvement. cRGDyk-free liposomal drug system with prolonged blood circulation time could accumulated in the tumor sites in the bone through enhanced permeability and retention (EPR) effects and however, did not exhibit desirable therapeutic efficacy superior to free cisplatin and free cRGDyk. This strongly suggested that ERP effects were not effective in treating metastases. By taking advantages of targeted drug delivery and synergistic antitumor activity of cRGDyk and loaded cisplatin, cRGDyk conjugated liposomal drug system could inhibit osteoclastic and osteoblastic bone lesions, relieve pain, and improve overall survival. Inspired by their enhanced therapeutic efficacy and low organ toxicity, cRGDyk conjugated liposomes could serve as an effective drug system for targeted and synergistic therapy of bone metastases. PMID:25456829

  19. The Relation between Bone and Stone Formation

    OpenAIRE

    Krieger, Nancy S.; Bushinsky, David A.

    2012-01-01

    Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total body calcium. The source of this additional urine calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD) which is correlated with the increase in urine calcium excretion. ...

  20. CD44v6 in peripheral blood and bone marrow of patients with gastric cancer as micro-metastasis

    Institute of Scientific and Technical Information of China (English)

    Dao-Rong Wang; Guo-Yu Chen; Xun-Liang Liu; Yi Miao; Jian-Guo Xia; Lin-Hai Zhu; Dong Tang

    2006-01-01

    AIM: To detect the expression of CD44 correlated with the ability of micro-metastasis in peripheral blood and bone marrow of patients with gastric cancer and to deduce its clinical significance.METHODS: Preoperative peripheral blood and bone marrow specimens from 46 patients with gastric cancer and 6 controls were studied by semi-quantitative RTPCR amplification of CD44v6mRNA. Preoperative and postoperative peripheral blood specimens from 40patients with gastric cancer and 14 controls were studied by quantitative RT-PCR amplification of CD44v6mRNA in the corresponding period.RESULTS: Semi-quantitative RT-PCR amplification showed that CD44v6mRNA expression of peripheral blood and bone marrow was positive in 39 (84.8%)and 40 (86.9%) of 46 patients with gastric cancer,respectively. In peripheral blood, CD44v6mRNA expression was positive for diffuse type in 30 (93.8%)of 32 patients and for intestinal type in 9 (64.3%)of 14 patients. On the other hand, in bone marrow,CD44v6mRNA expression was positive for diffuse type in 31 (96.9%) of 32 patients and for intestinal type in 10 (71.4%) of 14 patients. There was a significant difference between the diffuse type and intestinal type.Quantitative RT-PCR amplification demonstrated that CD44v6mRNA was not expressed in the peripheral blood of controls and CD44v6mRNA expression was positive for preoperative peripheral blood in 40 patients with gastric cancer, the expression levels being from 4.9×102 to 3.2×105 copies/g RNA. The average expression level of CD44v6mRNA in peripheral blood was 3.9×1010copies/g RNA. The expression levels of CD44v6mRNA in peripheral blood in gastric cancer patients after curative operation increased from 5.5×100 to 7.6×10copies/g RNA (P=0.00496). After curative operation, the expression level decreased markedly.CONCLUSION: Semi-quantitative and quantitative RTPCR amplification for CD44v6mRNA is a sensitive and specific method for the detection of micro-metastasis in peripheral blood and bone

  1. Bone metastasis treatment using magnetic resonance-guided high intensity focused ultrasound

    NARCIS (Netherlands)

    Yeo, Sin Yuin; Elevelt, Aaldert; Donato, Katia; van Rietbergen, Bert; ter Hoeve, Natalie D.; van Diest, Paul J.; Grüll, Holger

    2015-01-01

    Objectives: Bone pain resulting from cancer metastases reduces a patient's quality of life. Magnetic Resonance-guided High Intensity Focused Ultrasound (MR-HIFU) is a promising alternative palliative thermal treatment technique for bone metastases that has been tested in a few clinical studies. Here

  2. Development of a bone-targeted pH-sensitive liposomal formulation containing doxorubicin: physicochemical characterization, cytotoxicity, and biodistribution evaluation in a mouse model of bone metastasis

    Science.gov (United States)

    Ferreira, Diêgo dos Santos; Faria, Samilla Dornelas; Lopes, Sávia Caldeira de Araújo; Teixeira, Cláudia Salviano; Malachias, Angelo; Magalhães-Paniago, Rogério; de Souza Filho, José Dias; Oliveira, Bruno Luis de Jesus Pinto; Guimarães, Alexander Ramos; Caravan, Peter; Ferreira, Lucas Antônio Miranda; Alves, Ricardo José; Oliveira, Mônica Cristina

    2016-01-01

    Background Despite recent advances in cancer therapy, the treatment of bone tumors remains a major challenge. A possible underlying hypothesis, limitation, and unmet need may be the inability of therapeutics to penetrate into dense bone mineral, which can lead to poor efficacy and high toxicity, due to drug uptake in healthy organs. The development of nanostructured formulations with high affinity for bone could be an interesting approach to overcome these challenges. Purpose To develop a liposomal formulation with high affinity for hydroxyapatite and the ability to release doxorubicin (DOX) in an acidic environment for future application as a tool for treatment of bone metastases. Materials and methods Liposomes were prepared by thin-film lipid hydration, followed by extrusion and the sulfate gradient-encapsulation method. Liposomes were characterized by average diameter, ζ-potential, encapsulation percentage, X-ray diffraction, and differential scanning calorimetry. Release studies in buffer (pH 7.4 or 5), plasma, and serum, as well as hydroxyapatite-affinity in vitro analysis were performed. Cytotoxicity was evaluated by MTT assay against the MDA-MB-231 cell line, and biodistribution was assessed in bone metastasis-bearing animals. Results Liposomes presented suitable diameter (~170 nm), DOX encapsulation (~2 mg/mL), controlled release, and good plasma and serum stability. The existence of interactions between DOX and the lipid bilayer was proved through differential scanning calorimetry and small-angle X-ray scattering. DOX release was faster when the pH was in the range of a tumor than at physiological pH. The bone-targeted formulation showed a strong affinity for hydroxyapatite. The encapsulation of DOX did not interfere in its intrinsic cytotoxicity against the MDA-MB-231 cell line. Biodistribution studies demonstrated high affinity of this formulation for tumors and reduction of uptake in the heart. Conclusion These results suggest that bone-targeted p

  3. Nonlinear pattern formation in bone growth and architecture

    Directory of Open Access Journals (Sweden)

    Phil eSalmon

    2015-01-01

    Full Text Available The 3D morphology of bone arises through adaptation to its required engineering performance. Genetically and adaptively bone travels along a complex spatio-temporal trajectory to acquire optimal architecture. On a cellular, micro-anatomical scale, what mechanisms coordinate the activity of osteoblasts and osteoclasts to produce complex and efficient bone architectures? One mechanism is examined here – chaotic nonlinear pattern formation (NPF – which underlies in a unifying way natural structures as disparate as trabecular bone, swarms of birds flying, island formation, fluid turbulence and others. At the heart of NPF is the fact that simple rules operating between interacting elements, and Turing-like interaction between global and local signals, lead to complex and structured patterns. The study of group intelligence exhibited by swarming birds or shoaling fish has led to an embodiment of NPF called particle swarm optimization (PSO. This theoretical model could be applicable to the behavior of osteoblasts osteoclasts and osteocytes, seeing them operating socially in response simultaneously to both global and local signals (endocrine, cytokine, mechanical resulting in their clustered activity at formation and resorption sites. This represents problem-solving by social intelligence, and could potentially add further realism to in-silico simulation of bone modeling.What insights has NPF provided to bone biology? One example concerns the genetic disorder Juvenile Pagets Disease (JPD or Idiopathic Hyperphosphatasia, where the anomalous parallel trabecular architecture characteristic of this pathology is consistent with an NPF paradigm by analogy with known experimental NPF systems. Here coupling or feedback between osteoblasts and osteoclasts is the critical element.This NPF paradigm implies a profound link between bone regulation and its architecture: in bone the architecture is the regulation. The former is the emergent consequence of the

  4. Irradiation influence on the bone marrow function of patients who received external radiotherapy to the bone metastasis lesion

    International Nuclear Information System (INIS)

    The effects of external radiotherapy (EBRT) on the bone marrow function were studied in 49 patients who received regional EBRT to the bone metastatic lesions. The platelet counts showed gradual but significant decrease to 88.0% at 12 weeks after completing the irradiation compared to the baselines. The lymphocyte counts decreased rapidly and significantly to 74.3% at 2 weeks after starting the irradiation but recovered to the baseline levels at 12 weeks after the irradiation. The decreases in the lymphocytes showed weak correlations with the widths of the irradiation areas and the lymphocytes counts before the irradiation, respectively. There found no significant decrease in the other blood cell counts which provoked serious adverse events due to the EBRT. These results suggest that the regional irradiation to the bone metastatic lesions would not cause serious nor long-term myelosuppression. (author)

  5. Bone metastasis in breast cancer: The story of RANK-Ligand

    International Nuclear Information System (INIS)

    The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique pathophysiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach

  6. The impact of bisphosphonate therapy on survival of lung cancer patients with bone metastasis

    Directory of Open Access Journals (Sweden)

    Theodoros Kontakiotis

    2009-01-01

    Full Text Available SUMMARY. INTRODUCTION: Bone metastases occur in 20% to 40% of patients with lung cancer. Recent studies (most in vitro demonstrate an anti-proliferative effect of third-generation biphosphonates (BPs on lung tumours which may, indirectly, have an impact on the survival. OBJECTIVES: This was a study of the effects of treatment with BPs on the course and survival of lung cancer patients with bone metastases. PATIENTS AND METHODS: For the study 108 male patients with lung cancer (stage IV were recruited consecutively. Of these, 55/108 patients with positive bone scan experienced bone pain and received Nitrogen BPs (NBPs, specifically zoledronic acid (ZOL, 4 mg i.v. every 21 days (Group A. The other 53 patients received no NBPs, of which 30/53 had a positive bone scan (Group B and 23/53 a negative bone scan (Group C. All patients were treated with combination chemotherapy consisting of Docitaxel 100 mg/m2 and Carboplatin AUC = 6. RESULTS: Group A had a statistically significantly longer mean survival and time to progression than Groups B and C (p0.05. CONCLUSION: The addition of NBPs to the treatment regime appears to increase overall survival in lung cancer patients with bone metastases. Further studies are needed to support the potential usefulness of NBPs as an independent therapeutic agent against lung cancer. Pneumon 2009; 22(1:25–37

  7. Complementary roles of tumour specific PET tracer 18F-FAMT to 18F-FDG PET/CT for the assessment of bone metastasis

    International Nuclear Information System (INIS)

    The usefulness of 18F-FDG PET/CT for bone metastasis evaluation has already been established. The amino acid PET tracer [18F]-3-fluoro-alpha-methyl tyrosine (18F-FAMT) has been reported to be highly specific for malignancy. We evaluated the additional value of 18F-FAMT PET/CT to complement 18F-FDG PET/CT in the evaluation of bone metastasis. This retrospective study included 21 patients with bone metastases of various cancers who had undergone both 18F-FDG and 18F-FAMT PET/CT within 1 month of each other. 18F-FDG-avid bone lesions suspicious for malignancy were carefully selected based on the cut-off value for malignancy, and the SUVmax of the 18F-FAMT in the corresponding lesions were evaluated. A total of 72 18F-FDG-positive bone lesions suspected to be metastases in the 21 patients were used as the reference standard. 18F-FAMT uptake was found in 87.5 % of the lesions. In the lesions of lung cancer origin, the uptake of the two tracers showed a good correlation (40 lesions, r = 0.68, P 18F-FAMT uptake. Bone metastatic lesions of squamous cell carcinoma showed higher 18F-FAMT uptake than those of adenocarcinoma. No significant difference in 18F-FAMT uptake was seen between osteoblastic and osteolytic bone metastatic lesions. The usefulness of 18F-FAMT PET/CT for bone metastasis detection regardless of the lesion phenotype was demonstrated. The fact that 18F-FAMT uptake was confirmed by 18F-FDG uptake suggests that 18F-FAMT PET/CT has the potential to complement 18F-FDG PET/CT for the detection of bone metastases. (orig.)

  8. The impact of bisphosphonate therapy on survival of lung cancer patients with bone metastasis

    OpenAIRE

    Theodoros Kontakiotis; Georgios Ballasoulis; Theodora Tsiouda; Hellie Lithoxopoulou; Vasiliki Zarogoulidou; Efimia Boutsikou; Konstantinos Zarogoulidis

    2009-01-01

    SUMMARY. INTRODUCTION: Bone metastases occur in 20% to 40% of patients with lung cancer. Recent studies (most in vitro) demonstrate an anti-proliferative effect of third-generation biphosphonates (BPs) on lung tumours which may, indirectly, have an impact on the survival. OBJECTIVES: This was a study of the effects of treatment with BPs on the course and survival of lung cancer patients with bone metastases. PATIENTS AND METHODS: For the study 108 male patients with lung cancer (stage IV) wer...

  9. From aneurysmal bone cyst to telangiectatic osteosarcoma with metastasis in inguinal lymph nodes: Case report

    Directory of Open Access Journals (Sweden)

    Janevska Vesna

    2015-01-01

    Full Text Available Introduction. Aneurysmal bone cyst is a benign bone lesion composed of blood filled cystic cavities lined by fibrous septa. Its malignant transformation of is a rare event. Case report. We report a case of a lesion in the second metatarsal bone in a 29-year-old male, presented as a slight swelling of the right foot. After the curettage had been done, the diagnosis of aneurysmal bone cyst was made but the recurrence occurred 4 years later. The biopsy of the recurrent tumor showed compact neoplastic tissue consistent with diagnosis of giant cell tumor with malignancy. The malignant component was recognized as a high grade sarcoma with osteoid production. A tumor mass with the whole II metatarsal bone was extirpated and a resected part of fibula was transplanted. A year later, another recurrence occurred, an amputation was performed and a teleangiectatic osteosarcoma with ingvinal lymph nodes metastases was diagnosed. No other tumor mass was confirmed, either clinically or by imaging techniques at the time of his third operation. He died 4 months later with multiple pulmonary metastases. Conclusion. We emphasize the importance of team work in order to achieve the accurate diagnosis, highlighting careful radiological examinations, good sampling and awareness of unusual cases in bone tumor pathology.

  10. Bone marrow cells participate in tumor vessel formation that supports the growth of Ewing’s sarcoma in the lung

    OpenAIRE

    Zhou, Zhichao; Stewart, Keri Schadler; Yu, Ling; Kleinerman, Eugenie S.

    2010-01-01

    An MHC-mismatch bone marrow (BM) transplant Ewing’s sarcoma mouse model was used to investigate whether BM cells participate in the vessel formation that support Ewing’s sarcoma lung metastasis. BM cells from H-2Kb/d donor mice were transplanted into sublethally irradiated H-2Kd recipient mice. Donor BM cells were identified using the H-2Kb marker. Engraftment was confirmed by identifying the H-2Kb IL-1β-type specific polymorphism. After engraftment highly lung metastatic TC71-PM4 cells were ...

  11. Hypoxia induced E-cadherin involving regulators of Hippo pathway due to HIF-1α stabilization/nuclear translocation in bone metastasis from breast carcinoma

    International Nuclear Information System (INIS)

    The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E-cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia-orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-γ (PPARγ), and the involvement of Hippo pathway members, as regulators of transcription factors. To give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1α and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARγ activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1α nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1α protein; under this experimental condition HIF-1α appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1α in nuclei of human-bone metastasis. Thus, we identified

  12. Hypoxia induced E-cadherin involving regulators of Hippo pathway due to HIF-1α stabilization/nuclear translocation in bone metastasis from breast carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Maroni, Paola [Istituto Ortopedico Galeazzi, IRCCS, Milano (Italy); Matteucci, Emanuela [Dipartiimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano (Italy); Drago, Lorenzo; Banfi, Giuseppe [Istituto Ortopedico Galeazzi, IRCCS, Milano (Italy); Dipartiimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano (Italy); Bendinelli, Paola [Dipartiimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano (Italy); Desiderio, Maria Alfonsina, E-mail: a.desiderio@unimi.it [Dipartiimento di Scienze Biomediche per la Salute, Molecular Pathology Laboratory, Università degli Studi di Milano, Milano (Italy)

    2015-01-15

    The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E-cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia-orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-γ (PPARγ), and the involvement of Hippo pathway members, as regulators of transcription factors. To give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1α and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARγ activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1α nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1α protein; under this experimental condition HIF-1α appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1α in nuclei of human-bone metastasis. Thus, we identified

  13. Evaluation of genotoxic and cytotoxic effects of 153 Sm-EDTMP in peripheral blood lymphocytes of bone metastasis patients

    International Nuclear Information System (INIS)

    In this study the cellular damage in peripheral lymphocytes after exposure to 153 Sm-EDTMP (Samarium-153 ethylene-diamine-tetramietylene-phosphonate) was determined using the technique of micronuclei analysis and differential coloration.153 Sm-EDTMP is a radiopharmaceutical used for pain relief in patients with bone metastases. The analysis of the frequency of micronuclei in patient blood samples obtained one hour after endovenous administration of radiopharmaceutical (41 MBq/kg) showed no statistical difference in relation to basal values in binucleated cells. However the analysis of damage distribution in mononucleated cells, showed that the patients without previous radiotherapy treatment presented a significant increase in the frequency of cells with one micronucleus and in those who had taken previous radiotherapy treatment, in cells with two or more micronuclei. The in vitro experiments conducted with the exposition of total blood to three radiation concentrations of 153 Sm-EDTMP (0.370, 0.555 and 1.110 MBq/mL) during one hour showed an increase in the frequency of micronuclei and necrotic and apoptotic cells with increasing radiation dose. Dose-response curves for healthy donors and patients with bone metastasis without previous radiotherapy treatment were constructed. The comparison of the curves showed that patients presented higher radiosensitivity, either micronuclei or dead cell (necrotic or apoptotic) percentages, than healthy donors. (author)

  14. Characterization of metastasis formation and virotherapy in the human C33A cervical cancer model.

    Directory of Open Access Journals (Sweden)

    Ulrike Donat

    Full Text Available More than 90% of cancer mortalities are due to cancer that has metastasized. Therefore, it is crucial to intensify research on metastasis formation and therapy. Here, we describe for the first time the metastasizing ability of the human cervical cancer cell line C33A in athymic nude mice after subcutaneous implantation of tumor cells. In this model, we demonstrated a steady progression of lumbar and renal lymph node metastases during tumor development. Besides predominantly occurring lymphatic metastases, we visualized the formation of hematogenous metastases utilizing red fluorescent protein (RFP expressing C33A-RFP cells. RFP positive cancer cells were found migrating in blood vessels and forming micrometastases in lungs of tumor-bearing mice. Next, we set out to analyze the influence of oncolytic virotherapy in the C33A-RFP model and demonstrated an efficient virus-mediated reduction of tumor size and metastatic burden. These results suggest the C33A-RFP cervical cancer model as a new platform to analyze cancer metastases as well as to test novel treatment options to combat metastases.

  15. Surface microcracks signal osteoblasts to regulate alignment and bone formation.

    Science.gov (United States)

    Shu, Yutian; Baumann, Melissa J; Case, Eldon D; Irwin, Regina K; Meyer, Sarah E; Pearson, Craig S; McCabe, Laura R

    2014-11-01

    Microcracks are present in bone and can result from fatigue damage due to repeated, cyclically applied stresses. From a mechanical point, microcracks can dissipate strain energy at the advancing tip of a crack to improve overall bone toughness. Physiologically, microcracks are thought to trigger bone remodeling. Here, we examine the effect of microcracks specifically on osteoblasts, which are bone-forming cells, by comparing cell responses on microcracked versus non-microcracked hydroxyapatite (HA) specimens. Osteoblast attachment was found to be greater on microcracked HA specimens (pmicrocracks on HA. Cells also displayed a preferential attachment that was 75 to 90 μm away from the microcrack indent. After 21 days of culture, osteoblast maturation was notably enhanced on the HA with microcracks, as indicated by increased alkaline phosphatase activity and gene expression. Furthermore, examination of bone deposition by confocal laser scanning microscopy indicated preferential mineralization at microcrack indentation sites. Dissolution studies indicate that the microcracks increase calcium release, which could contribute to osteoblast responses. Our findings suggest that microcracks signal osteoblast attachment and bone formation/healing. PMID:25280696

  16. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass.

    Science.gov (United States)

    Shah, M; Kola, B; Bataveljic, A; Arnett, T R; Viollet, B; Saxon, L; Korbonits, M; Chenu, C

    2010-08-01

    Adenosine 5'-monophosphate-activated protein kinase (AMPK), a regulator of energy homeostasis, has a central role in mediating the appetite-modulating and metabolic effects of many hormones and antidiabetic drugs metformin and glitazones. The objective of this study was to determine if AMPK can be activated in osteoblasts by known AMPK modulators and if AMPK activity is involved in osteoblast function in vitro and regulation of bone mass in vivo. ROS 17/2.8 rat osteoblast-like cells were cultured in the presence of AMPK activators (AICAR and metformin), AMPK inhibitor (compound C), the gastric peptide hormone ghrelin and the beta-adrenergic blocker propranolol. AMPK activity was measured in cell lysates by a functional kinase assay and AMPK protein phosphorylation was studied by Western Blotting using an antibody recognizing AMPK Thr-172 residue. We demonstrated that treatment of ROS 17/2.8 cells with AICAR and metformin stimulates Thr-172 phosphorylation of AMPK and dose-dependently increases its activity. In contrast, treatment of ROS 17/2.8 cells with compound C inhibited AMPK phosphorylation. Ghrelin and propranolol dose-dependently increased AMPK phosphorylation and activity. Cell proliferation and alkaline phosphatase activity were not affected by metformin treatment while AICAR significantly inhibited ROS 17/2.8 cell proliferation and alkaline phosphatase activity at high concentrations. To study the effect of AMPK activation on bone formation in vitro, primary osteoblasts obtained from rat calvaria were cultured for 14-17days in the presence of AICAR, metformin and compound C. Formation of 'trabecular-shaped' bone nodules was evaluated following alizarin red staining. We demonstrated that both AICAR and metformin dose-dependently increase trabecular bone nodule formation, while compound C inhibits bone formation. When primary osteoblasts were co-treated with AICAR and compound C, compound C suppressed the stimulatory effect of AICAR on bone nodule formation

  17. Recognition of fibrous dysplasia of bone mimicking skeletal metastasis on 18F-FDG PET/CT imaging

    International Nuclear Information System (INIS)

    Fibrous dysplasia of bone (FDB) reveals intense 18F-FDG uptake mimicking metastases on 18F-FDG PET/CT. We reviewed sites of FDB revealed by 18F-FDG PET/CT imaging to allow identification of this abnormality. Eleven patients (7 male, 4 female, aged 16-78 years) were evaluated after 55 MBq (0.15 mCi)/kg 18F-FDG utilizing a 16-slice multiple detector CT (MDCT) whole-body PET scanner, with LOR algorithm 3D reconstruction. One- and 2-h imaging was performed in 9 patients. Standard uptake value (SUV) for each lesion, on early and delayed imaging, was calculated. Lesions were confirmed in 6 patients by biopsy. The PET images correlated with MDCT to establish the imaging characteristics. Solitary lesions were found in 4 patients, two lesions in 1 patient, and in 6 patients there were multiple bone lesions. The SUVearly ranged from 1.23 to 9.64 with an average of 3.76 ± 2.40. The SUVdelayed ranged from 1.76 to 11.42 with an average of 4.51 ± 3.07. The SUVdelayed decreased or increased slightly (-31% to 5%) in 6 of our patients, and increased significantly (11% to 39%) in 3. There was a negative correlation between SUVs and age, as well as the number of affected bones. In our study, FDB had wide skeletal distribution with variability of 18F-FDG uptake and CT appearance. SUV in the delayed stage was seen to either decrease or increase on dual-time 18F-FDG PET scanning. It is very important to recognize the characteristics of this skeletal dysplasia to allow differentiation from skeletal metastasis. (orig.)

  18. Recognition of fibrous dysplasia of bone mimicking skeletal metastasis on 18F-FDG PET/CT imaging

    Energy Technology Data Exchange (ETDEWEB)

    Su, Ming Gang; Tian, Rong; Fan, Qiu Ping; Tian, Ye; Li, Fang Lan; Li, Lin; Kuang, An Ren [Sichuan University School of Medicine, National Key Discipline of Medical Imaging and Nuclear Medicine, Department of Nuclear Medicine, West China Hospital, Chengdu, Sichuan (China); Miller, John Howard [Loma Linda University School of Medicine, Division of Pediatric Radiology, Department of Radiology, Loma Linda, CA (United States)

    2011-03-15

    Fibrous dysplasia of bone (FDB) reveals intense 18F-FDG uptake mimicking metastases on 18F-FDG PET/CT. We reviewed sites of FDB revealed by 18F-FDG PET/CT imaging to allow identification of this abnormality. Eleven patients (7 male, 4 female, aged 16-78 years) were evaluated after 55 MBq (0.15 mCi)/kg 18F-FDG utilizing a 16-slice multiple detector CT (MDCT) whole-body PET scanner, with LOR algorithm 3D reconstruction. One- and 2-h imaging was performed in 9 patients. Standard uptake value (SUV) for each lesion, on early and delayed imaging, was calculated. Lesions were confirmed in 6 patients by biopsy. The PET images correlated with MDCT to establish the imaging characteristics. Solitary lesions were found in 4 patients, two lesions in 1 patient, and in 6 patients there were multiple bone lesions. The SUV{sub early} ranged from 1.23 to 9.64 with an average of 3.76 {+-} 2.40. The SUV{sub delayed} ranged from 1.76 to 11.42 with an average of 4.51 {+-} 3.07. The SUV{sub delayed} decreased or increased slightly (-31% to 5%) in 6 of our patients, and increased significantly (11% to 39%) in 3. There was a negative correlation between SUVs and age, as well as the number of affected bones. In our study, FDB had wide skeletal distribution with variability of 18F-FDG uptake and CT appearance. SUV in the delayed stage was seen to either decrease or increase on dual-time 18F-FDG PET scanning. It is very important to recognize the characteristics of this skeletal dysplasia to allow differentiation from skeletal metastasis. (orig.)

  19. Effects of Cadmium on BMP Induced Bone Formation

    Institute of Scientific and Technical Information of China (English)

    陈秋生; 徐顺清

    2003-01-01

    To demonstrate the direct effects of cadmium on activities of bone morphogenetic protein (BMP), a complex containing BMP and cadmium chloride (CdCl2) was implanted beneath the abdominal skin of young male Wistar rats. The activity of BMP was studied by observing the histological changes, and measuring the activity of alkaline phosphatase (ALP) and acid phosphatase (ACP) and calcium content of the implants at different time points. Our results showed that during bone formation induced by BMP, cadmium inhibited the activities of osteoblasts and osteoclasts, and slowed the deposition of calcium. It is concluded that cadmium can directly affect biological activities of BMP directly.

  20. Disassociation of bone resorption and formation by GLP-2

    DEFF Research Database (Denmark)

    Henriksen, Dennis B; Alexandersen, Peter; Hartmann, Bolette;

    2007-01-01

    We have previously shown that a single subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women results in a dose-dependent decrease in the nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of...... collagen type I (s-CTX and u-CTX) and u-DPD, markers of bone resorption. In contrast, bone formation, as assessed by serum osteocalcin and procollagen type I N-terminal propeptide (PINP), appeared to be unaffected by treatment with exogenous GLP-2. These effects were further investigated in a 14-day study....... The aim was to demonstrate that a parenteral formulation of GLP-2 is safe and well tolerated after repeated dosing in healthy postmenopausal women for 14 days. It was further investigated whether the effects on bone turnover markers were sustained throughout the study period. The study was a double...

  1. A novel 3-D mineralized tumor model to study breast cancer bone metastasis.

    Directory of Open Access Journals (Sweden)

    Siddharth P Pathi

    Full Text Available BACKGROUND: Metastatic bone disease is a frequent cause of morbidity in patients with advanced breast cancer, but the role of the bone mineral hydroxyapatite (HA in this process remains unclear. We have developed a novel mineralized 3-D tumor model and have employed this culture system to systematically investigate the pro-metastatic role of HA under physiologically relevant conditions in vitro. METHODOLOGY/PRINCIPAL FINDINGS: MDA-MB231 breast cancer cells were cultured within non-mineralized or mineralized polymeric scaffolds fabricated by a gas foaming-particulate leaching technique. Tumor cell adhesion, proliferation, and secretion of pro-osteoclastic interleukin-8 (IL-8 was increased in mineralized tumor models as compared to non-mineralized tumor models, and IL-8 secretion was more pronounced for bone-specific MDA-MB231 subpopulations relative to lung-specific breast cancer cells. These differences were pathologically significant as conditioned media collected from mineralized tumor models promoted osteoclastogenesis in an IL-8 dependent manner. Finally, drug testing and signaling studies with transforming growth factor beta (TGFbeta confirmed the clinical relevance of our culture system and revealed that breast cancer cell behavior is broadly affected by HA. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HA promotes features associated with the neoplastic and metastatic growth of breast carcinoma cells in bone and that IL-8 may play an important role in this process. The developed mineralized tumor models may help to reveal the underlying cellular and molecular mechanisms that may ultimately enable more efficacious therapy of patients with advanced breast cancer.

  2. Measurement of serum marker for bone metastasis (1-CTP) in hepatobiliary and pancreas malignancies

    OpenAIRE

    Nanashima, Atsushi; Takeshita, Hiroaki; Tobinaga, Syuuichi; Araki, Masato; Sumida, Yorihisa; Kunizaki, Masaki; Tanaka, Kenji; Abo, Takafumi; HIDAKA, SHIGEKAZU; Sawai, Terumitsu; Yasutake, Toru; Nagayasu, Takeshi

    2010-01-01

    Background/Aims: Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (1CTP) is a sensitive serum marker for metastatic bone carcinomas and may also be associated with invasiveness of various carcinomas. To clarify the significance of 1CTP in hepato-biliary pancreas malignancies, we examined the relationship between clinicopathological features and serum level of 1CTP. Methodology: The subjects were 75 patients who underwent surgical resections including 27 patients with l...

  3. CD13-positive bone marrow-derived myeloid cells promote angiogenesis, tumor growth, and metastasis

    OpenAIRE

    Dondossola, Eleonora; Rangel, Roberto; Guzman-Rojas, Liliana; Barbu, Elena M.; Hosoya, Hitomi; St. John, Lisa S.; Molldrem, Jeffrey J.; Corti, Angelo; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

    2013-01-01

    The progression of many solid tumors is associated with increased vascularization. We previously recognized involvement in tumor development and angiogenesis of tumor stromal cells expressing the CD13 protease aminopeptidase. The basic biological concept of participation of nontumor cells in the cancer stroma microenvironment is strengthened in the present study by our finding that a CD11b+CD13+ myeloid subset of bone marrow-derived cells affects pericyte biology and angiogenesis and thereby ...

  4. Squamous cell carcinoma of the renal pelvis presenting as sacral bone metastasis

    OpenAIRE

    Hameed, Zeeshan B M; Pillai, Sunil Bhaskara; Hegde, Padmaraj; Talengala, Bhat Shaila

    2014-01-01

    We present a rare presentation of squamous cell carcinoma of the kidney with chronic low backache. The diagnosis of this uncommon tumour of the renal pelvis was achieved after incidentally detecting a large staghorn calculus, which on further imaging with contrast-enhanced CT of the abdomen and pelvis was suggestive of the features of renal tumour with sacral bone lesion. The rarity of this metastatic tumour, with its unusual presentation, is discussed.

  5. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein

    OpenAIRE

    Yiwei Li; Mingxin Che; Sunita Bhagat; Kerrie-Lynn Ellis; Omer Kucuk; Doerge, Daniel R.; Judith Abrams; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  6. Regulation of Gene Expression and Inhibition of Experimental Prostate Cancer Bone Metastasis by Dietary Genistein1

    OpenAIRE

    Li, Yiwei; Che, Mingxin; Bhagat, Sunita; Ellis, Kerrie-Lynn; KUCUK, Omer; Doerge, Daniel R.; Abrams, Judith; Cher, Michael L.; Sarkar, Fazlul H

    2004-01-01

    Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary g...

  7. HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation

    Directory of Open Access Journals (Sweden)

    Anna Spina

    2015-01-01

    Full Text Available Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.

  8. A novel mouse model of human breast cancer stem-like cells with high CD44+CD24-/lower phenotype metastasis to human bone

    Institute of Scientific and Technical Information of China (English)

    LING Li-jun; WANG Feng; WANG Shui; LIU Xiao-an; SHEN En-chao; DING Qiang; LU Chao; XU Jian; CAO Qin-hong; ZHU Hai-qing

    2008-01-01

    Background A satisfactory animal model of breast cancer metastasizing to bone is unavailable. In this study, we used human breast cancer stem-like cells and human bone to build a novel "human-source" model of human breast cancer skeletal metastasis.Methods Human breast cancer stem-like cells, the CD44+/CD24-/lower subpopulation, was separated and cultured. Before injection with the stem-like cells, mice were implanted with human bone in the right or left dorsal flanks. Animals in Groups A, B, and C were injected with 1x105, 1x106 human breast cancer stem-like cells, and 1x106 parental MDA-MB-231 cells, respectively. A positive control group (D) without implantation of human bone was also injected with 1x106 MDA-MB-231 cells. Immunohistochemistry was performed for determination of CD34, CD105, smooth muscle antibody, CD44, CD24, cytokine, CXC chemokine receptor-4 (CXCR4), and osteopontin (OPN). mRNA levels of CD44, CD24, CXCR4, and OPN in bone metastasis tissues were analyzed by real-time quantitative polymerase chain reaction (PCR). Results Our results demonstrated that cells in implanted human bones of group B, which received 1x106 cancer stem-like cells, stained strongly positive for CD44, CXCR4, and OPN, whereas those of other groups showed no or minimum staining. Moreover, group B had the highest incidence of human bone metastasis (77.8%, P=0.0230) and no accompaniment of other tissue metastasis. The real-time PCR showed an increase of CD44, CXCR4, and OPN mRNA in metastatic bone tissues in group B compared with those of groups C and D, however the expression of CD24 mRNA in group B were the lowest. Conclusions In the novel "human source" model of breast cancer, breast cancer stem-like cells demonstrated a higher human bone-seeking ability. Its mechanism might be related to the higher expressions of CD44, CXCR4, and OPN, and the lower expression of CD24 in breast cancer stem-like cells.

  9. Tracheal cartilage regeneration and new bone formation by slow release of bone morphogenetic protein (BMP)-2.

    Science.gov (United States)

    Igai, Hitoshi; Chang, Sung Soo; Gotoh, Masashi; Yamamoto, Yasumichi; Yamamoto, Masaya; Tabata, Yasuhiko; Yokomise, Hiroyasu

    2008-01-01

    We investigated the efficiency of bone morphogenetic protein (BMP)-2 released slowly from gelatin sponge for tracheal cartilage regeneration. A 1-cm gap was made in the mid-ventral portion of each of 10 consecutive tracheal cartilages. In the control group (n = 4), the resulting gap was left untreated. In the gelatin group (n = 4), plain gelatin was implanted in the gap. In the BMP-2 group (n = 4), gelatin containing 100 microg BMP-2 was implanted. We euthanatized all dogs in each group at 1, 3, 6, and 12 months after the implantation, respectively, and then examined the implant site macro- and microscopically. In the BMP-2 group, regenerated fibrous cartilage and newly formed bone were observed at 1 and 12 months. Regenerated cartilage was observed at the ends of the host cartilage stumps, with newly formed bone in the middle portion. The gaps were filled with regenerated cartilage and newly formed bone. At 3 and 6 months, regenerated cartilage, but not newly formed bone, was evident. The regenerated cartilage was covered with perichondrium and showed continuity with the host cartilage. We succeeded in inducing cartilage regeneration and new bone formation in canine trachea by slow release of 100 microg BMP-2 from gelatin. PMID:18204324

  10. Multi-protein delivery by nanodiamonds promotes bone formation.

    Science.gov (United States)

    Moore, L; Gatica, M; Kim, H; Osawa, E; Ho, D

    2013-11-01

    Bone morphogenetic proteins (BMPs) are well-studied regulators of cartilage and bone development that have been Food and Drug Administration (FDA)-approved for the promotion of bone formation in certain procedures. BMPs are seeing more use in oral and maxillofacial surgeries because of recent FDA approval of InFUSE(®) for sinus augmentation and localized alveolar ridge augmentation. However, the utility of BMPs in medical and dental applications is limited by the delivery method. Currently, BMPs are delivered to the surgical site by the implantation of bulky collagen sponges. Here we evaluate the potential of detonation nanodiamonds (NDs) as a delivery vehicle for BMP-2 and basic fibroblast growth factor (bFGF). Nanodiamonds are biocompatible, 4- to 5-nm carbon nanoparticles that have previously been used to deliver a wide variety of molecules, including proteins and peptides. We find that both BMP-2 and bFGF are readily loaded onto NDs by physisorption, forming a stable colloidal solution, and are triggered to release in slightly acidic conditions. Simultaneous delivery of BMP-2 and bFGF by ND induces differentiation and proliferation in osteoblast progenitor cells. Overall, we find that NDs provide an effective injectable alternative for the delivery of BMP-2 and bFGF to promote bone formation. PMID:24045646

  11. BMP-13 Emerges as a Potential Inhibitor of Bone Formation

    Directory of Open Access Journals (Sweden)

    Bojiang Shen, Divya Bhargav, Aiqun Wei, Lisa A Williams, Helen Tao, David D F Ma, Ashish D Diwan

    2009-01-01

    Full Text Available Bone morphogenetic protein-13 (BMP-13 plays an important role in skeletal development. In the light of a recent report that mutations in the BMP-13 gene are associated with spine vertebral fusion in Klippel-Feil syndrome, we hypothesized that BMP-13 signaling is crucial for regulating embryonic endochondral ossification. In this study, we found that BMP-13 inhibited the osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs in vitro. The endogenous BMP-13 gene expression in MSCs was examined under expansion conditions. The MSCs were then induced to differentiate into osteoblasts in osteo-inductive medium containing exogenous BMP-13. Gene expression was analysed by real-time PCR. Alkaline phosphatase (ALP expression and activity, proteoglycan (PG synthesis and matrix mineralization were assessed by cytological staining or ALP assay. Results showed that endogenous BMP-13 mRNA expression was higher than BMP-2 or -7 during MSC growth. BMP-13 supplementation strongly inhibited matrix mineralization and ALP activity of osteogenic differentiated MSCs, yet increased PG synthesis under the same conditions. In conclusion, BMP-13 inhibited osteogenic differentiation of MSCs, implying that functional mutations or deficiency of BMP-13 may allow excess bone formation. Our finding provides an insight into the molecular mechanisms and the therapeutic potential of BMP-13 in restricting pathological bone formation.

  12. The homing of bone marrow MSCs to non-osseous sites for ectopic bone formation induced by osteoinductive calcium phosphate.

    NARCIS (Netherlands)

    Song, G.; Habibovic, P.; Bao, C.; Hu, J.; Blitterswijk, van C.A.; Yuan, H.; Chen, W.; Xu, H.H.K.

    2013-01-01

    Osteoinductive biomaterials are promising for bone repair. There is no direct proof that bone marrow mesenchymal stem cells (BMSCs) home to non-osseous sites and participate in ectopic bone formation induced by osteoinductive bioceramics. The objective of this study was to use a sex-mismatched beagl

  13. Anti-S100A4 Antibody Suppresses Metastasis Formation by Blocking Stroma Cell Invasion

    OpenAIRE

    Jörg Klingelhöfer; Birgitte Grum-Schwensen; Beck, Mette K.; Rikke Stagaard Petersen Knudsen; Mariam Grigorian; Eugene Lukanidin; Noona Ambartsumian

    2012-01-01

    The small Ca-binding protein, S100A4, has a well-established metastasis-promoting activity. Moreover, its expression is tightly correlated with poor prognosis in patients with numerous types of cancer. Mechanistically, the extracellular S100A4 drives metastasis by affecting the tumor microenvironment, making it an attractive target for anti-cancer therapy. In this study, we produced a function-blocking anti-S100A4 monoclonal antibody with metastasis-suppressing activity. Antibody treatment si...

  14. Peptide-induced de novo bone formation after tooth extraction prevents alveolar bone loss in a murine tooth extraction model.

    Science.gov (United States)

    Arai, Yuki; Aoki, Kazuhiro; Shimizu, Yasuhiro; Tabata, Yasuhiko; Ono, Takashi; Murali, Ramachandran; Mise-Omata, Setsuko; Wakabayashi, Noriyuki

    2016-07-01

    Tooth extraction causes bone resorption of the alveolar bone volume. Although recombinant human bone morphogenetic protein 2 (rhBMP-2) markedly promotes de novo bone formation after tooth extraction, the application of high-dose rhBMP-2 may induce side effects, such as swelling, seroma, and an increased cancer risk. Therefore, reduction of the necessary dose of rhBMP-2 which can still obtain sufficient bone mass is necessary by developing a new osteogenic reagent. Recently, we showed that the systemic administration of OP3-4 peptide, which was originally designed as a bone resorption inhibitor, had osteogenic ability both in vitro and in vivo. This study evaluated the ability of the local application of OP3-4 peptide to promote bone formation in a murine tooth extraction model with a very low-dose of BMP. The mandibular incisor was extracted from 10-week-old C57BL6/J male mice and a gelatin hydrogel containing rhBMP-2 with or without OP3-4 peptide (BMP/OP3-4) was applied to the socket of the incisor. Bone formation inside the socket was examined radiologically and histologically at 21 days after the extraction. The BMP/OP3-4-group showed significant bone formation inside the mandibular extraction socket compared to the gelatin-hydrogel-carrier-control group or rhBMP-2-applied group. The BMP/OP3-4-applied mice showed a lower reduction of alveolar bone and fewer osteoclast numbers, suggesting that the newly formed bone inside the socket may prevent resorption of the cortical bone around the extraction socket. Our data revealed that OP3-4 peptide promotes BMP-mediated bone formation inside the extraction socket of mandibular bone, resulting in preservation from the loss of alveolar bone. PMID:27118173

  15. Pharmacologic inhibitors of IkappaB kinase suppress growth and migration of mammary carcinosarcoma cells in vitro and prevent osteolytic bone metastasis in vivo.

    Science.gov (United States)

    Idris, Aymen I; Libouban, Hélène; Nyangoga, Hervé; Landao-Bassonga, Euphemie; Chappard, Daniel; Ralston, Stuart H

    2009-08-01

    The NF-kappaB signaling pathway is known to play an important role in the regulation of osteoclastic bone resorption and cancer cell growth. Previous studies have shown that genetic inactivation of IkappaB kinase (IKK), a key component of NF-kappaB signaling, inhibits osteoclastogenesis, but the effects of pharmacologic IKK inhibitors on osteolytic bone metastasis are unknown. Here, we studied the effects of the IKK inhibitors celastrol, BMS-345541, parthenolide, and wedelolactone on the proliferation and migration of W256 cells in vitro and osteolytic bone destruction in vivo. All compounds tested inhibited the growth and induced apoptosis of W256 cells as evidenced by caspase-3 activation and nuclear morphology. Celastrol, BMS-345541, and parthenolide abolished IL1beta and tumor necrosis factor alpha-induced IkappaB phosphorylation and prevented nuclear translocation of NF-kappaB and DNA binding. Celastrol and parthenolide but not BMS-345541 prevented the activation of both IKKalpha and IKKbeta, and celastrol inhibited IKKalpha/beta activation by preventing the phosphorylation of TAK1, a key receptor-associated factor upstream of IKK. Celastrol and parthenolide markedly reduced the mRNA expression of matrix metalloproteinase 9 and urinary plasminogen activator, and inhibited W256 migration. Administration of celastrol or parthenolide at a dose of 1 mg/kg/day suppressed trabecular bone loss and reduced the number and size of osteolytic bone lesions following W256 injection in rats. Histomorphometric analysis showed that both compounds decreased osteoclast number and inhibited bone resorption. In conclusion, pharmacologic inhibitors of IKK are effective in preventing osteolytic bone metastasis in this model and might represent a promising class of agents to the prevention and treatment of metastatic bone disease associated with breast cancer. PMID:19671767

  16. Bone Tissue Engineering with Multilayered Scaffolds-Part II: Combining Vascularization with Bone Formation in Critical-Sized Bone Defect.

    Science.gov (United States)

    Sathy, Binulal Nelson; Watson, Brendan M; Kinard, Lucas A; Spicer, Patrick P; Dahlin, Rebecca L; Mikos, Antonios G; Nair, Shantikumar

    2015-10-01

    Our previous in vivo study showed that multilayered scaffolds made of an angiogenic layer embedded between an osteogenic layer and an osteoconductive layer, with layer thickness in the 100-400 μm range, resulted in through-the-thickness vascularization of the construct even in the absence of exogenous endothelial cells. The angiogenic layer was a collagen-fibronectin gel, and the osteogenic layer was made from nanofibrous polycaprolactone while the osteoconductive layer was made either from microporous hydroxyapatite or microfibrous polycaprolactone. In this follow-up study, we implanted these acellular and cellular multilayered constructs in critical-sized rat calvarial defects and evaluated their vascularization and bone formation potential. Vascularization and bone formation at the defect were evaluated and quantified using microcomputed tomography (microCT) followed by perfusion of the animals with the radio opaque contrast agent, MICROFIL. The extent of bony bridging and union within the critical-sized defect was evaluated using a previously established scoring system from the microCT data set. Similarly the new bone formation in the defect was quantified from the microCT data set as previously reported. Histological evaluation at 4 and 12 weeks validated the microCT findings. Our experimental results showed that acellular multilayered scaffolds with microscale-thick nanofibers and porous ceramic discs with angiogenic zone at their interface can regenerate functional vasculature and bone similar to that of cellular constructs in critical-sized calvarial defects. This result suggests that suitably bioengineered acellular multilayered constructs can be an improved and more translational approach in functional in vivo bone regeneration. PMID:26262560

  17. Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk Neuroblastoma

    International Nuclear Information System (INIS)

    Purpose/Objectives: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Methods and Materials: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with 131I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Results: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Conclusions: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they

  18. Likelihood of Bone Recurrence in Prior Sites of Metastasis in Patients With High-Risk Neuroblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Polishchuk, Alexei L. [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Li, Richard [Division of Radiation Oncology, Dana Farber/Boston Children' s Cancer and Blood Disorders Center, Brigham and Women' s Hospital, Harvard Medical School, Boston, Massachusetts (United States); Hill-Kayser, Christine [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (United States); Little, Anthony [Division of Oncology, Children' s Hospital of Philadelphia, Philadelphia, Pennsylvania (United States); Hawkins, Randall A. [Department of Radiology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Hamilton, Jeffrey; Lau, Michael [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Tran, Hung Chi [Division of Hematology/Oncology, Children' s Hospital of Los Angeles, Los Angeles, California (United States); Strahlendorf, Caron [Division of Hematology and Oncology, Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia (Canada); Lemons, Richard S. [Division of Pediatric Hematology/Oncology, University of Utah School of Medicine, Salt Lake City, Utah (United States); Weinberg, Vivian [Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); Matthay, Katherine K.; DuBois, Steven G. [Department of Pediatrics, University of California at San Francisco School of Medicine and UCSF Benioff Children' s Hospital, San Francisco, California (United States); and others

    2014-07-15

    Purpose/Objectives: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy. Methods and Materials: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with {sup 131}I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation. Results: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites. Conclusions: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore

  19. Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats

    Directory of Open Access Journals (Sweden)

    Belfrage Ola

    2012-12-01

    Full Text Available Abstract Background Bone grafts are frequently used in orthopaedic surgery. Graft remodelling is advantageous but can occur too quickly, and premature bone resorption might lead to decreased mechanical integrity of the graft. Bisphosphonates delay osteoclastic bone resorption but may also impair formation of new bone. We hypothesize that these effects are dose dependent. In the present study we evaluate different ways of applying bisphosphonates locally to the graft in a bone chamber model, and compare that with systemic treatment. Methods Cancellous bone grafts were placed in titanium chambers and implanted in the tibia of 50 male rats, randomly divided into five groups. The first group served as negative control and the grafts were rinsed in saline before implantation. In the second and third groups, the grafts were soaked in a zoledronic acid solution (0.5 mg/ml for 5 seconds and 10 minutes respectively before being rinsed in saline. In the fourth group, 8 μL of zoledronic acid solution (0.5 mg/ml was pipetted onto the freeze-dried grafts without rinsing. The fifth group served as positive control and the rats were given zoledronic acid (0.1 mg/kg systemically as a single injection two weeks after surgery. The grafts were harvested at 6 weeks and analysed with histomorphometry, evaluating the ingrowth distance of new bone into the graft as an equivalent to the anabolic osteoblast effect and the amount (bone volume/total volume; BV/TV of remaining bone in the remodelled graft as equivalent to the catabolic osteoclast effect. Results In all chambers, almost the entire graft had been revascularized but only partly remodelled at harvest. The ingrowth distance of new bone into the graft was lower in grafts soaked in zoledronic acid for 10 minutes compared to control (p = 0.007. In all groups receiving zoledronic acid, the BV/TV was higher compared to control. Conclusions This study found a strong inhibitory effect on bone resorption by

  20. VEGF stimulates intramembranous bone formation during craniofacial skeletal development.

    Science.gov (United States)

    Duan, Xuchen; Bradbury, Seth R; Olsen, Bjorn R; Berendsen, Agnes D

    2016-01-01

    Deficiency of vascular endothelial growth factor A (VEGF) has been associated with severe craniofacial anomalies in both humans and mice. Cranial neural crest cell (NCC)-derived VEGF regulates proliferation, vascularization and ossification of cartilage and membranous bone. However, the function of VEGF derived from specific subpopulations of NCCs in controlling unique aspects of craniofacial morphogenesis is not clear. In this study a conditional knockdown strategy was used to genetically delete Vegfa expression in Osterix (Osx) and collagen II (Col2)-expressing NCC descendants. No major defects in calvaria and mandibular morphogenesis were observed upon knockdown of VEGF in the Col2(+) cell population. In contrast, loss of VEGF in Osx(+) osteoblast progenitor cells led to reduced ossification of calvarial and mandibular bones without affecting the formation of cartilage templates in newborn mice. The early stages of ossification in the developing jaw revealed decreased initial mineralization levels and a reduced thickness of the collagen I (Col1)-positive bone template upon loss of VEGF in Osx(+) precursors. Increased numbers of proliferating cells were detected within the jaw mesenchyme of mutant embryos. Explant culture assays revealed that mandibular osteogenesis occurred independently of paracrine VEGF action and vascular development. Reduced VEGF expression in mandibles coincided with increased phospho-Smad1/5 (P-Smad1/5) levels and bone morphogenetic protein 2 (Bmp2) expression in the jaw mesenchyme. We conclude that VEGF derived from Osx(+) osteoblast progenitor cells is required for optimal ossification of developing mandibular bones and modulates mechanisms controlling BMP-dependent specification and expansion of the jaw mesenchyme. PMID:26899202

  1. Anti-S100A4 antibody suppresses metastasis formation by blocking stroma cell invasion

    DEFF Research Database (Denmark)

    Klingelhöfer, Jörg; Grum-Schwensen, Birgitte; Beck, Mette K;

    2012-01-01

    microenvironment, making it an attractive target for anti-cancer therapy. In this study, we produced a function-blocking anti-S100A4 monoclonal antibody with metastasis-suppressing activity. Antibody treatment significantly reduced metastatic burden in the lungs of experimental animals by blocking the recruitment......The small Ca-binding protein, S100A4, has a well-established metastasis-promoting activity. Moreover, its expression is tightly correlated with poor prognosis in patients with numerous types of cancer. Mechanistically, the extracellular S100A4 drives metastasis by affecting the tumor...... of T cells to the site of the primary tumor. In vitro studies demonstrated that this antibody efficiently reduced the invasion of T cells in a fibroblast monolayer. Moreover, it was capable of suppressing the invasive growth of human and mouse fibroblasts. We presume therefore that the antibody...

  2. Hemi body irradiation: An economical way of palliation of pain in bone metastasis in advanced cancer

    Directory of Open Access Journals (Sweden)

    Santanu Pal

    2014-01-01

    Full Text Available Background: The primary aim of this prospective non-randomized study was to evaluate the effect of hemi-body irradiation (HBI on pain and quality of life in cancer patients with extensive bone metastases. The secondary aim was to evaluate side-effects and cost-effectiveness of the treatment. Materials and Methods: Between March 2008 and December 2010, a total of 23 (male = 14, female = 9, median age = 60 years diagnosed cases of metastatic cancer patients (prostate = 11, breast = 6, and lung = 6 received HBI, which was delivered as lower (n = 7 (dose = 8 Gy, upper (n = 8 (dose = 6 Gy, or sequential HBI (n = 8 with a Telecobalt unit (Theratron 780C. Among them, one lung cancer patient died at 2 months and one prostate cancer patient defaulted after the second follow-up. Thus, 21 patients (male = 13, female = 8, median age = 65 years (prostatic cancer = 10, breast cancer = 6, and lung cancer = 5 were followed up for a minimum of 6 months. Evaluations were performed before and at 2, 4, 8, 16, and 24 weeks after treatment. Pain evaluation was done by Visual Analogue Scale (VAS, Verbal Rating Scale (VRS, Percentage of Pain Relief (PRR, and Global Pain Score (GPS. Toxicity was assessed by CTC v-3 toxicity scores in the medical record. Assessment of oral morphine consumption was done before and after radiation using paired t-test, and correlation analysis was also done with decrease of morphine consumption and reduction of pain score using statistical analysis. Results: Response (control of pain was partial (PR in 67% and complete (CR in 22% of patients. For most patients, the pain control lasted throughout the follow-up period (6 months. From 66.66% patients requiring 13 or more Morphine (10 mg tablets per day prior to HBI, none of the patients required to consume 13 or more Morphine (10 mg tablets per day following HBI, which was correlated with significant reduction in various pain scores (P < 0.05. One way ANOVA with Dunnett′s Multiple Comparison

  3. 全身骨显像诊断肺癌骨转移的临床价值%Clinical value of the whole body bone imaging in diagnosing bone metastasis from lung cancer

    Institute of Scientific and Technical Information of China (English)

    贾莉; 夏正武; 马世兴

    2011-01-01

    Objective: To explore clinical value of the whole body bone imaging in diagnosing bone metastasis from lung cancer, in order to guide staging and treatment of patients with lung cancer. Methods: 126 patients with pathological diagnosis of lung cancer were performed whole body bone imaging, CT and ALP, blood calcium inspection. Probability of bone metastasis from lung cancer of the different pathological type and different clinical stage were counted. The whole body bone imaging and clinical factors of suspicious bone metastasis (including bone pain, alkaline phosphatase, high calcium lev -els, arbitrary or a few) for diagnosis accuracy of bone metastases were statistical compared. Results: The incidence of bone metastasis from lung cancer was 27.8%, and the bone metastases occurrence probability of peripheral lung cancer was higher than central lung cancer (P<0.01), bone metastases occurrence probability of lung adenocarcinoma was higher than lung squamous cell carcinoma (P<0.01), bone metastases occurrence probability of period Ⅲ, IV patients was obviously higher than that of period I , II (P<0.01). The sensitivity (94.3%), specific degrees (84.6%), accuracy (87.3%) of the whole body bone imaging diagnosis of bone metastases from lung cancer were higher than the clinical factors of suspicious bone metas -tasis diagnosis of bone metastases. Conclusion: Whole body bone imaging should be a routine examination in patients with lung cancer. The clinical significance is important to determine stage and treatment of lung cancer.%目的:探讨全身骨显像在诊断肺癌骨转移的临床价值,以便更好地指导肺癌患者的分期及治疗.方法:126例病理确诊为肺癌的患者均行全身骨显像、CT及碱性磷酸酶、血钙检查.统计肺癌患者不同病理类型、不同临床分期发生骨转移的几率,将全身骨显像与可疑骨转移临床因素(包括骨痛、碱性磷酸酶升高、高钙血症中任意一项或几项)诊断骨转移

  4. Radiofrequency thermal ablation for pain control in patients with single painful bone metastasis from hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Carrafiello, Gianpaolo [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: gcarraf@tin.it; Lagana, Domenico [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: donlaga@gmail.com; Ianniello, Andrea [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: ianand@libero.it; Nicotera, Paolo [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: paolonicotera@virgilio.it; Fontana, Federico [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: fede.fontana@libero.it; Dizonno, Massimiliano [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: massimilianodizonno@libero.it; Cuffari, Salvatore [Service of Anaesthesiology and Palliative Care, University of Insubria, 21100 Varese (Italy)], E-mail: salvatore.cuffari@libero.it; Fugazzola, Carlo [Department of Radiology, Vascular and Interventional Radiology, University of Insubria, 21100 Varese (Italy)], E-mail: carlo.fugazzola@ospedale.varese.it

    2009-08-15

    Objective: The aim of this study was to assess the safety and the efficacy of radiofrequency thermal ablation (RFA) for pain relief and analgesics use reduction in two patients with painful bone metastases from hepatocellular carcinoma (HCC). Materials and methods: Two patients with lytic metastases from HCC located at the left superior ileo-pubic branch and at the middle arch of VII rib, performed RFA displacing a LeVeen Needle (3.5 and 4.0 cm diameter) under US (ultrasonography) and fluoroscopic guidance. Two methods were used to determine the response of both patients: the first method was to measure patient's worst pain with a Brief Pain Inventory (BPI) 1 day after the procedure, every week for 1 month, and thereafter at week 8 and 12 (total follow-up 3 months); Second method was to evaluate patient's analgesics use recorded at week 1, 4, 8 and 12. Analgesic medication use was translated into a morphine-equivalent dose. Results: The RFA were well tolerated by the patients who did not develop any complication. Both patients obtained substantial reduction of pain, which decreased from a mean score of 8 to approximately 2 in 4 weeks. In both patients we observed a reduction in the use of morphine dose-equivalent after a peak at week 1. CT (computed tomography) imaging, performed at 1 month after RFA, demonstrated that both procedures were technically successful and safe because consistent necrosis and no evidence for complications were observed. Conclusion: RFA provides a potential alternative method for palliation of painful osteolytic metastases from HCC; the procedure is safe, and the pain relief is substantial.

  5. Trauma-induced heterotopic bone formation and the role of the immune system: A review.

    Science.gov (United States)

    Kraft, Casey T; Agarwal, Shailesh; Ranganathan, Kavitha; Wong, Victor W; Loder, Shawn; Li, John; Delano, Matthew J; Levi, Benjamin

    2016-01-01

    Extremity trauma, spinal cord injuries, head injuries, and burn injuries place patients at high risk of pathologic extraskeletal bone formation. This heterotopic bone causes severe pain, deformities, and joint contractures. The immune system has been increasingly implicated in this debilitating condition. This review summarizes the various roles immune cells and inflammation play in the formation of ectopic bone and highlights potential areas of future investigation and treatment. Cell types in both the innate and adaptive immune system such as neutrophils, macrophages, mast cells, B cells, and T cells have all been implicated as having a role in ectopic bone formation through various mechanisms. Many of these cell types are promising areas of therapeutic investigation for potential treatment. The immune system has also been known to also influence osteoclastogenesis, which is heavily involved in ectopic bone formation. Chronic inflammation is also known to have an inhibitory role in the formation of ectopic bone, whereas acute inflammation is necessary for ectopic bone formation. PMID:26491794

  6. Imaging symptomatic bone morphogenetic protein-2-induced heterotopic bone formation within the spinal canal: case report.

    Science.gov (United States)

    Chryssikos, Timothy; Crandall, Kenneth M; Sansur, Charles A

    2016-05-01

    Heterotopic bone formation within the spinal canal is a known complication of bone morphogenetic protein-2 (BMP-2) and presents a clinical and surgical challenge. Imaging modalities are routinely used for operative planning in this setting. Here, the authors present the case of a 59-year-old woman with cauda equina syndrome following intraoperative BMP-2 administration. Plain film myelographic studies showed a region of severe stenosis that was underappreciated on CT myelography due to a heterotopic bony lesion mimicking the dorsal aspect of a circumferentially patent thecal sac. When evaluating spinal stenosis under these circumstances, it is important to carefully consider plain myelographic images in addition to postmyelography CT images as the latter may underestimate the true degree of stenosis due to the potentially similar radiographic appearances of evolving BMP-2-induced heterotopic bone and intrathecal contrast. Alternatively, comparison of sequentially acquired noncontrast CT scans with CT myelographic images may also assist in distinguishing BMP-2-induced heterotopic bony lesions from the thecal sac. Further studies are needed to elucidate the roles of the available imaging techniques in this setting and to characterize the connection between the radiographic and histological appearances of BMP-2-induced heterotopic bone. PMID:26824586

  7. Tibial bone metastasis as an initial presentation of endometrial carcinoma diagnosed by fine-needle aspiration cytology: A case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Sarag Aboujafar Boukhar

    2015-01-01

    Full Text Available Endometrial cancer is the most common gynecologic malignancy in the United States. However, bony metastasis is infrequent and exceptionally rare as the initial presentation. We report a case of a 77-year-old female with a clinically silent endometrial carcinoma who presented with a left tibial metastasis as the first manifestation of her disease. Ours is only the third case diagnosed by fine-needle aspiration (FNA cytology, and the first to detail the cytomorphologic features of metastatic endometrial cancer to bone. These microscopic findings, including three-dimensional cohesive clusters with cellular overlapping and cuboidal to columnar cells exhibiting low nuclear: cytoplasmic ratios and partially vacuolated cytoplasm, differ significantly from those of endometrial carcinoma on a Papanicolaou test. The tumor bore similarity to the more commonly encountered metastatic colon cancer, but immunohistochemical staining enabled reliable distinction between these entities. A review of osseous metastases of endometrial cancer demonstrates a predilection for bones of the lower extremity and pelvis with a predominance of the endometrioid histologic subtype. In about a quarter of the cases, the bony metastasis was the first manifestation of the cancer. FNA was an effective diagnostic modality for this unusual presentation of a common malignancy. Awareness of this entity and its differential diagnosis is essential for accurate and timely diagnosis.

  8. The role of palliative and symptomatic radiation therapy of bone metastases; Il ruolo della radioterapia palliativa e sintomatica delle metastasi ossee

    Energy Technology Data Exchange (ETDEWEB)

    Tordiglione, M.; Luraghi, R.; Antognoni, P. [Varese Ospedale di Circolo, Varese (Italy). Div. di radiologia

    1999-05-01

    The aim of the study is to assess the optimal irradiation schedule for patients affected by bone metastases and to discuss the use of radiopharmaceuticals. The efficacy of external beam irradiation in the palliation of bone metastasis-related symptoms is confirmed by the literature review, even with short treatments and single-dose administrations. This is important for both patient expectations and the necessity for improved resource allocation with reference to the territorial distribution and waiting lists of radiotherapy centers. [Italian] Scopo di questo lavoro e' individuare, attraverso l'analisi della letteratura, le modalita' ottimali del trattamento radiante dei pazienti affetti da metastasi ossee. L'efficacia della radioterapia transcutanea nella palliazione dei sintomi correlati alle metastasi ossee viene confermata dai dati della letteratura con trattamenti brevi, anche in frazione singola. A parte deve essere menzionato il caso della radioisotopoterapia: i nuclidi che piu' si avvicinano alle caratteristiche ottimali hanno per ora limitata diffusione soprattutto a causa dei costi del trattamento, nonostante risultati del tutto sovrapponibili a quelli della radioterapia transcutanea.

  9. Balloon sacroplasty as a palliative pain treatment in patients with metastasis-induced bone destruction and pathological fractures

    Energy Technology Data Exchange (ETDEWEB)

    Andresen, R.; Luedtke, C.W.; Kamusella, P.; Wissgott, C. [Westkuestenklinikum Heide, Academic Teaching Hospital of the Universities of Kiel, Luebeck and Hamburg, Heide (Germany). Inst. of Diagnostic and Interventional Radiology/Neuroradiology; Radmer, S. [Center of Orthopedics, Berlin (Germany). Orthopedic Surgery and Traumatology; Schober, H.C. [Municipal Hospital Suedstadt Rostock, Academic Teaching Hospital of the University of Rostock (Germany). Dept. of Internal Medicine

    2014-09-15

    Purpose: In the case of metastatic involvement of the sacrum with destruction and consecutive pathological fracture, intense disabling pain is one of the defining factors. The feasibility, safety and pain development with cement augmentation were to be investigated. Materials and Methods: CT-guided balloon sacroplasty was conducted in 10 patients with metastasis-induced bone destruction of the sacrum. After establishment of the entry point, a K-wire was first introduced as far as the central tumor lesion via the short, or transiliac axis. A cannula was then positioned over the wire. Under CT guidance, a balloon catheter was introduced through the cannula and inflated and deflated several times. The PMMA cement was then injected into the preformed cavity. The procedure was completed by a spiral CT control using the thin-slice technique. Pain intensity was determined using a visual analog scale (VAS) before the procedure, on the 2nd postoperative day and 6 months after the intervention. Finally, the patients were asked to state how satisfied they were. Results: Balloon sacroplasty was technically feasible in all patients. The control CT scan showed central distribution of the cement in the tumor lesion. On average 6+/-1.78 (4-10) ml of PMMA cement were introduced per treated lesion. A significant (p < 0.001) reduction in pain according to the VAS occurred in all patients from 9.3+/-0.67 (8-10) pre-operatively to 2.7+/-1.28 (1-5) on the 2nd postoperative day and 2.9+/-0.81 (2-5) 6 months after the intervention. All of the patients were re-mobilized after the procedure and underwent the further therapeutic measures as planned. Conclusion: Balloon sacroplasty is a helpful therapeutic option in the overall palliative treatment of patients with tumor-induced destruction. It is a safe and practicable procedure that markedly reduces disabling pain. (orig.)

  10. Balloon sacroplasty as a palliative pain treatment in patients with metastasis-induced bone destruction and pathological fractures

    International Nuclear Information System (INIS)

    Purpose: In the case of metastatic involvement of the sacrum with destruction and consecutive pathological fracture, intense disabling pain is one of the defining factors. The feasibility, safety and pain development with cement augmentation were to be investigated. Materials and Methods: CT-guided balloon sacroplasty was conducted in 10 patients with metastasis-induced bone destruction of the sacrum. After establishment of the entry point, a K-wire was first introduced as far as the central tumor lesion via the short, or transiliac axis. A cannula was then positioned over the wire. Under CT guidance, a balloon catheter was introduced through the cannula and inflated and deflated several times. The PMMA cement was then injected into the preformed cavity. The procedure was completed by a spiral CT control using the thin-slice technique. Pain intensity was determined using a visual analog scale (VAS) before the procedure, on the 2nd postoperative day and 6 months after the intervention. Finally, the patients were asked to state how satisfied they were. Results: Balloon sacroplasty was technically feasible in all patients. The control CT scan showed central distribution of the cement in the tumor lesion. On average 6+/-1.78 (4-10) ml of PMMA cement were introduced per treated lesion. A significant (p < 0.001) reduction in pain according to the VAS occurred in all patients from 9.3+/-0.67 (8-10) pre-operatively to 2.7+/-1.28 (1-5) on the 2nd postoperative day and 2.9+/-0.81 (2-5) 6 months after the intervention. All of the patients were re-mobilized after the procedure and underwent the further therapeutic measures as planned. Conclusion: Balloon sacroplasty is a helpful therapeutic option in the overall palliative treatment of patients with tumor-induced destruction. It is a safe and practicable procedure that markedly reduces disabling pain. (orig.)

  11. Evaluation of sequential FDG-PET/CT for monitoring bone metastasis of breast cancer during therapy. Correlation between morphological and metabolic changes with tumor markers

    International Nuclear Information System (INIS)

    The purpose of this study was to clarify the significance of positron emission tomography (PET) and computed tomography (CT) findings for evaluating the bone metastasis of breast cancer during therapy. Forty-seven patients with bone metastases from breast cancer who underwent sequential 18F-flourodeoxyglucose (FDG)-PET/CT studies during therapy were enrolled. A total of 771 lesions were identified. The changes in the PET and CT findings were compared with the tumor marker levels in each patient by calculating the weighted kappa value. The correlation between the PET and CT findings was examined for each lesion by an adjusted Chi-square test. The change in the tumor marker levels was substantially correlated with the PET findings and moderately correlated with the CT findings (weighted kappa=0.780 and 0.585 for quadratic weighting, respectively). An increase in FDG uptake was correlated with lytic changes on the CT images (62/65, 95.4%, p<0.05). Sclerotic changes suggested improvement, but sclerosis and progression occurred at the same time in some lesions. Changes of FDG uptake are useful for evaluating individual bone metastases in cases of breast cancer during therapy. Lytic change on CT images suggests progression of bone metastasis. The lysis-progression/sclerosis-improvement pattern was observed in the majority of subjects, but a sclerosis-progression pattern was also observed. The hybrid pattern of increase of FDG uptake on PET/lytic change on CT is most accurate to show progression of bone metastases. Assessments of these processes during therapy are necessary for the precise evaluation of bone metastases. (author)

  12. Bone metastasis: review and critical analysis of random allocation trials of local field treatment

    International Nuclear Information System (INIS)

    Purpose: Compare and contrast reports of random allocation clinical trials of local field radiation therapy of metastases to bone to determine the techniques producing the best results (frequency, magnitude, and duration of benefit), and relate these to the goals of complete relief of pain and prevention of disability for the remaining life of the patient. Methods and Materials: Review all published reports of random allocation clinical trials, and perform a systematic analysis of the processes and outcomes of the several trial reports. Results: All trials were performed on selected populations of patients with symptomatic metastases and most studies included widely diverse groups with regard to: (a) site of primary tumor, (b) location, extent, size, and nature of metastases, (c) duration of survival after treatment. All trial reports lack sufficient detail for full and complete analysis. Much collected information is not now available for reanalysis and many important data sets were apparently never collected. Several of the variations in patient and tumor characteristics were found to be much more important than treatment dose in the outcome results. Treatment planning and delivery techniques were unsophisticated and probably resulted in a systematic delivery of less than the assigned dose to some metastases. In general the use and benefit of retreatment was greater in those patients who initially received lower doses but the basis and dose of retreatment was not documented. Follow-up of patients was varied with a large proportion of surviving patients lost to follow-up in several studies. The greatest difference in the reports is the method of calculation of results. The applicability of Kaplan-Meier actuarial analysis, censoring the lost and dead patients, as used in studies with loss to follow-up of a large number of patients is questionable. The censoring involved is 'informative' (the processes of loss relate to the outcome) and not acceptable since it

  13. [Bone metabolic markers and diagnosis of abnormal bone and calcium metabolism].

    Science.gov (United States)

    Fukunaga, M; Sone, T

    2001-07-01

    Bone metabolic markers increase in blood or urine, when bone formation or bone resorption accelerates. Reference values of bone metabolic markers are determined in male or female, and in pre- or post-menopause, respectively. Values of bone metabolic markers in most patients with primary osteoporosis were distributed within a reference value, mean+/-1.96 SD. When measured values exceeded a reference values, we should survey a possibility of abnormal calcium or bone metabolism such as primary hyperparathyroidism, renal osteodystrophy, hyperthyroidism and Paget's disease of bone or bone metastasis associated with malignant tumor. PMID:15775589

  14. Impaired bone formation in Pdia3 deficient mice.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available 1α,25-Dihydroxyvitamin D3 [1α,25(OH2D3] is crucial for normal skeletal development and bone homeostasis. Protein disulfide isomerase family A, member 3 (PDIA3 mediates 1α,25(OH2D3 initiated-rapid membrane signaling in several cell types. To understand its role in regulating skeletal development, we generated Pdia3-deficient mice and examined the physiologic consequence of Pdia3-disruption in embryos and Pdia3+/- heterozygotes at different ages. No mice homozygous for the Pdia3-deletion were found at birth nor were there embryos after E12.5, indicating that targeted disruption of the Pdia3 gene resulted in early embryonic lethality. Pdia3-deficiency also resulted in skeletal manifestations as revealed by µCT analysis of the tibias. In comparison to wild type mice, Pdia3 heterozygous mice displayed expanded growth plates associated with decreased tether formation. Histomorphometry also showed that the hypertrophic zone in Pdia3+/- mice was more cellular than seen in wild type growth plates. Metaphyseal trabecular bone in Pdia3+/- mice exhibited an age-dependent phenotype with lower BV/TV and trabecular numbers, which was most pronounced at 15 weeks of age. Bone marrow cells from Pdia3+/- mice exhibited impaired osteoblastic differentiation, based on reduced expression of osteoblast markers and mineral deposition compared to cells from wild type animals. Collectively, our findings provide in vivo evidence that PDIA3 is essential for normal skeletal development. The fact that the Pdia3+/- heterozygous mice share a similar growth plate and bone phenotype to nVdr knockout mice, suggests that PDIA3-mediated rapid membrane signaling might be an alternative mechanism responsible for 1α,25(OH2D3's actions in regulating skeletal development.

  15. New simulation model for bone formation markers in osteoporosis patients treated with once-weekly teriparatide

    Institute of Scientific and Technical Information of China (English)

    Sakae Tanaka; Taiji Adachi; Tatsuhiko Kuroda; Toshitaka Nakamura; Masataka Shiraki; Toshitsugu Sugimoto; Yasuhiro Takeuchi; Mitsuru Saito; John P Bilezikian

    2014-01-01

    Daily 20-mg and once-weekly 56.5-mg teriparatide (parathyroid hormone 1–34) treatment regimens increase bone mineral density (BMD) and prevent fractures, but changes in bone turnover markers differ between the two regimens. The aim of the present study was to explain changes in bone turnover markers using once-weekly teriparatide with a simulation model. Temporary increases in bone formation markers and subsequent decreases were observed during once-weekly teriparatide treatment for 72 weeks. These observations support the hypothesis that repeated weekly teriparatide administration stimulates bone remodeling, replacing old bone with new bone and leading to a reduction in the active remodeling surface. A simulation model was developed based on the iterative remodeling cycle that occurs on residual old bone. An increase in bone formation and a subsequent decrease were observed in the preliminary simulation. For each fitted time point, the predicted value was compared to the absolute values of the bone formation and resorption markers and lumbar BMD. The simulation model strongly matched actual changes in bone turnover markers and BMD. This simulation model indicates increased bone formation marker levels in the early stage and a subsequent decrease. It is therefore concluded that remodeling-based bone formation persisted during the entire treatment period with once-weekly teriparatide.

  16. ECT在乳腺癌骨转移的临床应用价值%Clinical Application value of ECT in bone Metastasis of Breast Cancer

    Institute of Scientific and Technical Information of China (English)

    李明浩; 崔时珍; 玄日

    2013-01-01

    Objective Clinical application value of ECT in breast cancer bone metastasis .Method Of the 76 cases confirmed by pathology to breast cancer patients give systemic ECT inspection and analysis and summary information .Results In breast cancer patients combined with bone metastases ,ECT high diagnostic value,signifi-cantly higher than the CT and x-ray.Conclusion ECT in the early detection of breast cancer bone metastasis has been of great value.%目的探讨ECT在乳腺癌骨转移的临床应用价值。方法对76例经病理证实为乳腺癌患者行全身 ECT检查,并分析总结资料。结果在乳腺癌骨转移患者中,ECT诊断价值较高,明显高于CT及X线。结论 ECT在早期发现乳腺癌骨转移方面有重要价值。

  17. Melanoma Cell Expression of CD200 Inhibits Tumor Formation and Lung Metastasis via Inhibition of Myeloid Cell Functions

    OpenAIRE

    Talebian, Fatemeh; Liu, Jin-Qing; Liu, Zhenzhen; Khattabi, Mazin; He, Yukai; Ganju, Ramesh; Bai, Xue-feng

    2012-01-01

    CD200 is a cell surface glycoprotein that functions through engaging CD200 receptor on cells of the myeloid lineage and inhibits their functions. Expression of CD200 has been implicated in a variety of human cancer cells including melanoma cells and has been thought to play a protumor role. To investigate the role of cancer cell expression of CD200 in tumor formation and metastasis, we generated CD200-positive and CD200-negative B16 melanoma cells. Subcutaneous injection of CD200-positive B16...

  18. Ectopic bone formation in bone marrow stem cell seeded calcium phosphate scaffolds as compared to autograft and (cell seeded) allograft

    NARCIS (Netherlands)

    Eniwumide, J.O.; Yuan, H.; Cartmell, S.H.; Meijer, G.J.; Bruijn, J.D. de

    2007-01-01

    Improvements to current therapeutic strategies are needed for the treatment of skeletal defects. Bone tissue engineering offers potential advantages to these strategies. In this study, ectopic bone formation in a range of scaffolds was assessed. Vital autograft and devitalised allograft served as co

  19. The Diagnostic Value of DWIBS in Various Types of Bone Metastasis%背景抑制全身扩散加权成像对不同类型骨转移瘤诊断价值的探讨

    Institute of Scientific and Technical Information of China (English)

    孙梦恬; 程敬亮; 张勇; 白洁; 王斐斐; 孟云

    2013-01-01

    目的 探讨不同类型骨转移瘤的背景抑制全身扩散加权成像(DWIBS)的影像特点.方法 研究对象包括47例经病理穿刺或临床证实骨转移瘤患者和29名正常志愿者.骨转移病灶按X线或CT表现分为3组:溶骨性转移组、成骨性转移组及混合性转移组.所有研究对象均行DWIBS.正常志愿者及不同类型骨转移瘤表观扩散系数(ADC)值的多组间比较采用单因素方差分析,不同类型骨转移瘤各组间两两比较采用LSD法,P<0.05为差异有统计学意义.不同类型骨转移瘤对比噪声比(CNR)值的多组间比较采用单因素方差分析,LSD法进行两两比较,P<0.05为差异有统计学意义.结果 29名正常志愿者骨骼系统在DWIBS上表现为明显的低信号.22例溶骨性转移者DWIBS上呈明显高信号;15例成骨性转移者DWIBS上呈稍高信号或低信号;10例混合性转移者DWIBS上呈高信号.正常志愿者骨组织的平均ADC值为(74.09±79.07)×10-6mm2/s,溶骨性、成骨性和混合性骨转移瘤的ADC值分别为(1103.47±81.05)×10-6mm2/s,(456.09±86.55)×10-6mm2/s和(816.72±91.20)×10-6mm2/s,溶骨性、成骨性和混合性转移组患者ADC值均明显高于正常志愿者,差异有统计学意义(F=689.156,P<0.05).各组间进行两两比较,溶骨性转移组ADC值最高,成骨性转移组最低,混合性转移组介于二者之间.溶骨性、成骨性和混合性转移组CNR值分别为(7.04±1.04)%、(1.00±0.34)%,(4.67±0.61)%,各组间两两比较差异均有统计学意义(F=108.493,P<0.05),溶骨性转移组CNR值最高,成骨性转移组最低,混合性转移组介于二者之间.结论 DWIBS是诊断骨转移瘤的有效检查方法,可对溶骨性、成骨性、混合性骨转移瘤的扩散特性进行量化.%Objective To study the imaging features of various types of bone metastasis on DWIBS. Methods 47 patients with malignant bone metastases and 29 healthy volunteers were enrolled in this study. All

  20. Bone Formation Process of β-TCP Ceramics with Tetracycline Tracing

    Institute of Scientific and Technical Information of China (English)

    DAI Hong-lian; LI Shi-pu; LU Xu-hui; WANG Xin-yu

    2004-01-01

    To study the new bone formation in the bone defect area after implantation, the tetracycline tracing method was used. The results show that new bone formed in 1 month, and the formation rate of new bone was very high (8.164μm/day),considerably faster than that of control groups (3.219μm/day).The new bone grew up quickly and βTCP particles were surrounded by double fluorescence bands which became more obvious. The new bone formation rate was maximal at 2 months, and then gradually reduced. The rate was steady at 4 months, and then reduced to resembling as the normal physiologic metabolism of bone, which indicated the implanted materials were completely replaced by bone. Calcium phosphatematerials had the ability of osteoconduction.

  1. Studies on the roles of stromal CXCL14 in tumor growth, progression and metastasis formation

    OpenAIRE

    Sjöberg, Elin

    2016-01-01

    Cancer consists of several diseases that are characterized by accumulation of genetic and epigenetic alterations that provide cells with certain capabilities to form tumors. Among these acquired capabilities are enhanced invasion that allow cancer cells to escape from the primary tumor, enter the circulation and eventually reach distant tissues where they form metastasis. Breast and prostate cancer are the most common cancers in Sweden with about 9000 new cases diagnosed each y...

  2. Humanized mouse model of ovarian cancer recapitulates patient solid tumor progression, ascites formation, and metastasis.

    Directory of Open Access Journals (Sweden)

    Richard B Bankert

    Full Text Available Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγ(null (NSG mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.

  3. Fusion of bone marrow-derived cells with cancer cells:metastasis as a secondary disease in cancer

    Institute of Scientific and Technical Information of China (English)

    John M. Pawelek

    2014-01-01

    This perspective article highlights the leukocyte-cancer cellhybrid theory as a mechanism for cancer metastasis. Beginning from the first proposal of the theory more than a century ago and continuing today with the first proof for this theory in a human cancer, the hybrid theory offers a unifying explanation for metastasis. In this scenario, leukocyte fusion with a cancer cellis a secondary disease superimposed upon the early tumor, giving birth to a new, malignant cellwith a leukocyte-cancer cellhybrid epigenome.

  4. Melanoma cell expression of CD200 inhibits tumor formation and lung metastasis via inhibition of myeloid cell functions.

    Directory of Open Access Journals (Sweden)

    Fatemeh Talebian

    Full Text Available CD200 is a cell surface glycoprotein that functions through engaging CD200 receptor on cells of the myeloid lineage and inhibits their functions. Expression of CD200 has been implicated in a variety of human cancer cells including melanoma cells and has been thought to play a protumor role. To investigate the role of cancer cell expression of CD200 in tumor formation and metastasis, we generated CD200-positive and CD200-negative B16 melanoma cells. Subcutaneous injection of CD200-positive B16 melanoma cells inhibited tumor formation and growth in C57BL/6 mice but not in Rag1⁻/⁻C57BL/6 mice. However, i.v. injection of CD200-positive B16 melanoma cells dramatically inhibited tumor foci formation in the lungs of both C57BL/6 and Rag1⁻/⁻C57BL6 mice. Flow cytometry analysis revealed higher expression of CD200R in Gr1⁺ myeloid cells in the lung than in peripheral myeloid cells. Depletion of Gr1⁺ cells or stimulation of CD200R with an agonistic antibody in vivo dramatically inhibited tumor foci formation in the lungs. In addition, treatment with tumor antigen specific CD4 or CD8 T cells or their combination yielded a survival advantage for CD200 positive tumor bearing mice over mice bearing CD200-negative tumors. Taken together, we have revealed a novel role for CD200-CD200R interaction in inhibiting tumor formation and metastasis. Targeting CD200R may represent a novel approach for cancer immunotherapy.

  5. Toe metastasis: A rare pattern of cervical cancer spread ☆

    OpenAIRE

    Ciccone, Marcia A.; Conturie, Charlotte L.; Lee, Cassie M.; Matsuo, Koji

    2014-01-01

    Highlights • Toe metastasis is a rare pattern of cervical cancer spread. • Enlarged erythematous toe is an important sign suggesting bone metastasis. • Toe metastasis represents a grave prognostic indicator of cervical cancer.

  6. Immunological and Nonimmunological Effects of Indoleamine 2,3-Dioxygenase on Breast Tumor Growth and Spontaneous Metastasis Formation

    Directory of Open Access Journals (Sweden)

    Vera Levina

    2012-01-01

    Full Text Available The role of the tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO1, in tumor escape and metastasis formation was analyzed using two pairs of Ido1+ and Ido1− murine breast cancer cell lines. Ido1 expression in 4T1 cells was knocked down by shRNA, and Ido1 expression in NT-5 cells was upregulated by stable transfection. Growth of Ido1− tumors and spontaneous metastasis formation were inhibited in immunocompetent mice. A higher level of cytotoxic T lymphocytes was generated by spleen cells from mice bearing Ido1− tumors than Ido1+ tumors. Tumor and metastatic growth was enhanced in immunodeficient mice, confirming an intensified immune response in the absence of Ido1 expression. However, Ido1+ tumors grow faster than Ido1− tumors in immunodeficient SCID/beige mice (lacking T, B, and NK cells suggesting that some Ido1-controlled nonimmunological mechanisms may be involved in tumor cell growth regulation. In vitro experiments demonstrated that downregulation of Ido1 in tumor cells was associated with decreased cell proliferation, increased apoptosis, and changed expression of cell cycle regulatory genes, whereas upregulation of Ido1 in the cells had the opposite effects. Taken together, our findings indicate that Ido1 expression could exert immunological and nonimmunological effects in murine breast tumor cells.

  7. Ectopic bone formation in bone marrow stem cell seeded calcium phosphate scaffolds as compared to autograft and (cell seeded allograft

    Directory of Open Access Journals (Sweden)

    J O Eniwumide

    2007-08-01

    Full Text Available Improvements to current therapeutic strategies are needed for the treatment of skeletal defects. Bone tissue engineering offers potential advantages to these strategies. In this study, ectopic bone formation in a range of scaffolds was assessed. Vital autograft and devitalised allograft served as controls and the experimental groups comprised autologous bone marrow derived stem cell seeded allograft, biphasic calcium phosphate (BCP and tricalcium phosphate (TCP, respectively. All implants were implanted in the back muscle of adult Dutch milk goats for 12 weeks. Micro-computed tomography (µCT analysis and histomorphometry was performed to evaluate and quantify ectopic bone formation. In good agreement, both µCT and histomorphometric analysis demonstrated a significant increase in bone formation by cell-seeded calcium phosphate scaffolds as compared to the autograft, allograft and cell-seeded allograft implants. An extensive resorption of the autograft, allograft and cell-seeded allograft implants was observed by histology and confirmed by histomorphometry. Cell-seeded TCP implants also showed distinct signs of degradation with histomorphometry and µCT, while the degradation of the cell-seeded BCP implants was negligible. These results indicate that cell-seeded calcium phosphate scaffolds are superior to autograft, allograft or cell-seeded allograft in terms of bone formation at ectopic implantation sites. In addition, the usefulness of µCT for the efficient and non-destructive analysis of mineralised bone and calcium phosphate scaffold was demonstrated.

  8. Prevention of tumor metastasis formation by anti-variant CD44

    OpenAIRE

    1993-01-01

    A splice variant of CD44 (CD44v) originally discovered on metastases of a rat pancreatic adenocarcinoma (BSp73ASML) has been shown by transfection to confer metastatic behavior to nonmetastatic tumor cells (Gunthert U., M. Hofmann, W. Rudy, S. Reber, M. Zoller, I. Haussmann, S. Matzku, A. Wenzel, H. Ponta, and P. Herrlich. 1991. Cell. 65:13). A monoclonal antibody (mAb), 1.1ASML, to the metastasis-specific domain of the CD44v molecule retards growth of lymph node and lung metastases of the me...

  9. Scintigraphic dynamics valuation of bone metastasis in the course of the treatment of 153Sm-oksabifor

    International Nuclear Information System (INIS)

    In the present study we examined the role of bone scan with 99mTc-pyrophosphate treatment planning 153Sm-oksabifor followed by analysis of post-treatment monitoring of cancer patients with bone metastases

  10. Solitary Plasmacytoma of the Sternum Mimicking Bone Metastasis in a Patient with a History of Breast Cancer Evaluated by F-18-FDG PET/CT

    International Nuclear Information System (INIS)

    A 65-year-old woman with a history of breast cancer (stage T2N0M0 treated with left breast conservative therapy 7 years previously followed by hormone therapy) underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG PET/CT) for restaging due to increased serum tumour markers levels (CA15-3, 37 U/ml and CEA, 8 ng/ml). The patient presented thoracic pain before performing F-18-FDG PET/CT. PET/CT demonstrated an area of increased F-18-FDG uptake corresponding to an osteolytic lesion occupying the upper sternum suspicious for bone metastasis. No other areas of abnormal F-18-FDG uptake were detected in the rest of the body. Based on this PET/CT finding, the patient performed biopsy of the sternal lesion. Histology demonstrated the presence of a sternal plasmacytoma and the patient was addressed to radiation therapy. The role of F-18-FDG PET/CT in patients with multiple myeloma is well known, whereas only some articles evaluated the usefulness of this method in patients with solitary plasmacytomas. In particular, F-18-FDG PET/CT may be useful in demonstrating the evolution of solitary plasmacytomas in multiple myeloma. In our case F-18-FDG PET/CT was useful in detecting a solitary plasmacytoma of the sternum mimicking bone metastasis in a patient with history of breast cancer, correctly addressing to further histological evaluation

  11. Solitary Plasmacytoma of the Sternum Mimicking Bone Metastasis in a Patient with a History of Breast Cancer Evaluated by F-18-FDG PET/CT

    Energy Technology Data Exchange (ETDEWEB)

    Treglia, Giorgio; Luca, Giovanella [Oncology Institute of Southern Switzerland, Bellinzona (Switzerland); Barbara, Muoio; Carmelo, Caldarella [Catholic Univ., Rome (Italy)

    2014-06-15

    A 65-year-old woman with a history of breast cancer (stage T2N0M0 treated with left breast conservative therapy 7 years previously followed by hormone therapy) underwent fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (F-18-FDG PET/CT) for restaging due to increased serum tumour markers levels (CA15-3, 37 U/ml and CEA, 8 ng/ml). The patient presented thoracic pain before performing F-18-FDG PET/CT. PET/CT demonstrated an area of increased F-18-FDG uptake corresponding to an osteolytic lesion occupying the upper sternum suspicious for bone metastasis. No other areas of abnormal F-18-FDG uptake were detected in the rest of the body. Based on this PET/CT finding, the patient performed biopsy of the sternal lesion. Histology demonstrated the presence of a sternal plasmacytoma and the patient was addressed to radiation therapy. The role of F-18-FDG PET/CT in patients with multiple myeloma is well known, whereas only some articles evaluated the usefulness of this method in patients with solitary plasmacytomas. In particular, F-18-FDG PET/CT may be useful in demonstrating the evolution of solitary plasmacytomas in multiple myeloma. In our case F-18-FDG PET/CT was useful in detecting a solitary plasmacytoma of the sternum mimicking bone metastasis in a patient with history of breast cancer, correctly addressing to further histological evaluation.

  12. Comparison of 99mTc-3PRGD2 integrin receptor imaging with 99mTc-MDP bone scan in diagnosis of bone metastasis in patients with lung cancer: a multicenter study.

    Directory of Open Access Journals (Sweden)

    Weibing Miao

    Full Text Available 99mTc-3PRGD2, a promising tracer targeting integrin receptor, may serve as a novel tumor-specific agent for single photon emission computed tomography (SPECT. A multi-center study was prospectively designed to evaluate the diagnostic accuracy of 99mTc-3PRGD2 imaging for bone metastasis in patients with lung cancer in comparison with the conventional 99mTc-MDP bone scan.The patients underwent whole-body scan and chest tomography successively at both 1 h and 4 h after intravenous injection of 11.1 MBq/Kg 99mTc-3PRGD2. 99mTc-MDP whole-body bone scan was routinely performed within 1 week for comparison. Three experienced nuclear medicine physicians blindly read the 99mTc-3PRGD2 and 99mTc-MDP images. The final diagnosis was established based on the comprehensive assessment of all available data.A total of 44 patients (29 male, 59±10 years old with suspected lung cancer were recruited from 4 centers. Eighty-nine bone lesions in 18 patients were diagnosed as metastases and 23 bone lesions in 9 patients were benign. In a lesion-based analysis, 99mTc-3PRGD2 imaging demonstrated a sensitivity, specificity, and accuracy of 92.1%, 91.3%, and 92.0%, respectively. The corresponding diagnostic values for 99mTc-MDP bone scan were 87.6%, 60.9%, and 82.1%, respectively in the same patients. 99mTc-MDP bone scan had better contrast in most lesions, whereas the 99mTc-3PRGD2 imaging seemed to be more effective to exclude pseudo-positive lesions and detect bone metastases without osteogenesis.99mTc-3PRGD2 is a novel tumor-specific agent based on SPECT technology with a promising value in diagnosis of bone metastasis in patients with lung cancer.ClinicalTrials.gov NCT01737112.

  13. Surface microcracks signal osteoblasts to regulate alignment and bone formation

    OpenAIRE

    Shu, Yutian; Melissa J. Baumann; Case, Eldon D.; Irwin, Regina K.; Meyer, Sarah E.; Pearson, Craig S.; McCabe, Laura R.

    2014-01-01

    Microcracks are present in bone and can result from fatigue damage due to repeated, cyclically applied stresses. From a mechanical point, microcracks can dissipate strain energy at the advancing tip of a crack to improve overall bone toughness. Physiologically, microcracks are thought to trigger bone remodeling. Here, we examine the effect of microcracks specifically on osteoblasts, which are bone-forming cells, by comparing cell responses on microcracked versus non-microcracked hydroxyapatit...

  14. Radiostrontium clearance and bone formation in response to simulated internal screw fixation

    International Nuclear Information System (INIS)

    Changes in radiostrontium clearance (SrC) and bone formation (tetracycline labeling) were observed in the femurs of skeletally mature dogs following the various operative steps involved in bone screw fixation. Drilling, but not periosteal stripping, produced a small but statistically significant increase in SrC and endosteal bone formation in the distal third of the bone. Strontium clearance values equivalent to those produced by drilling alone were recorded after screw fixation at low or high torque (5 versus 20 inch pounds), as well as by the insertion of loosely fitting stainless steel implants. Bone formation (equals the percentage tetracycline-labeled trabecular bone surfaces) was increased by 30% when SrC values exceeded 3.5 ml/100 g bone/min, and the relationship was linear when SrC values ranged between 1.0 and 7.0 ml/100 g bone/min. The changes in SrC and bone formation one-week after bone screw application are primarily those associated with a response to local trauma caused by drilling

  15. Bone formation in trabecular bone of thoracic and lumbar vertebral bodies as measured by tetracycline label evaluation

    International Nuclear Information System (INIS)

    Trabecular bone from thoracic and lumbar vertebral bodies of young adult beagles was evaluated for bone formation characteristics in eight beagles, using tetracycline pre-labeling. About 3 percent of the surface was continually-forming during a twelve day interval, while from 7 to 29 percent of the surface was forming bone intermittently over the twelve day span. Analysis of cross-sections provided a clearer picture of the results than did analysis of longitudinally-cut sections. There was no statistical difference in males and females or in oral vs. intravenous administration of tetracycline

  16. Correlation between absence of bone remodeling compartment canopies, reversal phase arrest, and deficient bone formation in post-menopausal osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Thomas L; Hauge, Ellen M; Rolighed, Lars; Bollerslev, Jens; Kjærsgaard-Andersen, Per; Delaisse, Jean-Marie

    2014-01-01

    bone surface from the marrow cavity. The present study on human iliac crest biopsy specimens reveals that BRC canopies appear frequently absent above both eroded and formative surfaces in post-menopausal osteoporosis patients, and that this absence was associated with bone loss in these patients. The...... surfaces was associated with a shift in the osteoblast morphological characteristics, from cuboidal to flattened. Collectively, this study shows that the BRCs are unique anatomical structures implicated in bone remodeling in a widespread disease, such as post-menopausal osteoporosis. Furthermore, it...

  17. Enhancement of bone formation in rabbits by recombinant human growth hormone

    International Nuclear Information System (INIS)

    We studied the effect of human recombinant growth hormone on diaphyseal bone in 40 adult rabbits. The diaphyseal periosteum of one femur in each animal was mechanically stimulated by a nylon cerclage band. The bands induced an increase in bone formation, bone mineral content, and maximum torque capacity of the diaphyseal bone at 1 and 2 months. Growth hormone enhanced the anabolic effect of the cerclage bands on bone metabolism, evidenced by a further increase in torsional strength of the femurs. (au) (32 refs.)

  18. 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...

  19. Bone metastasis in patients with non-small cell lung cancer: The diagnostic role of F-18 FDG PET/CT

    International Nuclear Information System (INIS)

    Purpose: To evaluate the performance of F-18 FDG PET/CT in the detection of bone metastasis in non-small cell lung cancer (NSCLC) patients. Materials and methods: Three hundred and sixty-two consecutive NSCLC patients who underwent F-18 FDG PET/CT scanning were retrospectively analyzed. Each image of PET/CT, combined CT, and PET was performed at 10 separate areas and interpreted blindly and separately. The sensitivity, specificity and accuracy of F-18 FDG PET/CT, combined CT and F-18 FDG PET were calculated and the results were statistically analyzed. Results: Bone metastasis was confirmed in 82 patients with 331 positive segments based on the image findings and clinical follow-up. On patient-based analysis, the sensitivity of F-18 FDG PET/CT (93.9%) was significantly higher than those of combined CT (74.4%) and F-18 FDG PET (84.1%), respectively (p < 0.05). The overall specificity and accuracy of combined CT, F-18 FDG PET, and F-18 FDG PET/CT were 90.7%, 93.2%, 98.9% and 87.0%, 91.2%, and 97.8%, respectively (compared with PET/CT, p < 0.05). On segment-based analysis, the sensitivity of the three modalities were 79.5%, 94.3%, and 98.8%, respectively (compared with PET/CT, p < 0.05). The overall specificity and accuracy of the three modalities were 87.9%, 89.2%, 98.6% and 84.5%, 91.2%, 98.7%, respectively (compared with PET/CT, p < 0.05). Conclusion: F-18 FDG PET/CT is superior to F-18 FDG PET or combined CT in detecting bone metastasis of NSCLC patients because of the complementation of CT and PET. It is worth noting that the added value of F-18 FDG PET/CT may beneficially impact the clinical management of NSCLC.

  20. The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

    Science.gov (United States)

    Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

    2013-10-01

    The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

  1. Short-term aluminum administration in the rat: reductions in bone formation without osteomalacia

    Energy Technology Data Exchange (ETDEWEB)

    Goodman, W.G.

    1984-05-01

    Aluminum may be a pathogenic factor in dialysis-associated osteomalacia. To study the early effects of Al on bone, cortical bone growth was measured in pair-fed rats given Al and control rats over two consecutive intervals of 28 (period I) and 16 (period II) days, respectively, using tetracycline labeling of bone. Al (2 mg elemental Al per rat) was administered intraperitoneally for 5 days each week, except for the first week of study, when an incremental dose of Al was given. Control rats received saline vehicle only. For the entire 44-day study, bone and matrix formation were reduced from control values in rats given Al. Although bone and matrix formation remained at control levels during period I in rats given Al, both measurements decreased from control values during period II. During Al exposure, bone and matrix apposition at the periosteum were reduced from control levels in period II, but not in period I. Neither osteoid width nor mineralization front width increased from control values in rats given Al. These findings indicate that Al reduces bone and matrix formation early in the course of Al exposure and prior to the development of histologic osteomalacia. Rather than acting as an inhibitor of mineralization, the early effect of Al on bone is the suppression of matrix synthesis. Our results suggest that the state of low bone formation seen in dialysis-associated osteomalacia may be the consequence of a direct toxic effect of Al on the cellular activity of osteoblasts. 29 references, 3 tables.

  2. Recombinant human bone morphogenetic protein-2 suspended in fibrin glue enhances bone formation during distraction osteogenesis in rabbits

    Science.gov (United States)

    Li, Yunfeng; Li, Rui; Hu, Jing; Song, Donghui; Jiang, Xiaowen

    2016-01-01

    Introduction Bone morphogenetic protein-2 (BMP-2) has high potential for bone formation, but its in vivo effects are unpredictable due to the short life time. This study was designed to evaluate the effects of recombinant human (rh) BMP-2 suspended in fibrin on bone formation during distraction osteogenesis (DO) in rabbits. Material and methods The in vitro release kinetics of rhBMP-2 suspended in fibrin was tested using an enzyme-linked immunosorbent assay. Unilateral tibial lengthening for 10 mm was achieved in 48 rabbits. At the completion of osteodistraction, vehicle, fibrin, rhBMP-2 or rhBMP-2 suspended in fibrin (rhBMP-2 + fibrin) was injected into the center of the lengthened gap, with 12 animals in each group. Eight weeks later, the distracted callus was examined by histology, micro-CT and biomechanical testing. Radiographs of the distracted tibiae were taken at both 4 and 8 weeks after drug treatment. Results It was found that fibrin prolonged the life span of rhBMP-2 in vitro with sustained release during 17 days. The rhBMP-2 + fibrin treated animals showed the best results in bone mineral density, bone volume fraction, cortical bone thickness by micro-CT evaluation and mechanical properties by the three-point bending test when compared to the other groups (p < 0.05). In histological images, rhBMP-2 + fibrin treatment showed increased callus formation and better gap bridging compared to the other groups. Conclusions The results of this study suggest that fibrin holds promise to be a good carrier of rhBMP-2, and rhBMP-2 suspended in fibrin showed a stronger promoting effect on bone formation during DO in rabbits. PMID:27279839

  3. In Vivo Bone Formation Within Engineered Hydroxyapatite Scaffolds in a Sheep Model.

    Science.gov (United States)

    Lovati, A B; Lopa, S; Recordati, C; Talò, G; Turrisi, C; Bottagisio, M; Losa, M; Scanziani, E; Moretti, M

    2016-08-01

    Large bone defects still represent a major burden in orthopedics, requiring bone-graft implantation to promote the bone repair. Along with autografts that currently represent the gold standard for complicated fracture repair, the bone tissue engineering offers a promising alternative strategy combining bone-graft substitutes with osteoprogenitor cells able to support the bone tissue ingrowth within the implant. Hence, the optimization of cell loading and distribution within osteoconductive scaffolds is mandatory to support a successful bone formation within the scaffold pores. With this purpose, we engineered constructs by seeding and culturing autologous, osteodifferentiated bone marrow mesenchymal stem cells within hydroxyapatite (HA)-based grafts by means of a perfusion bioreactor to enhance the in vivo implant-bone osseointegration in an ovine model. Specifically, we compared the engineered constructs in two different anatomical bone sites, tibia, and femur, compared with cell-free or static cell-loaded scaffolds. After 2 and 4 months, the bone formation and the scaffold osseointegration were assessed by micro-CT and histological analyses. The results demonstrated the capability of the acellular HA-based grafts to determine an implant-bone osseointegration similar to that of statically or dynamically cultured grafts. Our study demonstrated that the tibia is characterized by a lower bone repair capability compared to femur, in which the contribution of transplanted cells is not crucial to enhance the bone-implant osseointegration. Indeed, only in tibia, the dynamic cell-loaded implants performed slightly better than the cell-free or static cell-loaded grafts, indicating that this is a valid approach to sustain the bone deposition and osseointegration in disadvantaged anatomical sites. PMID:27075029

  4. Low-intensity pulsed ultrasound prompts tissue-engineered bone formation after implantation surgery

    Institute of Scientific and Technical Information of China (English)

    Wang Juyong; Wang Juqiang; Asou Yoshinori; Paul Fu; Shen Huiliang; Chen Jiani; Sotome Shinichi

    2014-01-01

    Background A practical problem impeding clinical translation is the limited bone formation seen in artificial bone grafts.Low-pressure/vacuum seeding and dynamic culturing in bioreactors have led to a greater penetration into the scaffolds,enhanced production of bone marrow cells,and improved tissue-engineered bone formation.The goal of this study was to promote more extensive bone formation in the composites of porous ceramics and bone marrow stromal cells (BMSCs).Methods BMSCs/β-tricalcium phosphate (β-TCP) composites were subcultured for 2 weeks and then subcutaneously implanted into syngeneic rats that were split into a low-intensity pulsed ultrasound (LIPUS) treatment group and a control group.These implants were harvested at 5,10,25,and 50 days after implantation.The samples were then biomechanically tested and analyzed for alkaline phosphate (ALP) activity and osteocalcin (OCN) content and were also observed by light microscopy.Results The levels of ALP activity and OCN content in the composites were significantly higher in the LIPUS group than in the control group.Histomorphometric analysis revealed a greater degree of soft tissue repair,increased blood flow,better angiogenesis,and more extensive bone formation in the LIPUS groups than in the controls.No significant difference in the compressive strength was found between the two groups.Conclusion LIPUS treatment appears to enhance bone formation and angiogenesis in the BMSCs/β3-TCP composites.

  5. MRI联合PSA在前列腺癌骨转移中的诊断价值研究%The diagnosis value of MRI combined PSA in prostate cancer bone metastasis

    Institute of Scientific and Technical Information of China (English)

    吴俊勇; 王炜; 李彤

    2012-01-01

    OBJECTIVE To investigate the application value of MRI combined PSA in prostate cancer bone metastasis. METHODS 74 prostate cancer patients were selected in our hospital, patients were tested for the serum PSA level and MRI after admission to detect the expression of prostate cancer bone metastasis. RESULTS All 74 patients in our group, the positive cases of prostate cancer bone metastasis were 43 cases (58.1%) , positive cases in prostate cancer bone metastasis with PSA≥ 20 μg/L group was 69.6%, significantly higher than PSA μg/L) < 20 μg/L groups 22.2%, the difference had a statistical significance, P< 0.05. CONCLUSION PSA has a good prediction effect on prostate cancer bone metastasis. When PSA ≥20 μg, the probability of prostate cancer bone metastasis increases significantly. PSA ≥20μg/L combined MRI can significantly improve the detection rate in prostate cancer bone metastasis.%目的 探讨MRI联合PSA检测在诊断前列腺癌骨转移中的应用价值.方法 选择某院收入的前列腺癌患者共74例,患者入院后检测血清PSA水平及MRI情况,从而检测前列腺癌骨转移患者表达情况.结果 所有74例患者中,前列腺癌骨转移阳性共43例(58.1%),PSA≥20 μg/L组患者前列腺癌骨转移阳性率为69.6%,显著高于PSA< 20 μg/L组的22.2%,两组对比差异有统计学意义(P<0.05).PSA≥20 μg/L组敏感度显著高于PSA(μg/L)<20 μg/L组,两组患者敏感性对比差异有统计学意义(P<0.05).结论 PSA具有较好的预测前列腺癌骨转移的作用,当PSA≥20 μg时,患者发生前列腺癌骨转移的概率显著增加.PSA≥20μg/L时再结合MRI检测,能显著提高前列腺瘤骨转移的诊断水平.

  6. μCT-Based, In Vivo Dynamic Bone Histomorphometry Allows 3D Evaluation of the Early Responses of Bone Resorption and Formation to PTH and Alendronate Combination Therapy

    Science.gov (United States)

    de Bakker, Chantal M. J.; Altman, Allison R.; Tseng, Wei-Ju; Tribble, Mary Beth; Li, Connie; Chandra, Abhishek; Qin, Ling; Liu, X. Sherry

    2015-01-01

    Current osteoporosis treatments improve bone mass by increasing net bone formation: anti-resorptive drugs such as bisphosphonates block osteoclast activity, while anabolic agents such as parathyroid hormone (PTH) increase bone remodeling, with a greater effect on formation. Although these drugs are widely used, their role in modulating formation and resorption is not fully understood, due in part to technical limitations in the ability to longitudinally assess bone remodeling. Importantly, it is not known whether or not PTH-induced bone formation is independent of resorption, resulting in controversy over the effectiveness of combination therapies that use both PTH and an anti-resorptive. In this study, we developed a μCT-based, in vivo dynamic bone histomorphometry technique for rat tibiae, and applied this method to longitudinally track changes in bone resorption and formation as a result of treatment with alendronate (ALN), PTH, or combination therapy of both PTH and ALN (PTH+ALN). Correlations between our μCT-based measures of bone formation and measures of bone formation based on calcein-labeled histology (r = 0.72 - 0.83) confirm the accuracy of this method. Bone remodeling parameters measured through μCT-based in vivo dynamic bone histomorphometry indicate an increased rate of bone formation in rats treated with PTH and PTH+ALN, together with a decrease in bone resorption measures in rats treated with ALN and PTH+ALN. These results were further supported by traditional histology-based measurements, suggesting that PTH was able to induce bone formation while bone resorption was suppressed. PMID:25554598

  7. The use of computed tomography to quantitate bone formation after distraction epiphysiolysis in the rabbit

    International Nuclear Information System (INIS)

    A study of limb lengthening by distraction epiphysiolysis in the rabbit tibia is presented. For this purpose a special external distraction device was developed, which allowed 10 mm lengthening of the leg. Bone formation in the distraction zone was quantified by means of computed tomography. Cross-sectional scan planes at 1.5 mm separation revealed bone formation proceeding for several weeks after the end of the distraction period. A period of bone remodeling followed, resulting in the formation of a solid cortical structure, similar to the diaphysis, in the distraction zone. (orig.)

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

    International Nuclear Information System (INIS)

    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

  9. 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.

  10. Increased bone formation in a rabbit long-bone defect model after single local and single systemic application of erythropoietin.

    Science.gov (United States)

    Omlor, Georg W; Kleinschmidt, Kerstin; Gantz, Simone; Speicher, Anja; Guehring, Thorsten; Richter, Wiltrud

    2016-08-01

    Background and purpose - Delayed bone healing with non-union is a common problem. Further options to increase bone healing together with surgery are needed. We therefore evaluated a 1-dose single application of erythropoietin (EPO), applied either locally to the defect or systemically during surgery, in a critical-size rabbit long-bone defect. Material and methods - 19 New Zealand White rabbits received a 15-mm defect in the radius diaphysis. An absorbable gelatin sponge was soaked with saline (control group and systemic treatment group) or EPO (local treatment group) and implanted into the gap. The systemic treatment group received EPO subcutaneously. In vivo micro-CT analysis was performed 4, 8, and 12 weeks postoperatively. Vascularization was evaluated histologically. Results - Semiquantitative histomorphometric and radiological evaluation showed increased bone formation (2.3- to 2.5-fold) in both treatment groups after 12 weeks compared to the controls. Quantitative determination of bone volume and tissue volume showed superior bone healing after EPO treatment at all follow-up time points, with the highest values after 12 weeks in locally treated animals (3.0- to 3.4-fold). More vascularization was found in both EPO treatment groups. Interpretation - Initial single dosing with EPO was sufficient to increase bone healing substantially after 12 weeks of follow-up. Local application inside the defect was most effective, and it can be administered directly during surgery. Apart from effects on ossification, systemic and local EPO treatment leads to increased callus vascularization. PMID:27348783

  11. The Effect of Skeletal Unloading on Bone Formation: Role of IGF-I

    Science.gov (United States)

    Bikle, D. D.; Kostenuik, P.; Holton, E. M.; Halloran, B. P.

    1999-01-01

    The best documented change in bone during space flight is the near cessation of bone formation. Space flight leads to a decrease in osteoblast number and activity, likely the result of altered differentiation of osteoblast precursors. The net result of these space flight induced changes is weaker bone. To understand the mechanism for these changes poses a challenge. Space flight studies must overcome enormous technical problems, and are necessarily limited in size and frequency. Therefore, ground based models have been developed to evaluate the effects of skeletal unloading. The hindlimb elevation (tail suspension) model simulates space flight better than other models because it reproduces the fluid shifts seen in space travel, is reversible, and is well tolerated by the animals with minimal evidence of stress as indicated by continued weight gain and normal levels and circadian rhythms of corticosterone. This is the model we have used for our experiments. Skeletal unloading by the hindlimb elevation method simulates a number of features of space flight in that bone formation, mineralization, and maturation are inhibited, osteoblast number is decreased, serum and skeletal osteocalcin levels fall, the ash content of bone decreases, and bone strength diminishes. We and others have shown that when osteoblasts or osteoprogenitor cells from the bones of the unloaded limbs are cultured in vitro they proliferate and differentiate more slowly, suggesting that skeletal unloading causes a persistent change in cell function which can be assessed in vitro. In contrast to the unweighted bones of the hindlimbs, no significant change in bone mass or bone formation is observed in the humeri, mandible, and cervical vertebrae during hindlimb elevation. The lack of effect of hindlimb elevation on bones like the humeri, mandible, and cervical vertebrae which are not unloaded by this procedure suggests that local factors rather than systemic effects dominate the response of bone to

  12. The Effect of Heparan Sulfate Application on Bone Formation during Distraction Osteogenesis

    OpenAIRE

    Gdalevitch, Marie; Kasaai, Bahar; Alam, Norine; DOHIN, Bruno; Lauzier, Dominique; Hamdy, Reggie C.

    2013-01-01

    Bone morphogenetic proteins (BMPs) are recognized for their ability to induce bone formation in vivo and in vitro. Their osteogenic and osteoinductive properties are tightly regulated by the secretion of specific BMP antagonists, which have been shown to physically bind and sometimes be blocked by the extracellular proteoglycan heparan sulphate side chains (from hereon referred to as HS). The purpose of this study was to investigate if local application of 5 µg of HS proteoglycan to a bone re...

  13. TGF-βand BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease

    Institute of Scientific and Technical Information of China (English)

    Mengrui Wu; Guiqian Chen; and Yi-Ping Li

    2016-01-01

    Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic skeletal development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during skeletal development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-βand BMP signaling is controlled by multiple factors, including the ubiquitin–proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-βand BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-βand BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines’ signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, skeletal development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.

  14. Heat and Radiofrequency Plasma Glow Discharge Pretreatment of a Titanium Alloy Promote Bone Formation and Osseointegration

    OpenAIRE

    MacDonald, Daniel E.; Rapuano, Bruce E.; Vyas, Parth; Lane, Joseph M.; Meyers, Kathleen; Wright, Timothy

    2013-01-01

    Orthopedic and dental implants manifest increased failure rates when inserted into low density bone. We determined whether chemical pretreatments of a titanium alloy implant material stimulated new bone formation to increase osseointegration in vivo in trabecular bone using a rat model. Titanium alloy rods were untreated or pretreated with heat (600°C) or radiofrequency plasma glow discharge (RFGD). The rods were then coated with the extracellular matrix protein fibronectin (1 nM) or left unc...

  15. The clinical value of SPECT/CT fusion imaging in the diagnosis of bone metastasis of breast cancer

    International Nuclear Information System (INIS)

    Objective: To evaluate the clinical value of SPECT/CT fusion imaging in the diagnosis and differential diagnosis the characteristic of the whole body bone scan radioactive hot lesions in patients with breast cancer. Methods: The abnormal radioactive hot lesions of whole body bone scan in 25 patients with breast cancer underwent SPECT/CT fusion imaging immediately. Another whole body bone scan and SPECT/CT fusion imaging were carried out 4 to 8 months later in all these patients. The whole body bone scan images, SPECT/CT images and fusion images were analyzed independently by two experienced nuclear medicine physicians and some of the equivocal CT images were analyzed by an experienced radiologist. Results: Among all the 37 abnormal radioactive hot bone lesions, 29 (29/37, 78.38%) lesions were confirmed metastatic lesions,including 2 vertebral lesions classified as benign lesions on the basis of the first examinations data; and 8 lesions were benign,including a rib lesion classified as benign lesion according to the first examinations data. The difference between whole body bone scan and SPECT/CT examination was statistically significant (χ2=6.975, P<0.05). The bone metastases are located mainly in spine and ribs. The sensitivity,specificity, positive and negative predictive values, and accuracy of whole-body bone scan and SPECT/CT fusion imaging were 82.76%, 75.00%, 92.31%, 54.55%, 81.08% and 93.10%, 87.50%, 96.43%, 77.78%, 91.89%, respectively. The area under the receiver operating characteristics curve was 0.860±0.056 for whole body bone scan and 0.974±0.020 for SPECT/CT. The area under the curve for SPECT/CT was significantly larger compared with the whole body bone scan (χ2=9.924, P<0.001). Conclusions: SPECT/CT fusion imaging is better than whole body bone scan alone to characterize the abnormal bone radioactive hot lesions and it can improve the accuracy of diagnosis. The patients should repeat the modality 4 to 8 months later if necessary. (authors)

  16. The Efect of Semelil (AngiparsW on Bone Resorption and Bone Formation Markers in Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Shirin Hasani-Ranjbar

    2012-01-01

    Full Text Available Background and purpose of the study: Diabetes mellitus has been recognized as a major risk factor for osteoporosis in which bone turnover is affected by different mechanisms. As the morbidity, mortality and financial cost related to osteoporosis are expected to rise in Iran in coming years, and considering the efficacy of AngiparsW for improvement of different ulcers which made it a new herbal drug in diabetic foot ulcer, there is a need toevaluate the effect of this new drug on different organs including bone resorption and bone formation markers.Methods: In this randomized, double- blind clinical trial, 61 diabetic patients were included. The subjects wererandomly divided into intervention and control groups. Subjects of intervention group received 100 mg of AngiparsW twice a day. Laboratory tests including bone resorption and bone formation markers were performed at baseline and after 3 months.Result: 31 patients in study group and 30 patients in control group finished the study. The mean age of the studypopulation and the mean disease duration was respectively 51.8 ± 6.2 and 7.5 ± 4.7 years with no significant differences between intervention and control patients. No statistically significant differences between patients and controls were observed in pyridinoline, osteocalcin, urine calcium, bone alkaline phosphatase and tumor necrosis factor (TNF-α. Only urine creatinine level significantly changed between two groups after 3 month of treatment (pvalue:0.029Conclusion: In conclusion, the findings of this study indicate that Semelil (AngiparsW had no beneficial or harmfuleffects on bone. It might be other effects of this new component on bone turnover process which need morestudies and more time to be discovered.

  17. The effect of semelil (angipars® on bone resorption and bone formation markers in type 2 diabetic patients

    Directory of Open Access Journals (Sweden)

    Hasani-Ranjbar Shirin

    2012-12-01

    Full Text Available Abstract Background and purpose of the study Diabetes mellitus has been recognized as a major risk factor for osteoporosis in which bone turnover is affected by different mechanisms. As the morbidity, mortality and financial cost related to osteoporosis are expected to rise in Iran in coming years, and considering the efficacy of Angipars® for improvement of different ulcers which made it a new herbal drug in diabetic foot ulcer, there is a need to evaluate the effect of this new drug on different organs including bone resorption and bone formation markers. Methods In this randomized, double- blind clinical trial, 61 diabetic patients were included. The subjects were randomly divided into intervention and control groups. Subjects of intervention group received 100 mg of Angipars® twice a day. Laboratory tests including bone resorption and bone formation markers were performed at baseline and after 3 months. Result 31 patients in study group and 30 patients in control group finished the study. The mean age of the study population and the mean disease duration was respectively 51.8 ± 6.2 and 7.5 ± 4.7 years with no significant differences between intervention and control patients. No statistically significant differences between patients and controls were observed in pyridinoline, osteocalcin, urine calcium, bone alkaline phosphatase and tumor necrosis factor (TNF-α. Only urine creatinine level significantly changed between two groups after 3 month of treatment (p-value: 0.029 Conclusion In conclusion, the findings of this study indicate that Semelil (Angipars® had no beneficial or harmful effects on bone. It might be other effects of this new component on bone turnover process which need more studies and more time to be discovered.

  18. Detection of Unknown sites of multiple enchondroma (Ollier′s Disease mimicking like metastasis using bone scintigraphy

    Directory of Open Access Journals (Sweden)

    Koramadai Karuppusamy Kamaleshwaran

    2015-01-01

    Full Text Available Ollier′s disease characterized by multiple skeletal enchondroma is a rare noninherited disease of unknown etiology. Majority of the skeletal enchondroma are present in the metaphyses and diaphysis of tubular limb bones. Ollier′s disease has a predilection for unilateral distribution. Malignant changes in Ollier′s disease may occur in adult patients. Radionuclide bone scanning is one method used to assess lesions depicted on radiographs or magnetic resonance images that are presumed to be enchondromas. Furthermore, a bone scan may give a clue to the multifocality of the disease. We report a case of right first phalangeal enchondroma in a 23-year-old male, who underwent bone scintigraphy detected multifocal asymmetric right side involvement of radius, humerus, femur, and tibia which confirm a diagnosis of Ollier′s disease.

  19. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis

    Directory of Open Access Journals (Sweden)

    Krishnangshu Bhanja Choudhury

    2011-01-01

    Conclusion: The use of bisphosphonates for 6 months or more results in a statistical significant improvement in bone pain, more so with zoledronic acid. Hypercalcemia, an SRE, was significantly less in the zoledronic acid arm.

  20. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development

    OpenAIRE

    Ducy, Patricia; Starbuck, Michael; Priemel, Matthias; Shen, Jianhe; Pinero, Gerald; Geoffroy, Valerie; Amling, Michael; Karsenty, Gerard

    1999-01-01

    The molecular mechanisms controlling bone extracellular matrix (ECM) deposition by differentiated osteoblasts in postnatal life, called hereafter bone formation, are unknown. This contrasts with the growing knowledge about the genetic control of osteoblast differentiation during embryonic development. Cbfa1, a transcriptional activator of osteoblast differentiation during embryonic development, is also expressed in differentiated osteoblasts postnatally. The perinatal lethality occurring in C...

  1. A supra-cellular model for coupling of bone resorption to formation during remodeling

    DEFF Research Database (Denmark)

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Pennypacker, Brenda L;

    2014-01-01

    canopy coverage above osteoclasts. This effect is in accordance with its toxic action on periosteoclastic cells. In contrast, odanacatib, an inhibitor preserving bone formation, increases the extent of the osteoclast-canopy interface. Interestingly, these distinct effects correlate with how fast bone...

  2. A review of bone metastasis and its treatments, with a special emphasis on local and systemic radiotherapy

    Directory of Open Access Journals (Sweden)

    Peiman Haddad

    2014-01-01

    Treatment of bone metastases consist of analgesics, radiotherapy, surgery and bisphosphonates. Control of bone metastases is a challenging process, necessitating a multi-disciplinary approach and teamwork between the treating physicians. Radiotherapy is the most useful modality for this purpose in oncology, given both as a local and systemic therapy. We hope that this review would be able to help in choosing the best treatment option for this common palliative situation in Iranian cancer patients.

  3. Internal targeted radiotherapy for bone metastasis: what about underlying physiopathology; Radiotherapie interne vectorisee (metabolique) des metastases osseuses: quid de la physiopathologie sous-jacente?

    Energy Technology Data Exchange (ETDEWEB)

    Vuillez, J.Ph. [Centre Hospitalier Universitaire, Hopital Michallon, Service de Biophysique et Medecine Nucleaire, 38 - Grenoble (France); Laval, G. [Centre Hospitalier Universitaire, Hopital Michallon, Unite de Recherche et de Soutien en Soins Palliatifs, 38 - Grenoble (France)

    2006-03-15

    Once tumours metastasize to bone, they are usually incurable and responsible for several devastating consequences: severe pain, pathologic fractures, life-threatening hypercalcemia, spinal cord compression and other nerve-compression syndromes. Understanding of physiopathological mechanisms responsible for these symptoms is critical for therapeutic approach, especially pain treatments. Three types of pain occur in tumour bone involvement: tonic or background pain, which are deep non-specific ache rising in intensity as the disease progresses; incident pain on movement (allodynia); and spontaneous pain which can be severe. Bone metastases could be osteolytic or osteoblastic. However, this classification actually represents two extremes of a continuum characterized by dys-regulation of the normal bone remodeling process. Biochemical mediators production is crucial as a part of this process. The bone microenvironment plays a critical role in the formation of osteoclasts through the production of macrophage colony-stimulating factor, receptor activator of nuclear factor kB ligand (RANKL)... Many of these mediators of osteolysis also have been shown to activate nociceptors: prostaglandins A and E, IL-1, IL-6, TNF. Thus there is a link between osteolytic destruction, inflammation and pain. It explains that severe pain could occur independently from fractures and in absence of any bone structure alteration and nervous compression. Also, pain is often disproportionate to tumour size or degree of bone involvement. Inflammatory and osteolytic processes depend on number, localization and organization of tumour cells inside bone and bone marrow tissues. All these parameters are crucial to take into account for a good understanding of treatments mechanisms of action, especially anti-inflammatory drugs (corticosteroid and others), bi-phosphonates, internal radiotherapy (strontium 89 or radiolabelled bi-phosphonates), external radiotherapy and chemotherapy or hormonotherapy

  4. Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption

    DEFF Research Database (Denmark)

    Karsdal, Morten A; Henriksen, Kim; Sørensen, Mette G;

    2005-01-01

    investigated the effect of inhibition of osteoclastic acidification in vivo by using the rat ovariectomy model withtwice daily oral dosing of NS3696 at 50 mg/kg for 6 weeks. We observed a 60% decrease in resorption (DPYR), increased tartrate-resistant acid phosphatase levels, and no effect on bone formation...

  5. Mechanical loading, damping, and load-driven bone formation in mouse tibiae.

    Science.gov (United States)

    Dodge, Todd; Wanis, Mina; Ayoub, Ramez; Zhao, Liming; Watts, Nelson B; Bhattacharya, Amit; Akkus, Ozan; Robling, Alexander; Yokota, Hiroki

    2012-10-01

    Mechanical loads play a pivotal role in the growth and maintenance of bone and joints. Although loading can activate anabolic genes and induce bone remodeling, damping is essential for preventing traumatic bone injury and fracture. In this study we investigated the damping capacity of bone, joint tissue, muscle, and skin using a mouse hindlimb model of enhanced loading in conjunction with finite element modeling to model bone curvature. Our hypothesis was that loads were primarily absorbed by the joints and muscle tissue, but that bone also contributed to damping through its compression and natural bending. To test this hypothesis, fresh mouse distal lower limb segments were cyclically loaded in axial compression in sequential bouts, with each subsequent bout having less surrounding tissue. A finite element model was generated to model effects of bone curvature in silico. Two damping-related parameters (phase shift angle and energy loss) were determined from the output of the loading experiments. Interestingly, the experimental results revealed that the knee joint contributed to the largest portion of the damping capacity of the limb, and bone itself accounted for approximately 38% of the total phase shift angle. Computational results showed that normal bone curvature enhanced the damping capacity of the bone by approximately 40%, and the damping effect grew at an accelerated pace as curvature was increased. Although structural curvature reduces critical loads for buckling in beam theory, evolution apparently favors maintaining curvature in the tibia. Histomorphometric analysis of the tibia revealed that in response to axial loading, bone formation was significantly enhanced in the regions that were predicted to receive a curvature-induced bending moment. These results suggest that in addition to bone's compressive damping capacity, surrounding tissues, as well as naturally-occurring bone curvature, also contribute to mechanical damping, which may ultimately affect

  6. Samarium-153-ethylene diamine tetramethylene phosphonate (EDTMP therapy in the management of refractory bone pain in a patient with carcinoma prostate and diffuse bone metastasis

    Directory of Open Access Journals (Sweden)

    R. Narayan

    2013-10-01

    Full Text Available Samarium-153-ethylene diamine tetramethylene phosphonate (samarium-153 EDTMP is a novel systemic radiopharmaceutical, used for treatment of bone pain due to metastatic disease. We report a patient with carcinoma prostate, diffuse metastatic bone disease with severe back pain that was refractory to analgesics and morphine. He was also found to be anaemic (haemoglobin 8.1 g/dL. Inspite of anaemia and diffuse metastatic bone disease being relative contraindications for the use samarium-153-EDTMP, because of its potential for causing radiation induced myelotoxicity, the patient was treated with this modality and showed a remarkable response in pain control within a few days. He developed mild radiation induced myelotoxicity, which was subsequently managed with blood transfusion and supportive care. The present case highlights the utility of samarium-153 EDTMP therapy in patients with intractable pain due to diffuse metastatic bone disease.

  7. Endobronchial mass formation after endobronchial ultrasound–transbronchial needle aspiration mimicking implantation metastasis

    OpenAIRE

    Kim, Soo Han; Lee, Yunkyoung; Park, Shinhee; Choi, Chang Min; Jo, Jungmin; Lee, Jae Cheol

    2015-01-01

    Key Clinical Message Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) has been widely used for diagnosing intrathoracic lymphadenopathy. Here, we present two cases of endobronchial polyp formation after an EBUS‐TBNA for suspicious malignant lymph nodes. An inflammatory polyp should be considered as a possible differential diagnosis for a newly developed mass after an EBUS‐TBNA.

  8. Normal tempo of bone formation in Turner syndrome despite signs of accelerated bone resorption

    DEFF Research Database (Denmark)

    Cleemann, Line Hartvig; Holm, Kirsten Bagge; Kobbernagel, Hanne;

    2011-01-01

    Aims: To evaluate area bone mineral density (aBMD) and volumetric BMD (vBMD) by dual-energy X-ray absorptiometry, and relations to bone markers and hormones in adolescent women with Turner syndrome (TS). Methods: Cross-sectional study in TS patients (n = 37, 16.7 ± 3.4 years) and control group (n...

  9. Normal Tempo of Bone Formation in Turner Syndrome despite Signs of Accelerated Bone Resorption

    DEFF Research Database (Denmark)

    Cleemann, Line; Holm, Kirsten; Kobbernagel, Hanne;

    2011-01-01

    Aims: To evaluate area bone mineral density (aBMD) and volumetric BMD (vBMD) by dual-energy X-ray absorptiometry, and relations to bone markers and hormones in adolescent women with Turner syndrome (TS). Methods: Cross-sectional study in TS patients (n = 37, 16.7 ± 3.4 years) and control group (n...

  10. Chondrocytes-Specific Expression of Osteoprotegerin Modulates Osteoclast Formation in Metaphyseal Bone

    OpenAIRE

    Baoli Wang; Hongting Jin; Bing Shu; Ranim R. Mira; Di Chen

    2015-01-01

    Bone marrow stromal cells/osteoblasts were originally thought to be the major player in regulating osteoclast differentiation through expressing RANKL/OPG cytokines. Recent studies have established that chondrocytes also express RANKL/OPG and support osteoclast formation. Till now, the in vivo function of chondrocyte-produced OPG in osteoclast formation and postnatal bone growth has not been directly investigated. In this study, chondrocyte-specific Opg transgenic mice were generated by using...

  11. [Recruitment of osteogenic cells to bone formation sites during development and fracture repair - German Version].

    Science.gov (United States)

    Böhm, A-M; Dirckx, N; Maes, C

    2016-04-01

    Recruitment of osteoblast lineage cells to their bone-forming locations is essential for skeletal development and fracture healing. In developing bones, osteoprogenitor cells invade the cartilage mold to establish the primary ossification center. Similarly, osteogenic cells infiltrate and populate the callus tissue that is formed following an injury. Proper bone development and successful fracture repair must, therefore, rely on controlled temporal and spatial navigation cues guiding the cells to the sites where new bone formation is needed. Some cellular mechanisms and molecular pathways involved have been elucidated. PMID:27003859

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

    International Nuclear Information System (INIS)

    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

  13. Ectopic bone formation of human bone morphogenetic protein-2 gene transfected goat bone marrow-derived mesenchymal stem cells in nude mice

    Institute of Scientific and Technical Information of China (English)

    汤亭亭; 徐小良; 戴尅戎; 郁朝锋; 岳冰; 楼觉人

    2005-01-01

    Objective: To evaluate the osteogenic potential of bone morphogenetic protein (BMP)-2 gene transfected goat bone marrow-derived mesenchymal stem cells (MSCs). Methods: Goat bone marrow- derived MSCs were transfected by Adv-human bone morphogenetic protein (hBMP)-2 gene(Group 1), Adv-beta gal transfected MSCs (Group 2)and uninfected MSCs(Group 3). Western blot analysis, alkaline phosphatase staining, Von Kossa staining and transmission electron microscopy were adopted to determine the phenotype of MSCs. Then the cells were injected into thigh muscles of the nude mice. Radiographical and histological evaluations were performed at different intervals. Results: Only Adv-hBMP-2 transfected MSCs produced hBMP-2. These cells were positive for alkaline phosphatase staining at the 12th day and were positive for Von Kossa staining at the 16th day after gene transfer. Electron microscopic observation showed that there were more rough endoplasmic reticulum, mitochondria and lysosomes in Adv-hBMP-2 transfected MSCs compared to MSCs of other two groups. At the 3rd and 6th weeks after cell injection, ectopic bones were observed in muscles of nude mice of Group 1. Only fibrous tissue or a little bone was found in other two groups. Conclusions: BMP-2 gene transfected MSCs can differentiate into osteoblasts in vitro and induce bone formation in vivo.

  14. Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling.

    Science.gov (United States)

    Joo, Adriane; Long, Roger; Cheng, Zhiqiang; Alexander, Courtney; Chang, Wenhan; Klein, Ophir D

    2016-07-01

    Skeletal development is regulated by the coordinated activity of signaling molecules that are both produced locally by cartilage and bone cells and also circulate systemically. During embryonic development and postnatal bone remodeling, receptor tyrosine kinase (RTK) superfamily members play critical roles in the proliferation, survival, and differentiation of chondrocytes, osteoblasts, osteoclasts, and other bone cells. Recently, several molecules that regulate RTK signaling have been identified, including the four members of the Sprouty (Spry) family (Spry1-4). We report that Spry2 plays an important role in regulation of endochondral bone formation. Mice in which the Spry2 gene has been deleted have defective chondrogenesis and endochondral bone formation, with a postnatal decrease in skeletal size and trabecular bone mass. In these constitutive Spry2 mutants, both chondrocytes and osteoblasts undergo increased cell proliferation and impaired terminal differentiation. Tissue-specific Spry2 deletion by either osteoblast- (Col1-Cre) or chondrocyte- (Col2-Cre) specific drivers led to decreased relative bone mass, demonstrating the critical role of Spry2 in both cell types. Molecular analyses of signaling pathways in Spry2(-/-) mice revealed an unexpected upregulation of BMP signaling and decrease in RTK signaling. These results identify Spry2 as a critical regulator of endochondral bone formation that modulates signaling in both osteoblast and chondrocyte lineages. PMID:27130872

  15. The clock genes Period 2 and Cryptochrome 2 differentially balance bone formation.

    Directory of Open Access Journals (Sweden)

    Erik Maronde

    Full Text Available BACKGROUND: Clock genes and their protein products regulate circadian rhythms in mammals but have also been implicated in various physiological processes, including bone formation. Osteoblasts build new mineralized bone whereas osteoclasts degrade it thereby balancing bone formation. To evaluate the contribution of clock components in this process, we investigated mice mutant in clock genes for a bone volume phenotype. METHODOLOGY/PRINCIPAL FINDINGS: We found that Per2(Brdm1 mutant mice as well as mice lacking Cry2(-/- displayed significantly increased bone volume at 12 weeks of age, when bone turnover is high. Per2(Brdm1 mutant mice showed alterations in parameters specific for osteoblasts whereas mice lacking Cry2(-/- displayed changes in osteoclast specific parameters. Interestingly, inactivation of both Per2 and Cry2 genes leads to normal bone volume as observed in wild type animals. Importantly, osteoclast parameters affected due to the lack of Cry2, remained at the level seen in the Cry2(-/- mutants despite the simultaneous inactivation of Per2. CONCLUSIONS/SIGNIFICANCE: This indicates that Cry2 and Per2 affect distinct pathways in the regulation of bone volume with Cry2 influencing mostly the osteoclastic cellular component of bone and Per2 acting on osteoblast parameters.

  16. Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats.

    Science.gov (United States)

    Jing, Da; Cai, Jing; Wu, Yan; Shen, Guanghao; Li, Feijiang; Xu, Qiaoling; Xie, Kangning; Tang, Chi; Liu, Juan; Guo, Wei; Wu, Xiaoming; Jiang, Maogang; Luo, Erping

    2014-10-01

    A large body of evidence indicates that pulsed electromagnetic fields (PEMF), as a safe and noninvasive method, could promote in vivo and in vitro osteogenesis. Thus far, the effects and underlying mechanisms of PEMF on disuse osteopenia and/or osteoporosis remain poorly understood. Herein, the efficiency of PEMF on osteoporotic bone microarchitecture, bone strength, and bone metabolism, together with its associated signaling pathway mechanism, was systematically investigated in hindlimb-unloaded (HU) rats. Thirty young mature (3-month-old), male Sprague-Dawley rats were equally assigned to control, HU, and HU + PEMF groups. The HU + PEMF group was subjected to daily 2-hour PEMF exposure at 15 Hz, 2.4 mT. After 4 weeks, micro-computed tomography (µCT) results showed that PEMF ameliorated the deterioration of trabecular and cortical bone microarchitecture. Three-point bending test showed that PEMF mitigated HU-induced reduction in femoral mechanical properties, including maximum load, stiffness, and elastic modulus. Moreover, PEMF increased serum bone formation markers, including osteocalcin (OC) and N-terminal propeptide of type 1 procollagen (P1NP); nevertheless, PEMF exerted minor inhibitory effects on bone resorption markers, including C-terminal crosslinked telopeptides of type I collagen (CTX-I) and tartrate-resistant acid phosphatase 5b (TRAcP5b). Bone histomorphometric analysis demonstrated that PEMF increased mineral apposition rate, bone formation rate, and osteoblast numbers in cancellous bone, but PEMF caused no obvious changes on osteoclast numbers. Real-time PCR showed that PEMF promoted tibial gene expressions of Wnt1, LRP5, β-catenin, OPG, and OC, but did not alter RANKL, RANK, or Sost mRNA levels. Moreover, the inhibitory effects of PEMF on disuse-induced osteopenia were further confirmed in 8-month-old mature adult HU rats. Together, these results demonstrate that PEMF alleviated disuse-induced bone loss by promoting skeletal anabolic activities

  17. Energy expenditure and bone formation share a common sensitivity to AP-1 transcription in the hypothalamus

    DEFF Research Database (Denmark)

    Rowe, Glenn C; Vialou, Vincent; Sato, Kazusa; Saito, Hiroaki; Yin, Min; Green, Thomas A; Lotinun, Sutada; Kveiborg, Marie; Horne, William C; Nestler, Eric J; Baron, Roland

    2012-01-01

    The regulation of bone and fat homeostasis and its relationship to energy expenditure has recently been the focus of increased attention due to its potential relevance to osteoporosis, obesity and diabetes. Although central effectors within the hypothalamus have been shown to contribute to the......-antagonistic properties, have increased energy expenditure and bone mass. Since these mice express ¿FosB in bone, fat and hypothalamus, we sought to determine 1) whether overexpression of ¿FosB within the hypothalamus was sufficient to regulate energy expenditure and whether it would also regulate bone mass, and 2......) whether these effects were due to antagonism to AP1. Our results show that stereotactic injection of an adeno-associated virus vector to restrict overexpression of ¿FosB to the ventral hypothalamus of wildtype mice induced a profound increase in both energy expenditure and bone formation and bone mass...

  18. Lineage tracking of mesenchymal and endothelial progenitors in BMP-induced bone formation.

    Science.gov (United States)

    Kolind, Mille; Bobyn, Justin D; Matthews, Brya G; Mikulec, Kathy; Aiken, Alastair; Little, David G; Kalajzic, Ivo; Schindeler, Aaron

    2015-12-01

    To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and αSMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid phosphatase (TRAP) activity (osteoclasts) and CD31 immunohistochemistry (vascular endothelial cells), and not alkaline phosphatase (AP) activity (osteoblasts). To further confirm the lack of a functional contribution of Tie2-lineage cells to BMP-induced bone, we developed conditional knockout mice where Tie2-lineage cells are rendered null for key bone transcription factor osterix (Tie2-cre:Osx(fx/fx) mice). Conditional knockout mice showed no difference in BMP-induced bone formation compared to littermate controls. Pulse labeling of mesenchymal cells with Tamoxifen in mice undergoing spine fusion revealed that αSMA-lineage cells contributed to the osteoblastic lineage (Col2.3-GFP), but not to endothelial cells or osteoclast populations. These data indicate that the αSMA+ and Tie2+ progenitor lineages make distinct cellular contributions to bone formation, angiogenesis, and resorption/remodeling. PMID:26141839

  19. Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

    OpenAIRE

    Sasaki, Soichiro; Baba, Tomohisa; Nishimura, Tatsunori; Hayakawa, Yoshihiro; Hashimoto, Shin-ichi; GOTO, Noriko(Graduate school of Education,Tokyo Gakugei University); Mukaida, Naofumi

    2016-01-01

    From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a ch...

  20. Effects of a cloned cell line with NK activity on bone marrow transplants, tumour development and metastasis in vivo

    Science.gov (United States)

    Warner, John F.; Dennert, Gunther

    1982-11-01

    Natural killer (NK) cells cloned in vitro have been transferred into NK-deficient hosts. These cells have been shown to have a role in the rejection of allogeneic bone marrow grafts, resistance to both radiation-induced thymic leukaemia and challenge with melanoma tumour cells. It appears that NK cells have an important role in immune surveillance.

  1. Primary melanoma tumor inhibits metastasis through alterations in systemic hemostasis.

    Science.gov (United States)

    Kirstein, Jennifer M; Hague, M Nicole; McGowan, Patricia M; Tuck, Alan B; Chambers, Ann F

    2016-08-01

    Progression from a primary tumor to distant metastases requires extensive interactions between tumor cells and their microenvironment. The primary tumor is not only the source of metastatic cells but also can also modulate host responses to these cells, leading to an enhancement or inhibition of metastasis. Tumor-mediated stimulation of bone marrow can result in pre-metastatic niche formation and increased metastasis. However, a primary tumor can also inhibit metastasis through concomitant tumor resistance-inhibition of metastatic growth by existing tumor mass. Here, we report that the presence of a B16F10 primary tumor significantly restricted numbers and sizes of experimental lung metastases through reduction of circulating platelets and reduced formation of metastatic tumor cell-associated thrombi. Tumor-bearing mice displayed splenomegaly, correlated with primary tumor size and platelet count. Reduction in platelet numbers in tumor-bearing animals was responsible for metastatic inhibition, as restoration of platelet numbers using isolated platelets re-established both tumor cell-associated thrombus formation and experimental metastasis. Consumption of platelets due to a B16F10 primary tumor is a form of concomitant tumor resistance and demonstrates the systemic impact of a growing tumor. Understanding the interplay between primary tumors and metastases is essential, as clarification of concomitant tumor resistance mechanisms may allow inhibition of metastatic growth following tumor resection. Key messages Mice with a primary B16F10 tumor had reduced metastasis vs. mice without a primary tumor. Tumor-bearing mice had splenomegaly and fewer platelets and tumor-associated thrombi. Restoring platelets restored tumor-associated thrombi and increased metastasis. This work shows the impact that a primary tumor can have on systemic metastasis. Understanding these interactions may lead to improved ways to inhibit metastasis. PMID:27048169

  2. Osteoclast formation from mononuclear phagocytes : role of bone forming cells

    OpenAIRE

    Burger, E.H.; Meer, J.W.M. van der; Nijweide, P. J.

    1984-01-01

    In a previous study, using co-cultures of embryonic bone rudiments stripped of periosteum, and mononuclear phagocytes of various sources, we found that multinucleated mineral-resorbing osteoclasts developed in vitro from radiosensitive mouse bone marrow mononuclear phagocytes (BMMP). (Burger, E. H., J. W. M. van der Meer, J. S. van de Gevel, C. W. Thesingh, and R. van Furth, 1982, J. Exp. Med. 156:1604-1614). In the present study, this co-culture technique was used to analyze the influence of...

  3. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    International Nuclear Information System (INIS)

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH1–34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis and

  4. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); O' Shea, Patrick J.; Fagura, Malbinder [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Pilling, James E. [Discovery Sciences, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Sanganee, Hitesh [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Wada, Hiroki [R and I IMed, AstraZeneca R and D, Molndal (Sweden); Courtney, Paul F. [DMPK, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Kavanagh, Stefan; Hall, Peter A. [Safety Assessment, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Escott, K. Jane [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom)

    2013-10-15

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis

  5. Measurement of 153Sm-EDTMP bone uptake by whole-body scintigraphy and its application to individualized treatment dosimetry of bone metastasis

    International Nuclear Information System (INIS)

    To calculate a safe and effective 153Sm-EDTMP therapy dose, a whole-body scintigraphy technique for prospective individual dosimetry was developed and the results were compared with 5 h urine collection method in 20 patients with bone metastases. Anterior and posterior whole-body images were obtained 10 min and 5 h after intravenous injection of 740 MBq 153Sm-EDTMP and the bone uptake value was determined. There is a close correlation between the bone uptake value obtained from the whole-body scintigraphy and 5 h urine collection method (r = 0.93). The radiation absorption dose to red marrow was limited to 1.4 Gy and the administered activity calculated from bone uptake value by whole-body scintigraphy was 1.40-2.27 GBq (mean 1.90 GBq). If the activity was calculated according to the standard body weight of 37 MBq·kg-1, the administered activity would be 1.75-2.41 GBq (mean 2.18), the radiation absorption dose to red marrow would be 1.37-2.27 Gy (mean 1.63 Gy), but at these doses significant myelotoxicity would be anticipated, thus emphasizing the need for individual prospective dosimetry

  6. In vivo cyclic loading as a potent stimulatory signal for bone formation inside tissue engineering scaffold

    Directory of Open Access Journals (Sweden)

    A Roshan-Ghias

    2010-02-01

    Full Text Available In clinical situations, bone defects are often located at load bearing sites. Tissue engineering scaffolds are future bone substitutes and hence they will be subjected to mechanical stimulation. The goal of this study was to test if cyclic loading can be used as stimulatory signal for bone formation in a bone scaffold. Poly(L-lactic acid (PLA/ 5% beta-tricalcium phosphate (beta-TCP scaffolds were implanted in both distal femoral epiphyses of eight rats. Right knees were stimulated (10N, 4Hz, 5 min five times, every two days, starting from the third day after surgery while left knees served as control. Finite element study of the in vivo model showed that the strain applied to the scaffold is similar to physiological strains. Using micro-computed tomography (CT, all knees were scanned five times after the surgery and the related bone parameters of the newly formed bone were quantified. Statistical modeling was used to estimate the evolution of these parameters as a function of time and loading. The results showed that mechanical stimulation had two effects on bone volume (BV: an initial decrease in BV at week 2, and a long-term increase in the rate of bone formation by 28%. At week 13, the BV was then significantly higher in the loaded scaffolds.

  7. A Computational Analysis of Bone Formation in the Cranial Vault in the Mouse

    Directory of Open Access Journals (Sweden)

    Chanyoung eLee

    2015-03-01

    Full Text Available Bones of the cranial vault are formed by the differentiation of mesenchymal cells into osteoblasts on a surface that surrounds the brain, eventually forming mineralized bone. Signaling pathways causative for the cell differentiation include the actions of extracellular proteins driven by information from genes. We assume that the interaction of cells and extracellular molecules which are associated with cell differentiation can be modeled using Turing’s reaction-diffusion model, a mathematical model for pattern formation controlled by two interacting molecules (activator and inhibitor. In this study we hypothesize that regions of high concentration of an activator develop into primary centers of ossification, the earliest sites of cranial vault bone. In addition to the Turing model, we use another diffusion equation to model a morphogen (potentially the same as the morphogen associated with formation of ossification centers associated with bone growth. These mathematical models were solved using the finite volume method. The computational domain and model parameters are determined using a large collection of experimental data showing skull bone formation in mouse at different embryonic days in both of normal and defect conditions. The results show that the relative locations of the five ossification centers that form in our model occur at the same position as those identified in experimental data. As bone grows from these ossification centers, sutures form between the bones.

  8. 肿瘤标志物对肺癌分期和骨转移诊断的价值%The diagnosis value of serum tumor marker for bone metastasis and stages of lung cancer

    Institute of Scientific and Technical Information of China (English)

    何泽来; 王火强; 宋玉

    2011-01-01

    目的 探讨肿瘤标志物癌胚抗原(CEA)、细胞角蛋白19的片段(CYFRA21-1)、神经稀醇酶(NSE)、糖类抗原(CA153)血清水平对肺癌分期及肺癌骨转移的辅助诊断价值.方法 检测206例肺癌患者血清4种标志物水平,比较各期肺癌之间、骨转移组和无骨转移组之间的肿瘤标志物表达水平和阳性率的差异.结果 骨转移组4项标志物水平均高于无骨转移组(P均<0.05);肺癌分期越晚,4项标志物阳性率越高;4项联检时灵敏度、准确率等均优于单项检查.结论 肿瘤标志物水平的检测对肺癌骨转移的诊断、肺癌分期(特别是肺癌后期)诊断有辅助价值,联合检查优于单项检查.%Objective To approach the auxiliary diagnosis value of serum tumor markers CEA,CYFRA21-1 ,NSE and CA153 levels for bone metastasis and stages of lung cancer.Methods To collect the serum tumor markers levels of 206 lung cancer patients with whole bone scanning, to analysis the difference of the express level and positive ratio of every stage patients and between bone metastasis group and non-bone metastasis group.Results The four kinds markers levels of bone metastasis group were all higher than non-bone metas tasis group(P all <0.05 ).Four tumor markers positive ratio were increasing with lung cancer stage developing.The sensitivity and accuracy when unite four tumor markers were superior to single marker inspect.Conclusions To detect four kinds tumor markers serum levels for bone metastasis and stages of lung cancer( special later stage of lung cancer) have assist diagnosis value.

  9. Time associated with intravenous zoledronic acid administration in patients with breast or prostate cancer and bone metastasis

    OpenAIRE

    Richhariya A; Qian Y; Zhao Y.; Chung K

    2012-01-01

    Akshara Richhariya1, Yi Qian2, Yufan Zhao2, Karen Chung11Amgen Inc, Global Health Economics, Thousand Oaks, CA, USA; 2Amgen Inc, Global Biostatistical Sciences, Thousand Oaks, CA, USAPurpose: Intravenous (IV) zoledronic acid (ZA) is commonly used to delay skeletal complications secondary to bone metastases. However, the time associated with ZA administration may represent a significant burden to healthcare providers and patients. This study assessed the time associated with IV ZA infusion in ...

  10. High circulating tumor cell concentrations in a specific subtype of gastric cancer with diffuse bone metastasis at diagnosis

    Science.gov (United States)

    Shimazu, Kazuhiro; Fukuda, Koji; Yoshida, Taichi; Inoue, Masahiro; Shibata, Hiroyuki

    2016-01-01

    AIM: To clarify the biological feature contributing to gastric cancer with diffuse bone metastases at diagnosis. METHODS: The participants visited the Department of Clinical Oncology, Akita University Hospital, from January 2014 to August 2015. The selection criterion for gastric cancer with diffuse bone metastases at diagnosis includes over 29 hot spots of bone scintigraphy. Circulating tumor cell were collected from 20 mL of peripheral venous blood drawn using a CellSearch kit and a CellTracks AutoPrep system by SRL, a clinical laboratory. The endpoints of this study were correlations between circulating tumor cells (CTC) count and therapeutic outcomes. RESULTS: Among 39 patients with gastric cancer, 5 patients met the criterion. The incidence of this subtype was 12.8%. CTC counts ranged from 235 to 6440 cells/7.5 mL of peripheral blood (median of 1724). These values were much higher than common gastric cancers (2 cells). In chemo-sensitive cases, CTC counts decreased within 14 d (median) from 275, 235 and 1724 to 2, 7 and 66, respectively. On the other hand, CTC counts increased after treatment failure or insensitive case from 2, 7 and 6440 to 787, 513 and 7885, respectively. The correlation between CTC count and survival time showed a trend, but did not reach significance (Y = 234.6 - 0.03X, P = 0.085). CONCLUSION: High CTC count is a biological hallmark of this subtype, and can be used as a direct and definitive indicator of therapeutic outcome.

  11. Forskolin enhances in vivo bone formation by human mesenchymal stromal cells.

    Science.gov (United States)

    Doorn, Joyce; Siddappa, Ramakrishnaiah; van Blitterswijk, Clemens A; de Boer, Jan

    2012-03-01

    Activation of the protein kinase A (PKA) pathway with dibutyryl cyclic adenosine monophosphate (db-cAMP) was recently shown to enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs) in vitro and bone formation in vivo. The major drawback of this compound is its inhibitory effect on proliferation of hMSCs. Therefore, we investigated whether fine-tuning of the dose and timing of PKA activation could enhance bone formation even further, with minimum effects on proliferation. To test this, we selected two different PKA activators (8-bromo-cAMP (8-br-cAMP) and forskolin) and compared their effects on proliferation and osteogenic differentiation with those of db-cAMP. We found that all three compounds induced alkaline phosphatase levels, bone-specific target genes, and secretion of insulin-like growth factor-1, although 8-br-cAMP induced adipogenic differentiation in long-term cultures and was thus considered unsuitable for further in vivo testing. All three compounds inhibited proliferation of hMSCs in a dose-dependent manner, with forskolin inhibiting proliferation most. The effect of forskolin on in vivo bone formation was tested by pretreating hMSCs before implantation, and we observed greater amounts of bone using forskolin than db-cAMP. Our data show forskolin to be a novel agent that can be used to increase bone formation and also suggests a role for PKA in the delicate balance between adipogenic and osteogenic differentiation. PMID:21942968

  12. Assessment of bone formation capacity using in vivo transplantation assays: procedure and tissue analysis

    DEFF Research Database (Denmark)

    Abdallah, Basem; Ditzel, Nicholas; Kassem, Moustapha

    2008-01-01

    ) in immunodeficient mice is the standard method for in vivo assessment of bone formation capacity of a particular cell type. The method is easy to perform and provides reproducible results. Assessment of the donor origin of tissue formation is possible, especially in the case of human-to-mouse transplanta tion...

  13. Effect of platelet-derived growth factor-BB on bone formation in calvarial defects: an experimental study in rabbits

    DEFF Research Database (Denmark)

    Vikjaer, D; Blom, S; Hjørting-Hansen, E;

    1997-01-01

    defects, and the bone formation was evaluated after 8 weeks. Healing of defects in both groups was characterized by the presence of newly formed bone along the edges of the original defect and by a central area of fibrous connective tissue. The newly formed bone in the rhPDGF-BB treated defects had a...... amount of bone marrow was increased 75% in the rhPDGF-BB-treated defect. The porosity of cortical lamella in the newly formed bone was 84% higher in the rhPDGF-BB-treated defects compared to the control. These results show that administration of a single dose of rhPDGF-BB stimulates bone formation in...

  14. Influence of interfacial properties and inhomogeneity on formation of microdamage in bone

    Science.gov (United States)

    Nakade, Rugved

    Microdamage accumulation at the nanoscopic level of bone affects the overall mechanical behavior of the bone. This makes it necessary to study the mechanisms through which microdamage accumulation can take place at the nanoscopic level. Experiments on bone's different hierarchy are difficult because of the small sizes of these hierarchical structures. Prevention of bone fractures is greatly enhanced with the help of predictive computational tools and hence used to evaluate the effects of microdamage in bone. There are two main types of microdamage that can form in the bone; linear cracks and diffuse damage. The bone nanostructure consists of mineral platelets embedded in soft protein called collagen and can be treated as a composite material. In this study, a two-dimensional probabilistic finite element model of the bone nanostructure was developed to evaluate the likely formation of the microdamage in the nanostructure due to changes in material properties of the nanostructure. The influence of the microdamage formation due to the collagen-mineral interface strength and also the effects of inhomogeneity were studied. To study interfacial strength effects, cohesive elements using bilinear traction separation laws were used to simulate the behavior of the interface (by way of interfacial debonding) between the collegen-mineral layers. Random field theory was used to assign spatially correlated random variables in order to assign inhomogeneous material properties to the bone. Correlation lengths were used to control the level of inhomogeneity in the model. The analysis showed that the type of microdamage was significantly influenced by the strength of the mineral-collagen interface. Probabilistic failure analyses indicated that strong interfaces resulted in limited interfacial debonding and narrow stress concentrations around an initial defect in the mineral-collagen composite, thereby suggesting that the likely location of failure was in same plane of the initial

  15. Low-Level Mechanical Vibrations can Reduce Bone Resorption and Enhance Bone Formation in the Growing Skeleton

    Energy Technology Data Exchange (ETDEWEB)

    Xie,L.; Jacobsen, J.; Busa, B.; Donahue, L.; Miller, L.; Rubin, C.; Judex, S.

    2006-01-01

    Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day{sup -1} (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P < 0.05) than in age-matched controls. Bone formation rates (BFR{center_dot}BS{sup -1}) on the endocortical surface of the metaphysis were 30% greater (P < 0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately

  16. Effect of Combined Calcium Hydroxide and Accelerated Portland Cement on Bone Formation and Soft Tissue Healing in Dog Bone Lesions

    Directory of Open Access Journals (Sweden)

    Khorshidi H

    2015-09-01

    Full Text Available Statement of Problem: Recent literatures show that accelerated Portland cement (APC and calcium hydroxide Ca (OH2 may have the potential to promote the bone regeneration. However, certain clinical studies reveal consistency of Ca (OH2, as one of the practical drawbacks of the material when used alone. To overcome such inconvenience, the combination of the Ca (OH2 with a bone replacement material could offer a convenient solution. Objectives: To evaluate the soft tissue healing and bone regeneration in the periodontal intrabony osseous defects using accelerated Portland cement (APC in combination with calcium hydroxide Ca (OH2, as a filling material. Materials and Methods: Five healthy adult mongrel dogs aged 2-3 years old (approximately 20 kg in weight with intact dentition and healthy periodontium were selected for this study. Two one-wall defects in both mesial and distal aspects of the 3rd premolars of both sides of the mandible were created. Therefore, four defects were prepared in each dog. Three defects in each dog were randomly filled with one of the following materials: APC alone, APC mixed with Ca (OH2, and Ca (OH2 alone. The fourth defect was left empty (control. Upon clinical examination of the sutured sites, the amount of dehiscence from the adjacent tooth was measured after two and eight weeks, using a periodontal probe mesiodistally. For histometric analysis, the degree of new bone formation was estimated at the end of the eighth postoperative week, by a differential point-counting method. The percentage of the defect volume occupied by new osteoid or trabecular bone was recorded. Results: Measurement of wound dehiscence during the second week revealed that all five APCs had an exposure of 1-2 mm and at the end of the study all samples showed 3-4 mm exposure across the surface of the graft material, whereas the Ca (OH2, control, and APC + Ca (OH2 groups did not show any exposure at the end of the eighth week of the study. The most

  17. Volume of Bone Metastasis Assessed with Whole-Body Diffusion-weighted Imaging Is Associated with Overall Survival in Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Perez-Lopez, Raquel; Lorente, David; Blackledge, Matthew D; Collins, David J; Mateo, Joaquin; Bianchini, Diletta; Omlin, Aurelius; Zivi, Andrea; Leach, Martin O; de Bono, Johann S; Koh, Dow-Mu; Tunariu, Nina

    2016-07-01

    Purpose To determine the correlation between the volume of bone metastasis as assessed with diffusion-weighted (DW) imaging and established prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) and the association with overall survival (OS). Materials and Methods This retrospective study was approved by the institutional review board; informed consent was obtained from all patients. The authors analyzed whole-body DW images obtained between June 2010 and February 2013 in 53 patients with mCRPC at the time of starting a new line of anticancer therapy. Bone metastases were identified and delineated on whole-body DW images in 43 eligible patients. Total tumor diffusion volume (tDV) was correlated with the bone scan index (BSI) and other prognostic factors by using the Pearson correlation coefficient (r). Survival analysis was performed with Kaplan-Meier analysis and Cox regression. Results The median tDV was 503.1 mL (range, 5.6-2242 mL), and the median OS was 12.9 months (95% confidence interval [CI]: 8.7, 16.1 months). There was a significant correlation between tDV and established prognostic factors, including hemoglobin level (r = -0.521, P < .001), prostate-specific antigen level (r = 0.556, P < .001), lactate dehydrogenase level (r = 0.534, P < .001), alkaline phosphatase level (r = 0.572, P < .001), circulating tumor cell count (r = 0.613, P = .004), and BSI (r = 0.565, P = .001). A higher tDV also showed a significant association with poorer OS (hazard ratio, 1.74; 95% CI: 1.02, 2.96; P = .035). Conclusion Metastatic bone disease from mCRPC can be evaluated and quantified with whole-body DW imaging. Whole-body DW imaging-generated tDV showed correlation with established prognostic biomarkers and is associated with OS in mCRPC. (©) RSNA, 2016 Online supplemental material is available for this article. PMID:26807894

  18. A correlative imaging based methodology for accurate quantitative assessment of bone formation in additive manufactured implants.

    Science.gov (United States)

    Geng, Hua; Todd, Naomi M; Devlin-Mullin, Aine; Poologasundarampillai, Gowsihan; Kim, Taek Bo; Madi, Kamel; Cartmell, Sarah; Mitchell, Christopher A; Jones, Julian R; Lee, Peter D

    2016-06-01

    A correlative imaging methodology was developed to accurately quantify bone formation in the complex lattice structure of additive manufactured implants. Micro computed tomography (μCT) and histomorphometry were combined, integrating the best features from both, while demonstrating the limitations of each imaging modality. This semi-automatic methodology registered each modality using a coarse graining technique to speed the registration of 2D histology sections to high resolution 3D μCT datasets. Once registered, histomorphometric qualitative and quantitative bone descriptors were directly correlated to 3D quantitative bone descriptors, such as bone ingrowth and bone contact. The correlative imaging allowed the significant volumetric shrinkage of histology sections to be quantified for the first time (~15 %). This technique demonstrated the importance of location of the histological section, demonstrating that up to a 30 % offset can be introduced. The results were used to quantitatively demonstrate the effectiveness of 3D printed titanium lattice implants. PMID:27153828

  19. The effects of n-3 long-chain polyunsaturated fatty acids on bone formation and growth factors in adolescent boys

    DEFF Research Database (Denmark)

    Damsgaard, C. T.; Mølgaard, C.; Gyldenløve, S. N.;

    2012-01-01

    NTRODUCTION: Animal studies indicate that n-3 long-chain polyunsaturated fatty acids (LCPUFAs) increase bone formation. To our knowledge, no studies have examined this in growing humans. This study investigated whether bone mass and markers of bone formation and growth were (i) associated with......-1 (IGF-1) during intervention (β = 0.24, P = 0.03, n = 78). DISCUSSION: DHA status and fish oil supplementation were not associated with bone mass or markers of bone formation in adolescent boys, but IGF-1 increased with increasing DHA status....

  20. Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells.

    Science.gov (United States)

    Schulze, Jochen; Bickert, Thomas; Beil, F Timo; Zaiss, Mario M; Albers, Joachim; Wintges, Kristofer; Streichert, Thomas; Klaetschke, Kristin; Keller, Johannes; Hissnauer, Tim-Nicolas; Spiro, Alexander S; Gessner, Andre; Schett, Georg; Amling, Michael; McKenzie, Andrew N J; Horst, Andrea Kristina; Schinke, Thorsten

    2011-04-01

    Since the hematopoetic system is located within the bone marrow, it is not surprising that recent evidence has demonstrated the existence of molecular interactions between bone and immune cells. While interleukin 1 (IL-1) and IL-18, two cytokines of the IL-1 family, have been shown to regulate differentiation and activity of bone cells, the role of IL-33, another IL-1 family member, has not been addressed yet. Since we observed that the expression of IL-33 increases during osteoblast differentiation, we analyzed its possible influence on bone formation and observed that IL-33 did not affect matrix mineralization but enhanced the expression of Tnfsf11, the gene encoding RANKL. This finding led us to analyze the skeletal phenotype of Il1rl1-deficient mice, which lack the IL-33 receptor ST2. Unexpectedly, these mice displayed normal bone formation but increased bone resorption, thereby resulting in low trabecular bone mass. Since this finding suggested a negative influence of IL-33 on osteoclastogenesis, we next analyzed osteoclast differentiation from bone marrow precursor cells and observed that IL-33 completely abolished the generation of TRACP(+) multinucleated osteoclasts, even in the presence of RANKL and macrophage colony-stimulating factor (M-CSF). Although our molecular studies revealed that IL-33 treatment of bone marrow cells caused a shift toward other hematopoetic lineages, we further observed a direct negative influence of IL-33 on the osteoclastogenic differentiation of RAW264.7 macrophages, where IL-33 repressed the expression of Nfatc1, which encodes one of the key transciption factors of osteoclast differentiation. Taken together, these findings have uncovered a previously unknown function of IL-33 as an inhibitor of bone resorption. PMID:20939024

  1. Time associated with intravenous zoledronic acid administration in patients with breast or prostate cancer and bone metastasis

    Directory of Open Access Journals (Sweden)

    Richhariya A

    2012-02-01

    Full Text Available Akshara Richhariya1, Yi Qian2, Yufan Zhao2, Karen Chung11Amgen Inc, Global Health Economics, Thousand Oaks, CA, USA; 2Amgen Inc, Global Biostatistical Sciences, Thousand Oaks, CA, USAPurpose: Intravenous (IV zoledronic acid (ZA is commonly used to delay skeletal complications secondary to bone metastases. However, the time associated with ZA administration may represent a significant burden to healthcare providers and patients. This study assessed the time associated with IV ZA infusion in patients with bone metastases secondary to breast or prostate cancer (BC or PC in the clinic setting.Methods: Eligible BC or PC patients with bone metastases scheduled to receive IV ZA were observed at seven US-based oncology clinics. Trained observers recorded the time for preinfusion tasks, ZA drug preparation, intravenous infusion, and follow-up activities.Results: Data are reported for 39 patients (BC: 24; PC: 15. Mean administration time was 69 (standard deviation [SD] 42 minutes for all patients combined, 72 (SD 47 minutes for BC, and 65 (SD 33 minutes for PC. Activity times were comparable between tumor types. Mean time for preinfusion tasks (eg, assessment of vital signs, blood draw and ZA preparation were 12 (SD 20 minutes and 2 (SD 1 minutes, respectively. Mean time required for intravenous infusion (ZA infusion and hydration, when provided and follow-up activities were 54 (SD 31 minutes and 2 (SD 1 minutes, respectively.Conclusion: Infusion time was the greatest time commitment associated with IV ZA administration, representing 78% of the total time on average. Time for preinfusion activities varied substantially. Overall, the mean time for ZA administration represents a notable time burden for healthcare providers and patients.Keywords: time and motion, bisphosphonates, zoledronic acid, intravenous administration

  2. SU-E-J-162: Quality Assurance Procedures for MR Guided Focused Ultrasound Treatment of Bone Metastasis

    International Nuclear Information System (INIS)

    Purpose: The purpose of this work is to develop and verify our quality assurance (QA) procedures to ensure the safety and efficacy of MR-guided focused ultrasound (MRgFUS) treatment of bone metastases. Methods: A practical QA program was developed. Monthly and daily QA (DQA) procedures were performed. The major QA items included the checks of the machine hardware, software and patient safety features. Briefly, these checks/tests include: 1) the cooling system reservoir and treatment table; 2) power to the treatment table; 3) the MR coil; 4) the transducer position with MRI; 5) image display on the treatment work station; 6) the effective focal spot in 3 directions using MR thermometry; and 7) all the safety devices including a sonication lamp, and the emergency stop-sonication switches. In order to avoid patient skin burn, it is important to remove gas bubbles in the interfaces between the treatment table and the gel pad, and the gel pad and patients skin during the patient setup. Our QA procedures have been verified and evaluated through patient treatments. Seven patients with scapula, humeral head, sacrum, ilium, pubic ramus and acetabular bone metastases were treated using MRgFUS. Results: Our study showed that all seven patients tolerated the MRgFUS treatment well. No skin toxicity or other complications were observed. The pain score (0–10) using the visual analog scale (VAS) was significantly reduced from 8.0 ± 1.1 before treatment to 4.7 ± 3.0, 3.0 ± 1.5, 3.2 ± 2.8 and 3.4 ± 1.5 at one day, one month, two months and three months after the MRgFUS treatment, respectively. Conclusion: We demonstrated that with the appropriate QA procedures, MRgFUS is a safe, effective and noninvasive treatment modality for palliation of bone metastases

  3. Technetium-99m methylene diphosphonate uptake in the brachialis muscle hematoma in a patient with prostate cancer and coagulation disorder mimicking bone metastasis evaluated by single-photon emission tomography-computed tomography/computed tomography

    International Nuclear Information System (INIS)

    We report a case of 79-year-old male with prostate cancer and coagulation disorder presented with left shoulder pain. He underwent bone scintigraphy to rule out metastasis, which showed intense foci of tracer activity in the left axilla. Hybrid single-photon emission tomography-computed tomography (SPECT/CT) of the shoulder region localized tracer uptake to the left brachialis muscle hematoma. (author)

  4. Thrombospondin 1 promotes synaptic formation in bone marrow-derived neuron-like cells★

    OpenAIRE

    Huang, Yun; Lu, Mingnan; Guo, Weitao; Zeng, Rong; Wang, Bin; Wang, Huaibo

    2013-01-01

    In this study, a combination of growth factors was used to induce bone marrow mesenchymal stem cells differentiation into neuron-like cells, in a broader attempt to observe the role of thrombospondin 1 in synapse formation. Results showed that there was no significant difference in the differentiation rate of neuron-like cells between bone marrow mesenchymal stem cells with thrombospondin induction and those without. However, the cell shape was more complex and the neurites were dendritic, wi...

  5. Kartogenin induces cartilage-like tissue formation in tendon–bone junction

    OpenAIRE

    Zhang, Jianying; Wang, James H-C.

    2014-01-01

    Tendon–bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells...

  6. Premature loss of bone remodeling compartment canopies is associated with deficient bone formation

    DEFF Research Database (Denmark)

    Jensen, Pia Rosgaard; Andersen, Thomas Levin; Søe, Kent; Hauge, Ellen Margrethe; Bollerslev, Jens; Amling, Michael; Barvencik, Florian; Delaissé, Jean-Marie

    2011-01-01

    support to this hypothesis by analyzing the changes in prevalence of BRC canopies during the progress of the remodeling cycle in a cohort of healthy individuals and in patients with endogenous Cushing's syndrome (CS), and by relating these changes in prevalence with the extent of bone forming surfaces...

  7. Osteogenic protein 1 device increases bone formation and bone graft resorption around cementless implants

    DEFF Research Database (Denmark)

    Jensen, Thomas B; Overgaard, Søren; Lind, Martin;

    2002-01-01

    In each femoral condyle of 8 Labrador dogs, a non weight-bearing hydroxyapatite-coated implant was inserted surrounded by a 3 mm gap. Each gap was filled with bone allograft or ProOsteon with or without OP-1 delivered in a bovine collagen type I carrier (OP-1 device). 300 microg OP-1 was used in ...

  8. The importance of assessing the rate of bone turnover and the balance between bone formation and bone resorption during daily teriparatide administration for osteoporosis: a pilot study.

    Science.gov (United States)

    Nakatoh, Shinichi

    2016-03-01

    This study aimed to examine the importance of simultaneously measuring bone formation and resorption markers during daily teriparatide administration. In 135 women with osteoporosis, bone mineral density (BMD) was measured at 0, 24, and 48 weeks after teriparatide administration. Bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b were measured at 0, 4, 12, 24, 36, and 48 weeks. Subanalyses were performed in groups divided according to the BMD change at 48 weeks (increased and decreased groups), history of fragility fracture (acute and chronic groups), and treatment prior to teriparatide administration (alendronate, raloxifene, and naïve groups). The scatter diagram of multiple of median formation (MoMf) and multiple of median resorption (MoMr) showed that the distribution gradually spread to a high turnover by week 24. A significant correlation was observed between the rate of change in BMD at week 48 and the turnover rate [√(MoMf(2) + MoMr(2))] at week 0. Significant differences were observed in the turnover rate between the acute and chronic groups at weeks 0 and 4 and between the groups divided according to prior treatment from week 0 to 24. Because the assessment of either bone formation markers or bone resorption markers may result in erroneous data, it is necessary to assess them together during teriparatide treatment. The turnover rate at treatment initiation is a useful indicator to predict changes in BMD. When evaluating the turnover rate and balance (MoMf/MoMr), one should consider patient characteristics, including history of fragility fracture and prior treatment. PMID:26031934

  9. Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival.

    Science.gov (United States)

    Ma, Yifei; Zhou, Wang; He, Shaohui; Xu, Wei; Xiao, Jianru

    2016-09-15

    Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy. PMID:27164264

  10. Nanosized Hydroxyapatite Coating on PEEK Implants Enhances Early Bone Formation: A Histological and Three-Dimensional Investigation in Rabbit Bone

    Directory of Open Access Journals (Sweden)

    Pär Johansson

    2015-06-01

    Full Text Available Polyether ether ketone (PEEK has been frequently used in spinal surgery with good clinical results. The material has a low elastic modulus and is radiolucent. However, in oral implantology PEEK has displayed inferior ability to osseointegrate compared to titanium materials. One idea to reinforce PEEK would be to coat it with hydroxyapatite (HA, a ceramic material of good biocompatibility. In the present study we analyzed HA-coated PEEK tibial implants via histology and radiography when following up at 3 and 12 weeks. Of the 48 implants, 24 were HA-coated PEEK screws (test and another 24 implants served as uncoated PEEK controls. HA-coated PEEK implants were always osseointegrated. The total bone area (BA was higher for test compared to control implants at 3 (p < 0.05 and 12 weeks (p < 0.05. Mean bone implant contact (BIC percentage was significantly higher (p = 0.024 for the test compared to control implants at 3 weeks and higher without statistical significance at 12 weeks. The effect of HA-coating was concluded to be significant with respect to early bone formation, and HA-coated PEEK implants may represent a good material to serve as bone anchored clinical devices.

  11. Is Lipid Profile Associated with Bone Mineral Density and Bone Formation in Subjects with Spinal Cord Injury?

    Directory of Open Access Journals (Sweden)

    Hadis Sabour

    2014-01-01

    Full Text Available Purpose. The association between serum lipids and bone mineral density (BMD has been investigated previously but, up to now, these relationships have not yet been described in spinal cord injury (SCI. We tried to assess the correlation between serum triglyceride (TG, total cholesterol (TC, high-density lipoprotein (HDL, and low-density lipoprotein (LDL and BMD in male subjects with SCI. Methods. Dual-energy X-ray absorptiometry (DXA was used to assess BMD in femoral neck, trochanter, intertrochanteric zone, and lumbar vertebras. Blood samples were taken to measure serums lipids and bone biomarkers including osteocalcin, cross-linked type I collagen (CTX, and bone alkaline phosphatase (BALP. Partial correlation analysis was used to evaluate the relationships between mentioned measurements after adjustment for weight and age. Results. We found a positive correlation between HDL and femoral neck BMD (P: 0.004, r=0.33. HDL was negatively correlated with osteocalcin (P: 0.017, r=-0.31 which was not in consistency with its relationship with BMD. TC and LDL were not related to CTX, BALP and BMD. Conclusion. This study does not support a strong association between serum lipids and BMD in subjects with SCI. Moreover it seems that positive association between HDL and BMD is not mediated through increased bone formation.

  12. The chloride channel inhibitor NS3736 [corrected] prevents bone resorption in ovariectomized rats without changing bone formation

    DEFF Research Database (Denmark)

    Schaller, Sophie; Henriksen, Kim; Sveigaard, Christina;

    2004-01-01

    Chloride channel activity is essential for osteoclast function. Consequently, inhibition of the osteoclastic chloride channel should prevent bone resorption. Accordingly, we tested a chloride channel inhibitor on bone turnover and found that it inhibits bone resorption without affecting bone form...

  13. Primary breast cancer stem-like cells metastasise to bone, switch phenotype and acquire a bone tropism signature

    OpenAIRE

    D′Amico, L; Patanè, S; Grange, C.; Bussolati, B; Isella, C.; Fontani, L; Godio, L; Cilli, M; D′Amelio, P; Isaia, G; Medico, E; Ferracini, R; Roato, I

    2013-01-01

    Background: Bone metastases represent a common and severe complication in breast cancer, and the involvement of cancer stem cells (CSCs) in the promotion of bone metastasis is currently under discussion. Here, we used a human-in-mice model to study bone metastasis formation due to primary breast CSCs-like colonisation. Methods: Primary CD44+CD24− breast CSCs-like were transduced by a luciferase-lentiviral vector and injected through subcutaneous and intracardiac (IC) routes in non-obese/sever...

  14. Kinetic Analysis of 18F-Fluoride PET Images of Breast Cancer Bone Metastases

    OpenAIRE

    Doot, Robert K; Muzi, Mark; Peterson, Lanell M.; Schubert, Erin K; Gralow, Julie R.; Specht, Jennifer M.; Mankoff, David A.

    2010-01-01

    The most common site of metastasis for breast cancer is bone. Quantitative 18F-fluoride PET can estimate the kinetics of fluoride incorporation into bone as a measure of fluoride transport, bone formation, and turnover. The purpose of this analysis was to evaluate the accuracy and precision of 18F-fluoride model parameter estimates for characterizing regional kinetics in metastases and normal bone in breast cancer patients.

  15. Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis.

    Science.gov (United States)

    Liu, Guo-Xiao; Xi, Hong-Qing; Sun, Xiao-Yan; Wei, Bo

    2015-03-01

    The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. Periostin participates in normal physiological activities such as cardiac development, but is also involved in pathophysiological processes in vascular diseases, wound repair, bone formation, and tumor development. It is of increasing interest in tumor biology because it is frequently overexpressed in a variety of epithelial carcinomas and is functionally involved in multiple steps of metastasis progression. These include the maintenance of stemness, niche formation, EMT, the survival of tumor cells, and angiogenesis, all of which are indispensable for gastric cancer metastasis. Periostin has been reported to activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote metastasis. Therefore, periostin represents a potentially promising candidate for the inhibition of metastasis. In this review article, we summarize recent advances in knowledge concerning periostin, its antagonist PNDA-3, and their influence on such key processes in cancer metastasis as maintenance of stemness, niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and angiogenesis. In particular, we focus our attention on the role of periostin in gastric cancer metastasis, speculate as to the usefulness of periostin as a therapeutic and diagnostic target for gastric cancer metastasis, and consider potential avenues for future research. PMID:25759527

  16. Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

    OpenAIRE

    Kollmann, Katrin; Pestka, Jan Malte; Kühn, Sonja Christin; Schöne, Elisabeth; Schweizer, Michaela; Karkmann, Kathrin; Otomo, Takanobu; Catala-Lehnen, Philip; Failla, Antonio Virgilio; Marshall, Robert Percy; Krause, Matthias; Santer, Rene; Amling, Michael; Braulke, Thomas; Schinke, Thorsten

    2013-01-01

    Mucolipidosis type II (MLII) is a severe multi-systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock-in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency...

  17. Mechanical microenvironments and protein expression associated with formation of different skeletal tissues during bone healing.

    Science.gov (United States)

    Miller, Gregory J; Gerstenfeld, Louis C; Morgan, Elise F

    2015-11-01

    Uncovering the mechanisms of the sensitivity of bone healing to mechanical factors is critical for understanding the basic biology and mechanobiology of the skeleton, as well as for enhancing clinical treatment of bone injuries. This study refined an experimental method of measuring the strain microenvironment at the site of a bone injury during bone healing. This method used a rat model in which a well-controlled bending motion was applied to an osteotomy to induce the formation of pseudarthrosis that is composed of a range of skeletal tissues, including woven bone, cartilage, fibrocartilage, fibrous tissue, and clot tissue. The goal of this study was to identify both the features of the strain microenvironment associated with formation of these different tissues and the expression of proteins frequently implicated in sensing and transducing mechanical cues. By pairing the strain measurements with histological analyses that identified the regions in which each tissue type formed, we found that formation of the different tissue types occurs in distinct strain microenvironments and that the type of tissue formed is correlated most strongly to the local magnitudes of extensional and shear strains. Weaker correlations were found for dilatation. Immunohistochemical analyses of focal adhesion kinase and rho family proteins RhoA and CDC42 revealed differences within the cartilaginous tissues in the calluses from the pseudarthrosis model as compared to fracture calluses undergoing normal endochondral bone repair. These findings suggest the involvement of these proteins in the way by which mechanical stimuli modulate the process of cartilage formation during bone healing. PMID:25822264

  18. Laser Microablative Tunnel Formation to Initiate Alveolar Bone Regeneration. Pilot ex vivo Study

    Directory of Open Access Journals (Sweden)

    Karabut М.М.

    2013-12-01

    Full Text Available In recent years there has been demonstrated the ability of Erbium (Er laser to cause effective ablation of bone tissue with minimum collateral damage. Non-surgical treatment of periodontitis using Er laser improves probing depth and clinical attachment level. However, periodontal anti-inflammatory therapy should not be limited to these parameters, but also should initiate tissue regeneration including bone tissue damaged by the disease. The aim of the investigation was to evaluate feasibility and characterize the process of laser microablative tunnel formation in gingiva and alveolar bone using a pulse-periodic, single mode Er laser, and determine laser parameters providing appropriate size of the tunnel and coagulation zone needed to initiate healing and regeneration of the alveolar bone. Materials and Methods. Ex vivo pig jaw was used as a model for the study. To create a through-gingiva microperformation of the alveolar bone, we used a laboratory prototype of Er laser and delivery system Alta PE-AT (Dental Photonics, Inc.. Results. We performed a microperforation of a 1 mm thick gingiva and created a microcrater (tunnel in the underlying bone using a single pulse with energy 5, 10 and 30 mJ. The laser tunnel characteristics in the gingiva, bone and dentine were characterized as a function of laser irradiation parameters. Optical microscopy and histology examination did not reveal carbonization or significant collateral damage of the bone tissue. Conclusion. Using a laboratory prototype of Alta PE-AT Er laser we demonstrated feasibility of through gingiva laser microperforation of alveolar bone that can serve as the first step towards further study of healing and initiation of the alveolar bone regeneration.

  19. Pedunculated hepatocellular carcinoma and splenic metastasis

    Institute of Scientific and Technical Information of China (English)

    Mao-Lin Yan; Yao-Dong Wang; Zhi-De Lai; Yi-Feng Tian; Hong-Biao Chen; Fu-Nan Qiu; Song-Qiang Zhou

    2009-01-01

    Only a few cases of pedunculated hepatocellular carcinoma (P-HCC) have been reported in the literature. The common sites of extrahepatic metastases in patients with HCC are the lungs, regional lymph nodes,kidney, bone marrow and adrenals. Metastasis to spleen is mostly via hematogenous metastasis, direct metastasis to spleen was very rare. We report a case of P-HCC presenting as a left upper abdominal lesions which involved the spleen that was actually a P-HCC with splenic metastasis. This case is unique as P-HCC directly involved the spleen which is not via hematogenous metastasis.

  20. AMP-activated protein kinase (AMPK) activation regulates in vitro bone formation and bone mass

    OpenAIRE

    Shah, M; Kola, B; Bataveljic, A.; Arnett, T. R.; Viollet, B.; Saxon, L.; Korbonits, M.; C. Chenu

    2010-01-01

    Adenosine 5′-monophosphate-activated protein kinase (AMPK), a regulator of energy homeostasis, has a central role in mediating the appetite-modulating and metabolic effects of many hormones and antidiabetic drugs metformin and glitazones. The objective of this study was to determine if AMPK can be activated in osteoblasts by known AMPK modulators and if AMPK activity is involved in osteoblast function in vitro and regulation of bone mass in vivo. ROS 17/2.8 rat osteoblast-like cells were cult...

  1. Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene

    DEFF Research Database (Denmark)

    Grum-Schwensen, Birgitte; Klingelhofer, Jörg; Berg, Christian Hededam;

    2005-01-01

    distribution of host-derived stroma cells. Coinjection of CSML100 cells with immortalized S100A4(+/+) fibroblasts partially restored the dynamics of tumor development and the ability to form metastasis. These fibroblasts were characterized by an enhanced motility and invasiveness in comparison with S100A4...

  2. Thrombospondin 1 promotes synaptic formation in bone marrow-derived neuron-like cells

    Institute of Scientific and Technical Information of China (English)

    Yun Huang; Mingnan Lu; Weitao Guo; Rong Zeng; Bin Wang; Huaibo Wang

    2013-01-01

    In this study, a combination of growth factors was used to induce bone marrow mesenchymal stem cells differentiation into neuron-like cells, in a broader attempt to observe the role of thrombospondin 1 in synapse formation. Results showed that there was no significant difference in the differentiation rate of neuron-like cells between bone marrow mesenchymal stem cells with thrombospondin induction and those without. However, the cell shape was more complex and the neurites were dendritic, with unipolar, bipolar or multipolar morphologies, after induction with thrombospondin 1. The induced cells were similar in morphology to normal neurites. Immunohistochemical staining showed that the number of positive cells for postsynaptic density protein 95 and synaptophysin 1 protein was significantly increased after induction with thrombospondin 1. These findings indicate that thrombospondin 1 promotes synapse formation in neuron-like cells that are differentiated from bone marrow mesenchymal stem cells.

  3. FGFR3 promotes angiogenesis-dependent metastasis of hepatocellular carcinoma via facilitating MCP-1-mediated vascular formation.

    Science.gov (United States)

    Liu, Xinyu; Jing, Xiaoqian; Cheng, Xi; Ma, Ding; Jin, Zhijian; Yang, Weiping; Qiu, Weihua

    2016-05-01

    The biological role of fibroblast growth factor receptor 3 (FGFR3) in tumor angiogenesis of hepatocellular carcinoma (HCC) has not been discussed before. Our previous work had indicated FGFR3 was overexpressed in HCC, and silencing FGFR3 in Hu7 cells could regulate tumorigenesis via down-regulating the phosphorylation level of key members of classic signaling pathways including ERK and AKT. In the present work, we explored the role of FGFR3 in angiogenesis-dependent metastasis by using SMMC-7721 and QGY-7703 stable cell lines. Our results indicated FGFR3 could regulate in vitro cell migration ability and in vivo lung metastasis ability of HCC, which was in accordance with increased angiogenesis ability in vitro and in vivo. Using the supernatant from SMMC-7721/FGFR3 cells, we conducted a human angiogenesis protein microarray including 43 angiogenesis factors and found that FGFR3 modulated angiogenesis and metastasis of HCC mainly by promoting the protein level of monocyte chemotactic protein 1 (MCP-1). Silencing FGFR3 by short hairpin RNA (shRNA) could reduce MCP-1 level in lysates and supernatant of QGY-7703 cells and SMMC-7721 cells. Silencing MCP-1 in QGY-7703 or SMMC-7721 cells could induce similar phenotypes compared with silencing FGFR3. Our results suggested FGFR3 promoted metastasis potential of HCC, at least partially if not all, via facilitating MCP-1-mediated angiogenesis, in addition to previously found cell growth and metastasis. MCP-1, a key medium between HCC cells and HUVECs, might be a novel anti-vascular target in HCC. PMID:27044356

  4. Effect of recombinant human bone morphogenetic protein-2 on a novel lung cancer spine metastasis model in rodents.

    Science.gov (United States)

    Sonn, Kevin A; Kannan, Abhishek S; Bellary, Sharath S; Yun, Chawon; Hashmi, Sohaib Z; Nelson, John T; Ghodasra, Jason H; Nickoli, Michael S; Parimi, Vamsi; Ghosh, Anjan; Shawen, Nicholas; Ashtekar, Amruta; Stock, Stuart R; Hsu, Erin L; Hsu, Wellington K

    2016-07-01

    Lung cancer is the second most prevalent cancer. Spinal metastases are found in 30-90% of patients with death attributed to cancer. Due to bony destruction caused by metastases, surgical intervention is often required to restore spinal alignment and stability. While some research suggests that BMP-2 may possess tumorigenic effects, other studies show possible inhibition of cancer growth. Thirty-six athymic rats underwent intraosseous injection of lung adenocarcinoma cells into the L5 vertebral body. Cells were pre-treated with vehicle control (Group A) or rhBMP-2 (Group B) prior to implantation. At 4 weeks post-implantation, in vivo bioluminescent imaging (BLI) was performed to confirm presence of tumor and quantify signal. Plain radiographs and microComputed Tomography (microCT) were employed to establish and quantitate osteolysis. Histological analysis characterized pathologic changes in the vertebral body. At 4 weeks post-implantation, BLI showed focal signal in the L5 vertebral body in 93% of Group A animals and 89% of Group B animals. Average tumor burden by BLI radiance was 7.43 × 10(3)  p/s/cm(2) /sr (Group A) and 1.11 × 10(4)  p/s/cm(2) /sr (Group B). Radiographs and microCT demonstrated osteolysis in 100% of animals showing focal BLI signal. MicroCT demonstrated significant bone loss in both groups compared to age-matched controls but no difference between study groups. Histological analysis confirmed tumor invasion in the L5 vertebral body. These findings provide a reliable in vivo model to study isolated spinal metastases from lung cancer. Statement of Clinical Significance: The data support the notion that exposure to rhBMP-2 does not promote the growth of A549 lung cancer spine lesions. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1274-1281, 2016. PMID:26694749

  5. Chondrocytes-Specific Expression of Osteoprotegerin Modulates Osteoclast Formation in Metaphyseal Bone.

    Science.gov (United States)

    Wang, Baoli; Jin, Hongting; Shu, Bing; Mira, Ranim R; Chen, Di

    2015-01-01

    Bone marrow stromal cells/osteoblasts were originally thought to be the major player in regulating osteoclast differentiation through expressing RANKL/OPG cytokines. Recent studies have established that chondrocytes also express RANKL/OPG and support osteoclast formation. Till now, the in vivo function of chondrocyte-produced OPG in osteoclast formation and postnatal bone growth has not been directly investigated. In this study, chondrocyte-specific Opg transgenic mice were generated by using type II collagen promoter. The Col2-Opg transgenic mice showed delayed formation of secondary ossification center and localized increase of bone mass in proximal metaphysis of tibiae. TRAP staining showed that osteoclast numbers were reduced in both secondary ossification center and proximal metaphysis. This finding was further confirmed by in vitro chondrocyte/spleen cell co-culture assay. In contrast, the mineral apposition rates were not changed in Col2-Opg transgenic mice. TUNEL staining revealed more apoptotic hypertrophic chondrocytes in the growth plate of Col2-Opg mice. Flow cytometry analysis showed fewer RANK-expressing cells in the marrow of Col2a1-Opg mice, suggesting the role of OPG in blocking the differentiation of early mesenchymal progenitors into RANK-expressing pre-osteoclasts. Our results demonstrated that OPG expression in chondrocyte increases bone mass in the proximal metaphysis of tibiae through negative regulation of osteoclast formation. PMID:26329493

  6. cAMP/PKA Signaling Inhibits Osteogenic Differentiation and Bone Formation in Rodent Models

    NARCIS (Netherlands)

    Siddappa, Ramakrishnaiah; Mulder, Winfried; Steeghs, Ilse; Klundert, van de Christine; Fernandes, Hugo; Liu, Jun; Arends, Roel; Blitterswijk, van Clemens; Boer, de Jan

    2009-01-01

    We previously demonstrated that cAMP-mediated protein kinase A (PKA) activation induces in vitro osteogenesis and in vivo bone formation by human mesenchymal stem cells (hMSCs). To analyze the species-specific response of this phenomenon and to translate our findings into a clinical trial, suitable

  7. Forskolin enhances in vivo bone formation by human mesenchymal stromal cells

    NARCIS (Netherlands)

    Doorn, J.; Siddappa, R.; Blitterswijk, van C.A.; Boer, de J.

    2012-01-01

    Activation of the protein kinase A (PKA) pathway with dibutyryl cyclic adenosine monophosphate (db-cAMP) was recently shown to enhance osteogenic differentiation of human mesenchymal stromal cells (hMSCs) in vitro and bone formation in vivo. The major drawback of this compound is its inhibitory effe

  8. Hedgehog signaling mediates woven bone formation and vascularization during stress fracture healing.

    Science.gov (United States)

    Kazmers, Nikolas H; McKenzie, Jennifer A; Shen, Tony S; Long, Fanxin; Silva, Matthew J

    2015-12-01

    Hedgehog (Hh) signaling is critical in developmental osteogenesis, and recent studies suggest it may also play a role in regulating osteogenic gene expression in the post-natal setting. However, there is a void of studies directly assessing the effect of Hh inhibition on post-natal osteogenesis. This study utilized a cyclic loading-induced ulnar stress fracture model to evaluate the hypothesis that Hh signaling contributes to osteogenesis and angiogenesis during stress fracture healing. Immediately prior to loading, adult rats were given GDC-0449 (Vismodegib - a selective Hh pathway inhibitor; 50mg/kg orally twice daily), or vehicle. Hh signaling was upregulated in response to stress fracture at 3 days (Ptch1, Gli1 expression), and was markedly inhibited by GDC-0449 at 1 day and 3 days in the loaded and non-loaded ulnae. GDC-0449 did not affect Hh ligand expression (Shh, Ihh, Dhh) at 1 day, but decreased Shh expression by 37% at 3 days. GDC-0449 decreased woven bone volume (-37%) and mineral density (-17%) at 7 days. Dynamic histomorphometry revealed that the 7 day callus was composed predominantly of woven bone in both groups. The observed reduction in woven bone occurred concomitantly with decreased expression of Alpl and Ibsp, but was not associated with differences in early cellular proliferation (as determined by callus PCNA staining at 3 days), osteoblastic differentiation (Osx expression at 1 day and 3 days), chondrogenic gene expression (Acan, Sox9, and Col2α1 expression at 1 day and 3 days), or bone resorption metrics (callus TRAP staining at 3 days, Rankl and Opg expression at 1 day and 3 days). To evaluate angiogenesis, vWF immunohistochemistry showed that GDC-0449 reduced fracture callus blood vessel density by 55% at 3 days, which was associated with increased Hif1α gene expression (+30%). Dynamic histomorphometric analysis demonstrated that GDC-0449 also inhibited lamellar bone formation. Lamellar bone analysis of the loaded limb (directly adjacent

  9. Enhancement of Osteoclastic Bone Resorption and Suppression of Osteoblastic Bone Formation in Response to Reduced Mechanical Stress Do Not Occur in the Absence of Osteopontin

    Science.gov (United States)

    Ishijima, Muneaki; Rittling, Susan R.; Yamashita, Teruhito; Tsuji, Kunikazu; Kurosawa, Hisashi; Nifuji, Akira; Denhardt, David T.; Noda, Masaki

    2001-01-01

    Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN−/− mice using a tail suspension model. In contrast to the tail suspension–induced bone loss in wild-type mice, OPN−/− mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN−/− mice. Analysis of the mechanisms of OPN deficiency–dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN−/− mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN−/− mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts. PMID:11157060

  10. Effect of caffeic acid phenethyl ester on bone formation in the expanded inter-premaxillary suture

    Directory of Open Access Journals (Sweden)

    Kazancioglu HO

    2015-12-01

    Full Text Available Hakki Oguz Kazancioglu,1 Sertac Aksakalli,2 Seref Ezirganli,1 Muhammet Birlik,2 Mukaddes Esrefoglu,3 Ahmet Hüseyin Acar1 1Department of Oral and Maxillofacial Surgery, 2Department of Orthodontics, Faculty of Dentistry, 3Department of Histology, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey Background: Narrow maxilla is a common problem in orthodontics and dentofacial orthopedics. To solve this problem, a procedure called rapid maxillary expansion (RME has been used. However, relapse tendency is a major problem of RME. Although relapse tendency is not clearly understood, various treatment procedures and new application has been investigated. The present study aimed to investigate the possible effectiveness of caffeic acid phenethyl ester (CAPE on new bone formation in rat midpalatal suture after RME.Materials and methods: Twenty male Sprague Dawley rats were used in this study. The animals were randomly divided into two groups as control and CAPE group. In CAPE group, CAPE was administered systemically via intraperitoneal injection. RME procedure was performed on all animals. For this purpose, the springs were placed on the maxillary incisors of rats and activated for 5 days. After then, the springs were removed and replaced with short lengths of rectangular retaining wire for consolidation period of 15 days. At the end of the study, histomorphometric analysis was carried out to assess of new bone formation.Results: New bone formation was significantly greater in CAPE group than the control group (P<0.05. CAPE enhances new bone formation in midpalatal suture after RME.Conclusion: These results show that CAPE may decrease the time needed for retention. Keywords: rapid maxillary expansion, bone formation, caffeic acid phenethyl ester, midpalatal suture, histopathology

  11. A myostatin and activin decoy receptor enhances bone formation in mice.

    Science.gov (United States)

    Bialek, P; Parkington, J; Li, X; Gavin, D; Wallace, C; Zhang, J; Root, A; Yan, G; Warner, L; Seeherman, H J; Yaworsky, P J

    2014-03-01

    Myostatin is a member of the bone morphogenetic protein/transforming growth factor-β (BMP/TGFβ) super-family of secreted differentiation factors. Myostatin is a negative regulator of muscle mass as shown by increased muscle mass in myostatin deficient mice. Interestingly, these mice also exhibit increased bone mass suggesting that myostatin may also play a role in regulating bone mass. To investigate the role of myostatin in bone, young adult mice were administered with either a myostatin neutralizing antibody (Mstn-mAb), a soluble myostatin decoy receptor (ActRIIB-Fc) or vehicle. While both myostatin inhibitors increased muscle mass, only ActRIIB-Fc increased bone mass. Bone volume fraction (BV/TV), as determined by microCT, was increased by 132% and 27% in the distal femur and lumbar vertebrae, respectively. Histological evaluation demonstrated that increased BV/TV in both locations was attributed to increased trabecular thickness, trabecular number and bone formation rate. Increased BV/TV resulted in enhanced vertebral maximum compressive force compared to untreated animals. The fact that ActRIIB-Fc, but not Mstn-mAb, increased bone volume suggested that this soluble decoy receptor may be binding a ligand other than myostatin, that plays a role in regulating bone mass. This was confirmed by the significant increase in BV/TV in myostatin deficient mice treated with ActRIIB-Fc. Of the other known ActRIIB-Fc ligands, BMP3 has been identified as a negative regulator of bone mass. However, BMP3 deficient mice treated with ActRIIB-Fc showed similar increases in BV/TV as wild type (WT) littermates treated with ActRIIB-Fc. This result suggests that BMP3 neutralization is not the mechanism responsible for increased bone mass. The results of this study demonstrate that ActRIIB-Fc increases both muscle and bone mass in mice. Therefore, a therapeutic that has this dual activity represents a potential approach for the treatment of frailty. PMID:24333131

  12. Efficacy of Intraperitoneal Administration of PEGylated NELL-1 for Bone Formation

    Science.gov (United States)

    Tanjaya, Justine; Zhang, Yulong; Lee, Soonchul; Shi, Jiayu; Chen, Eric; Ang, Pia; Zhang, Xinli; Tetradis, Sotirios; Ting, Kang; Wu, Benjamin; Soo, Chia; Kwak, Jin Hee

    2016-01-01

    Abstract Systemically delivered NEL-like molecule-1 (NELL-1), a potent pro-osteogenic protein, promotes bone formation in healthy and osteoporotic mouse models. PEGylation of NELL-1 (NELL-PEG) increases the half-life of the protein in a mouse model without compromising its osteogenic potential, thereby improving its pharmacokinetics upon systemic delivery. This study consists of a twofold approach: a biodistribution test and an in vivo osteogenic potential test. The biodistribution test compared two commonly used administration methods for drug delivery other than intravenous—intraperitoneal (IP) and subcutaneous (SC)—to examine NELL-PEG biodistribution in mice. Compared to a single-dose SC injection (1.25 mg/kg), a single-dose IP administration yielded a higher protein uptake in the targeted bone sites. When the IP injection dose was doubled to 2.5 mg/kg, the protein remained in the femurs, tibias, and vertebrae for up to 72 h. Next, based on the results of the biodistribution study, IP administration was selected to further investigate the in vivo osteogenic effects of weekly NELL-PEG injection (q7d). In vivo, the IP administered NELL-PEG group showed significantly greater bone mineral density, bone volume fraction, and trabecular bone formation in the targeted bone sites compared to the phosphate-buffered saline control. In summary, weekly NELL-PEG injection via IP administration successfully enhanced the overall bone quality. These findings demonstrate that systemic delivery of NELL-PEG via IP administration may serve as an effective osteogenic therapy for preventing and treating osteoporosis. PMID:27354930

  13. Pyk2 regulates megakaryocyte-induced increases in osteoblast number and bone formation.

    Science.gov (United States)

    Cheng, Ying-Hua; Hooker, R Adam; Nguyen, Khanh; Gerard-O'Riley, Rita; Waning, David L; Chitteti, Brahmananda R; Meijome, Tomas E; Chua, Hui Lin; Plett, Artur P; Orschell, Christie M; Srour, Edward F; Mayo, Lindsey D; Pavalko, Fredrick M; Bruzzaniti, Angela; Kacena, Melissa A

    2013-06-01

    Preclinical and clinical evidence from megakaryocyte (MK)-related diseases suggests that MKs play a significant role in maintaining bone homeostasis. Findings from our laboratories reveal that MKs significantly increase osteoblast (OB) number through direct MK-OB contact and the activation of integrins. We, therefore, examined the role of Pyk2, a tyrosine kinase known to be regulated downstream of integrins, in the MK-mediated enhancement of OBs. When OBs were co-cultured with MKs, total Pyk2 levels in OBs were significantly enhanced primarily because of increased Pyk2 gene transcription. Additionally, p53 and Mdm2 were both decreased in OBs upon MK stimulation, which would be permissive of cell cycle entry. We then demonstrated that OB number was markedly reduced when Pyk2-/- OBs, as opposed to wild-type (WT) OBs, were co-cultured with MKs. We also determined that MKs inhibit OB differentiation in the presence and absence of Pyk2 expression. Finally, given that MK-replete spleen cells from GATA-1-deficient mice can robustly stimulate OB proliferation and bone formation in WT mice, we adoptively transferred spleen cells from these mice into Pyk2-/- recipient mice. Importantly, GATA-1-deficient spleen cells failed to stimulate an increase in bone formation in Pyk2-/- mice, suggesting in vivo the important role of Pyk2 in the MK-induced increase in bone volume. Further understanding of the signaling pathways involved in the MK-mediated enhancement of OB number and bone formation will facilitate the development of novel anabolic therapies to treat bone loss diseases. PMID:23362087

  14. Addition of Adipose-Derived Stem Cells to Mesenchymal Stem Cell Sheets Improves Bone Formation at an Ectopic Site

    Directory of Open Access Journals (Sweden)

    Zhifa Wang

    2016-02-01

    Full Text Available To determine the effect of adipose-derived stem cells (ADSCs added to bone marrow-derived mesenchymal stem cell (MSC sheets on bone formation at an ectopic site. We isolated MSCs and ADSCs from the same rabbits. We then prepared MSC sheets for implantation with or without ADSCs subcutaneously in the backs of severe combined immunodeficiency (SCID mice. We assessed bone formation at eight weeks after implantation by micro-computed tomography and histological analysis. In osteogenic medium, MSCs grew to form multilayer sheets containing many calcium nodules. MSC sheets without ADSCs formed bone-like tissue; although neo-bone and cartilage-like tissues were sparse and unevenly distributed by eight weeks after implantation. In comparison, MSC sheets with ADSCs promoted better bone regeneration as evidenced by the greater density of bone, increased mineral deposition, obvious formation of blood vessels, large number of interconnected ossified trabeculae and woven bone structures, and greater bone volume/total volume within the composite constructs. Our results indicate that although sheets of only MSCs have the potential to form tissue engineered bone at an ectopic site, the addition of ADSCs can significantly increase the osteogenic potential of MSC sheets. Thus, the combination of MSC sheets with ADSCs may be regarded as a promising therapeutic strategy to stimulate bone regeneration.

  15. Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts.

    Science.gov (United States)

    Keller, Johannes; Catala-Lehnen, Philip; Huebner, Antje K; Jeschke, Anke; Heckt, Timo; Lueth, Anja; Krause, Matthias; Koehne, Till; Albers, Joachim; Schulze, Jochen; Schilling, Sarah; Haberland, Michael; Denninger, Hannah; Neven, Mona; Hermans-Borgmeyer, Irm; Streichert, Thomas; Breer, Stefan; Barvencik, Florian; Levkau, Bodo; Rathkolb, Birgit; Wolf, Eckhard; Calzada-Wack, Julia; Neff, Frauke; Gailus-Durner, Valerie; Fuchs, Helmut; de Angelis, Martin Hrabĕ; Klutmann, Susanne; Tsourdi, Elena; Hofbauer, Lorenz C; Kleuser, Burkhard; Chun, Jerold; Schinke, Thorsten; Amling, Michael

    2014-01-01

    The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. PMID:25333900

  16. Radiographic evaluation and unusual bone formations in different genetic patterns in synpolydactyly

    International Nuclear Information System (INIS)

    To compare the radiological findings of heterozygous and homozygous subjects with synpolydactyly (SPD) and to discuss their unusual bone formations. Families with hand and foot SPD were examined. Genetic analysis was performed with blood samples and the pedigree was constructed. The affected individuals, especially those with distinctive phenotypic features, were invited to our orthopaedics clinic for further diagnostic studies. All participants underwent detailed clinical and X-ray examinations. Of the invited patients, 16 (five female and 11 male; age range 4-37 years, mean age 10.75 years) were included in our study, and hand and foot radiographs were obtained. All subjects had bilateral hand radiographs (32 hands), and 14 had bilateral foot radiographs (28 feet). Genetic analysis revealed 12 heterozygote (75%) and four (25%) homozygote phenotypes. Among patients enrolled into the study nine (three homozygotes, six heterozygotes) had SPD of both hands and feet bilaterally (tetrasynpolydactyly). Six unusual bone formations were observed in the hands and feet: delta phalanx, delta metacarpal/metatarsal, kissing delta phalanx, true double epiphysis, pseudoepiphysis and cone-shaped epiphysis. There were major differences in radiological and clinical manifestations of homozygote and heterozygote phenotypes. The homozygous SPD presented with very distinctive unusual bone formations. The existence and variety of unusual bones may indicate the severity of penetrance and expressivity of SPD. (orig.)

  17. Teriparatide Increases Bone Formation and Bone Mineral Density in Adult Women With Anorexia Nervosa

    Science.gov (United States)

    Wang, Irene S.; Miller, Karen K.; Herzog, David B.; Misra, Madhusmita; Lee, Hang; Finkelstein, Joel S.; Bouxsein, Mary L.; Klibanski, Anne

    2014-01-01

    Context: Anorexia nervosa (AN), a prevalent psychiatric disorder predominantly affecting women, is characterized by self-induced starvation and low body weight. Increased clinical fractures are common, and most women have low bone mineral density (BMD). Previously investigated treatments have led to no or modest increases in BMD in AN. Objective: Our objective was to investigate the effect of teriparatide (TPT; human PTH[1–34]), an anabolic agent, on low bone mass in women with AN. Design, Setting, and Patients: This randomized, placebo-controlled trial at a clinical research center included 21 women with AN: 10 (mean age ± SEM, 47 ± 2.7 years) treated with TPT and 11 (47.1 ± 2.3 years) treated with placebo. Interventions: TPT (20 μg SC) or placebo was administered for 6 months. Main Outcome Measures: Our primary outcome measure was change in BMD of the spine and hip by dual-energy x-ray absorptiometry. Secondary outcome measures included changes in serum N-terminal propeptide of type 1 procollagen (P1NP), C-terminal collagen cross-links, sclerostin, and IGF-1 levels. Results: At 6 months, spine BMD increased significantly more with TPT (posteroanterior spine, 6.0% ± 1.4%; lateral spine, 10.5% ± 2.5%) compared with placebo (posteroanterior spine, 0.2% ± 0.7%, P < .01; lateral spine, −0.6% ± 1.0%; P < .01). The results remained significant after controlling for baseline body mass index, P1NP, and IGF-1. Changes in femoral neck (P = .4) and total hip (P = 0.8) BMD were comparable in both groups, as were changes in weight. Serum P1NP levels increased after 3 months of TPT treatment and remained at this higher level at 6 months, whereas P1NP levels were unchanged in the placebo group (P = .02). TPT was well-tolerated by all subjects. Conclusions: This study demonstrates that TPT administration increases spine BMD substantially after only 6 months of therapy in women with AN. PMID:24456286

  18. Effects of magnetic resonance imaging (MRI) on the formation of mouse dentin and bone

    International Nuclear Information System (INIS)

    The effects of magnetic resonance imaging (MRI) on dentin and bone formation in mice were examined using standard autoradiographic and liquid scintillation procedures. It was observed that exposure to a standard 23.2 min clinical multislice MRI (0.15T) procedure caused a significant increase in the synthesis of the collagenous matrix of dentin in the incisors of mice. There were no significant effects on alveolar and tibial bone matrix synthesis. These results suggest that the magnetic fields associated with MRI can affect the activity of cells and/or tissues that are involved in rapid synthetic activity

  19. Zygomatico-coronoid ankylosis secondary to heterotopic bone formation: Combined treatment by surgery and radiation therapy

    International Nuclear Information System (INIS)

    Zygomatico-coronoid ankylosis is a rare, extra-articular form of ankylosis of the jaws. An unusual case is presented in which true bony zygomatico-coronoid ankylosis was produced by a mass of heterotopic bone. Surgical treatment consisted of an oblique ostectomy across the mandibular ascending ramus, with interposition of Silastic sheeting to form a pseudarthrosis. Since surgery is often the stimulus for this condition, 2000 rads were delivered to the surgical site postoperatively in order to inhibit recurrent heterotopic bone formation. The rationale and indications for this form of treatment are discussed. (orig.)

  20. Bone metastases in breast cancer and its risk factor

    International Nuclear Information System (INIS)

    Breast cancer is considered to often involve bone metastasis. Early detection and treatment of bone metastasis are essential in improving the prognosis of this disease. In 47 patients with bone metastasis confirmed with bone scintigraphy, we examined the appearance time of bone metastasis; bone metastasis was frequently observed with the progress of stage, but no association with the appearance time was found. Age was not associated with the incidence of bone metastasis but was found to be closely related to its appearance time. That is to say, patients with breast cancer below 40 years of age showed relatively early bone metastasis. Bone scintigraphy is required every 6 months at least for 3 years after the operation. In patients over 40 years of age, on the other hand, bone scintigraphy is required only once a year but has to be continued for 5 years or more, because they often show relatively late bone metastasis. (author)

  1. The expression of E-cadherin-catenin complex in patients with advanced gastric cancer: role in formation of metastasis.

    Directory of Open Access Journals (Sweden)

    Marek Ustymowicz

    2010-06-01

    Full Text Available The E-cadherin-catenin complex plays an important role in the process of cell adhesion. Its dysfunction is associated with a decrease in cell differentiation and with increased invasiveness and metastasis. Our aim was to evaluate the expression of E-cadherin and B-catenin in advanced gastric cancer in relation to selected clinico-pathomorphological parameters. Formalin-fixed, paraffin-embedded tissue specimens were immunohistochemically stained with monoclonal antibodies E-cadherin (NCL-E-Cad, Novocastra Laboratiries Ltd; dilution 1:50, beta-catenin (NCL-B-CAT, Novocastra Laboratories Ltd; dilution 1:100, alpha-catenin (alpha-E-caten, Santa Cruz Biotechnology; dilution 1:300 and gamma-catenin (gamma-catenin, Santa Cruz Biotechnology; dilution 1:100. The expressions of E-cadherin and alpha-, beta-, gamma-catenins in the main mass of tumor and lymph node metastasis were investigated in 91 patients with gastric cancer. No statistically significant correlation was observed between the expressions of E-cadherin, alpha-, beta-catenins and histological differentiation and between the expressions of E-cadherin, alpha-, gamma-catenins and location or depth of invasion. Moreover, the expression of alpha-, gamma-catenins in the main mass of tumor was not associated with lymph node metastasis. However, we found a relationship between the expression of beta-catenin in the main mass of tumor and lymph node metastasis and tumor location. The depth of invasion was correlated with positive expression of beta-catenin in the main mass of gastric cancer. A statistically significant association was observed between the expressions of E-cadherin and beta-catenin in the main mass of tumor and lymph node involvement. The expression of alpha-catenin in the main mass of tumor was also associated with histological differentiation and Lauren's classification. Statistical analysis showed an association between the expression of E-cadherin and postoperative survival time. No

  2. Assessment of bone formation and bone resorption in osteoporosis: a comparison between tetracycline-based iliac histomorphometry and whole body 85Sr kinetics

    International Nuclear Information System (INIS)

    Bone formation and resorption have been measured in patients with idiopathic osteoporosis by histomorphometry of 7.5-mm trephine biopsies and in the whole body by 85Sr radiotracer methodology and calcium balances. The studies were synchronized and most were preceded by double in vivo tetracycline labeling. Correlations between histological and kinetic bone formation indices were better when better when based on the extent of double tetracycline labels than on measurements of osteoid by visible light microscopy. Correction of the kinetic data for long-term exchange, using 5 months' serial whole body counting of retained 85Sr, improved the fit of the kinetic to the histological data. A statistical analysis of the measurement uncertainties showed that the residual scatter in the best correlations (between exchange-corrected bone formation rates and double-labeled osteoid surface indices) could be attributed to measurement imprecision alone. The exchange-corrected resorption rate correlated fairly well with iliac trabecular resorption surfaces, and using a volume referent rather than a surface referent for the histological index improved the statistical fit when patients with therapeutically accelerated bone turnover were included. A much better correlation was obtained by including osteoid volume acting as an independent predictor of bone resorption in a bivariate regression with a resorption surface index. The residual errors could then be accounted for by known measurement uncertainties. Whereas osteoid taking a double label closely predicted the kinetic rate of bone formation, further analysis suggested that osteoid that took no label or a single label was more closely related to bone resorption, presumably as a secondary result of the coupling of bone formation to bone resorption

  3. Bone microenvironment-mediated resistance of cancer cells to bisphosphonates and impact on bone osteocytes/stem cells.

    Science.gov (United States)

    Alasmari, Abeer; Lin, Shih-Chun; Dibart, Serge; Salih, Erdjan

    2016-08-01

    Anti-resorptive bisphosphonates (BPs) have been clinically used to prevent cancer-bone metastasis and cancer-induced bone pathologies despite the fact that the phenotypic response of the cancer-bone interactions to BP exposure is "uncharted territory". This study offers unique insights into the interplay between cancer stem cells and osteocytes/osteoblasts and mesenchymal stem cells using a three-dimensional (3D) live cancer-bone interactive model. We provide extraordinary cryptic details of the biological events that occur as a result of alendronate (ALN) treatment using 3D live cancer-bone model systems under specific bone remodeling stages. While cancer cells are susceptible to BP treatment in the absence of bone, they are totally unaffected in the presence of bone. Cancer cells colonize live bone irrespective of whether the bone is committed to bone resorption or formation and hence, cancer-bone metastasis/interactions are though to be "independent of bone remodeling stages". In our 3D live bone model systems, ALN inhibited bone resorption at the osteoclast differentiation level through effects of mineral-bound ALN on osteocytes and osteoblasts. The mineral-bound ALN rendered bone incapable of osteoblast differentiation, while cancer cells colonize the bone with striking morphological adaptations which led to a conclusion that a direct anti-cancer effect of BPs in a "live or in vivo" bone microenvironment is implausible. The above studies were complemented with mass spectrometric analysis of the media from cancer-bone organ cultures in the absence and presence of ALN. The mineral-bound ALN impacts the bone organs by limiting transformation of mesenchymal stem cells to osteoblasts and leads to diminished endosteal cell population and degenerated osteocytes within the mineralized bone matrix. PMID:27155840

  4. Case report and nursing observation of pressure sores at left femur in a lung cancer patient with bone metastasis%1例肺癌骨转移并发左股骨转子处压疮的护理

    Institute of Scientific and Technical Information of China (English)

    李艳; 刘佳丽

    2011-01-01

    目的 探讨肺癌骨转移并发左股骨转子处压疮的护理原则.方法对1例肺癌骨转移并发左股骨转子处压疮,采用湿性愈合治疗,观察治疗过程及疗效情况.结果 本例经积极护理及治疗处理后,左股骨转子处压疮创面完全愈合,周围皮肤痊愈,于治疗后11 d出院.出院后2周定期随访,无压疮复发情况发生.结论 肺癌骨转移并发左股骨转子处压疮的治疗关键在于正确的压疮分级评定、合理的治疗和并发症的预防.%Objective To evaluate the nursing principles of pressure sores at left femur in a lung cancer patient with bone metastasis.Methods Moist healing treatment was applied to a lung cancer patient with bone metastasis who has pressure sores at left femur and treatment process and its efficacy was closely observed.Results Pressure sores at left femur and around skin were completely healed, and left hospital after 11 days' treatment.After 2 weeks, a follow- up visit found no recurrence.Conclusion The key points of treatment in pressure sores at left femur in a lung cancer patient with bone metastasis were accurate pressure sores grade assessment, reasonable treatment and prevention of complications.

  5. In vivo ectopic bone formation by devitalized mineralized stem cell carriers produced under mineralizing culture condition.

    Science.gov (United States)

    Chai, Yoke Chin; Geris, Liesbet; Bolander, Johanna; Pyka, Grzegorz; Van Bael, Simon; Luyten, Frank P; Schrooten, Jan

    2014-12-01

    Functionalization of tissue engineering scaffolds with in vitro-generated bone-like extracellular matrix (ECM) represents an effective biomimetic approach to promote osteogenic differentiation of stem cells in vitro. However, the bone-forming capacity of these constructs (seeded with or without cells) is so far not apparent. In this study, we aimed at developing a mineralizing culture condition to biofunctionalize three-dimensional (3D) porous scaffolds with highly mineralized ECM in order to produce devitalized, osteoinductive mineralized carriers for human periosteal-derived progenitors (hPDCs). For this, three medium formulations [i.e., growth medium only (BM1), with ascorbic acid (BM2), and with ascorbic acid and dexamethasone (BM3)] supplemented with calcium (Ca(2+)) and phosphate (PO4 (3-)) ions simultaneously as mineralizing source were investigated. The results showed that, besides the significant impacts on enhancing cell proliferation (the highest in BM3 condition), the formulated mineralizing media differentially regulated the osteochondro-related gene markers in a medium-dependent manner (e.g., significant upregulation of BMP2, bone sialoprotein, osteocalcin, and Wnt5a in BM2 condition). This has resulted in distinguished cell populations that were identifiable by specific gene signatures as demonstrated by the principle component analysis. Through devitalization, mineralized carriers with apatite crystal structures unique to each medium condition (by X-ray diffraction and SEM analysis) were obtained. Quantitatively, BM3 condition produced carriers with the highest mineral and collagen contents as well as human-specific VEGF proteins, followed by BM2 and BM1 conditions. Encouragingly, all mineralized carriers (after reseeded with hPDCs) induced bone formation after 8 weeks of subcutaneous implantation in nude mice models, with BM2-carriers inducing the highest bone volume, and the lowest in the BM3 condition (as quantitated by nano-computed tomography

  6. Serum procollagen 1 amino-terminal propeptide (P1NP) in prostate cancer; pitfalls of its use as an early surrogate marker for bone metastasis

    International Nuclear Information System (INIS)

    Procollagen 1 amino-terminal propeptide (P1NP) is a bone formation marker and has been shown to have a strong association with the extent of bone metastases (BM) in patients with advanced prostate cancer. More recently, its levels were found to be affected by androgen deprivation therapies and bisphosphonates. We investigated the role of P1NP as a surrogate marker of sub-radiological skeletal metastases in prostate cancer patients with biochemical failure (BF). BePrepared is a prospective longitudinal substudy of RADAR trial in which serial P1NPs were collected at regular intervals for 123 patients who had completed RADAR protocol treatment. There was no trend identified in P1NP levels prior to diagnosis of BM. We found that there was no difference in P1NP concentrations at the time of diagnosis of BM in the group that developed BM compared with P1NP levels in groups with only nodal metastases or BF. In the group of patients who did not experience BF, P1NP was affected by previous luteinizing hormone-releasing hormone-agonist and bisphosphonate therapy. Hence, patients who received an 18-month course of androgen deprivation without bisphosphonates had significantly higher P1NP values than patients with shorter androgen deprivation therapy (ADT) course combined with a course of bisphosphonates. P1NP is not a sensitive serum marker of early BM in high-risk prostate cancer patients with BF and low prostate-specific antigen levels as its levels are affected by prior history of bone remodelling therapies such as ADT and bisphosphonates.

  7. Molecular mechanisms of metastasis in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Noel W.Clarke; Claire A.Hart; Mick D.Brown

    2009-01-01

    Prostate cancer (PCa) preferentially metastasizes to the bone marrow stroma of the axial skeleton.This activity is the principal cause of PCa morbidity and mortality.The exact mechanism of PCa metastasis is currently unknown,although considerable progress has been made in determining the key players in this process.In this review,we present the current understanding of the molecular processes driving PCa metastasis to the bone.

  8. The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro – evaluation towards understanding breast cancer cell bone metastasis

    Directory of Open Access Journals (Sweden)

    Du William

    2012-08-01

    Full Text Available Abstract Background Versican is detected in the interstitial tissues at the invasive margins of breast carcinoma, is predictive of relapse, and negatively impacts overall survival rates. The versican G3 domain is important in breast cancer cell growth, migration and bone metastasis. However, mechanistic studies evaluating versican G3 enhanced breast cancer bone metastasis are limited. Methods A versican G3 construct was exogenously expressed in the 66c14 and the MC3T3-E1 cell line. Cells were observed through light microscopy and viability analyzed by Coulter Counter or determined with colorimetric proliferation assays. The Annexin V-FITC apoptosis detection kit was used to detect apoptotic activity. Modified Chemotactic Boyden chamber migration invasion assays were applied to observe tumor migration and invasion to bone stromal cells and MC3T3-E1 cells. Alkaline phosphatase (ALP staining and ALP ELISA assays were performed to observe ALP activity in MC3T3-E1 cells. Results In the four mouse breast cancer cell lines 67NR, 66c14, 4T07, and 4T1, 4T1 cells expressed higher levels of versican, and showed higher migration and invasion ability to MC3T3-E1 cells and primary bone stromal cells. 4T1 conditioned medium (CM inhibited MC3T3-E1 cell growth, and even lead to apoptosis. Only 4T1 CM prevented MC3T3-E1 cell differentiation, noted by inhibition of alkaline phosphatase (ALP activity. We exogenously expressed a versican G3 construct in a cell line that expresses low versican levels (66c14, and observed that the G3-expressing 66c14 cells showed enhanced cell migration and invasion to bone stromal and MC3T3-E1 cells. This observation was prevented by selective EGFR inhibitor AG1478, selective MEK inhibitor PD 98059, and selective AKT inhibitor Triciribine, but not by selective JNK inhibitor SP 600125. Versican G3 enhanced breast cancer cell invasion to bone stromal cells or osteoblast cells appears to occur through enhancing EGFR/ERK or AKT signaling

  9. New Bone Formation in Tuberculous-Infected Vertebral Body Defect after Administration of Bone Marrow Stromal Cells in Rabbit Model

    Science.gov (United States)

    Kurniawati, Tri; Siregar, Nurjati Chairani; Syahrurachman, Agus; Dilogo, Ismail Hadisubroto; Iskandriati, Diah; Fitri, Arni Diana

    2016-01-01

    Study Design Preliminary experimental study using a rabbit spondylitis model. Purpose To observe the ossification in a micro-environment containing live Mycobacterium tuberculosis transplanted with bone marrow stromal cells (BMSCs) in rabbits. Overview of Literature BMSCs differentiate to osteoblasts and then osteocytes during ossification. Mycobacterium tuberculosis does not affect BMSC growth in vitro. Methods Six rabbits were divided into two groups of three rabbits. One group was positive for spondylitis tuberculosis by culture, polymerase chain reaction (PCR), and histopathologically. The other group was positive by PCR and histopathologically. Both groups were treated using BMSC transplantation and anti-tuberculosis drugs. After 6 weeks, ossification was evaluated by enumerating the number of osteoblasts, osteocytes, and lesion level of calcium. Results Mean number of osteoblasts was 207.00±31.00 in the first group and 220.33±73.46 in the second group. Mean number of intra-lesions osteocytes was in the first and second group was 18.33±30.04 and 31.00±26.87, respectively. Mean calcium level in the first group and second group was 2.94%±0.89% and 2.51%±0.13%, respectively. Total ossification score in the first and second group was 31.00 and 25.67, respectively. Conclusions Mycobacterium tuberculosis provides support for new bone formation by stimulating intra-lesion calcium metabolism. The microscopic environment containing live Mycobacterium tuberculosis enhances ossification. PMID:26949451

  10. Bone

    International Nuclear Information System (INIS)

    Bone scanning provides information on the extent of primary bone tumors, on possible metastatic disease, on the presence of osteomyelitis prior to observation of roentgenographic changes so that earlier therapy is possible, on the presence of collagen diseases, on the presence of fractures not disclosed by x-ray films, and on the evaluation of aseptic necrosis. However, the total effect and contribution of bone scanning to the diagnosis, treatment, and ultimate prognosis of pediatric skeletal diseases is, as yet, unknown. (auth)

  11. High-dose OxyContin to treat pain associated with bone metastasis in patients with small-cell lung cancer: a case study report

    Directory of Open Access Journals (Sweden)

    Zhou T

    2016-01-01

    patient quality of life, relieve pain, and help prolong patient survival. This article reports the treatment procedure and adverse reactions in a patient who was treated with high-dose OxyContin, with the aim of providing a reference for other clinical practitioners. Keywords: pain, OxyContin, bone metastasis, palliative care

  12. Phosphate Interacts With PTHrP to Regulate Endochondral Bone Formation

    OpenAIRE

    Liu, Eva S.; Zalutskaya, Alena; Chae, Byongsoo Timothy; Zhu, Eric D.; Gori, Francesca; Demay, Marie B.

    2014-01-01

    Phosphate and parathyroid hormone related peptide (PTHrP) are required for normal growth plate maturation. Hypophosphatemia impairs hypertrophic chondrocyte apoptosis leading to rachitic expansion of the growth plate; however, the effect of phosphate restriction on chondrocyte differentiation during endochondral bone formation has not been examined. Investigations were, therefore, undertaken to address whether phosphate restriction alters the maturation of embryonic d15.5 murine metatarsal el...

  13. Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.

    Science.gov (United States)

    Yang, M; Shao, J-H; Miao, Y-J; Cui, W; Qi, Y-F; Han, J-H; Lin, X; Du, J

    2014-08-01

    Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies. PMID:24722209

  14. Short-term aluminum administration in the rat. Effects on bone formation and relationship to renal osteomalacia.

    OpenAIRE

    Goodman, W G; Gilligan, J; Horst, R.

    1984-01-01

    Aluminum may be pathogenic in the osteomalacia observed in some patients receiving hemodialysis. To study the early effects of Al on bone growth, bone formation, mineralization, and resorption were measured during short-term Al exposure in the tibial cortex of pair-fed control (C, n = 10), aluminum-treated (AL, n = 9), subtotally nephrectomized control (NX-C, n = 7), and subtotally nephrectomized aluminum-treated (NX-AL, n = 8) rats using double tetracycline labeling of bone. Animals received...

  15. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

    OpenAIRE

    Jodi A. Carlson Scholz; Agnès Vignery; James Gilligan; Nozer Mehta; Xiaoqing Xu; Christopher Miller; Jesse Bible; Jiliang Li; Qing Zhang,

    2012-01-01

    Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH o...

  16. Effects of calcium phosphate/chitosan composite on bone healing in rats: calcium phosphate induces osteon formation.

    Science.gov (United States)

    Fernández, Tulio; Olave, Gilberto; Valencia, Carlos H; Arce, Sandra; Quinn, Julian M W; Thouas, George A; Chen, Qi-Zhi

    2014-07-01

    Vascularization of an artificial graft represents one of the most significant challenges facing the field of bone tissue engineering. Over the past decade, strategies to vascularize artificial scaffolds have been intensively evaluated using osteoinductive calcium phosphate (CaP) biomaterials in animal models. In this work, we observed that CaP-based biomaterials implanted into rat calvarial defects showed remarkably accelerated formation and mineralization of new woven bone in defects in the initial stages, at a rate of ∼60 μm/day (0.8 mg/day), which was considerably higher than normal bone growth rates (several μm/day, 0.1 mg/day) in implant-free controls of the same age. Surprisingly, we also observed histological evidence of primary osteon formation, indicated by blood vessels in early-region fibrous tissue, which was encapsulated by lamellar osteocyte structures. These were later fully replaced by compact bone, indicating complete regeneration of calvarial bone. Thus, the CaP biomaterial used here is not only osteoinductive, but vasculogenic, and it may have contributed to the bone regeneration, despite an absence of osteons in normal rat calvaria. Further investigation will involve how this strategy can regulate formation of vascularized cortical bone such as by control of degradation rate, and use of models of long, dense bones, to more closely approximate repair of human cortical bone. PMID:24460696

  17. Glycation of human cortical and cancellous bone captures differences in the formation of Maillard reaction products between glucose and ribose.

    Directory of Open Access Journals (Sweden)

    Grażyna E Sroga

    Full Text Available To better understand some aspects of bone matrix glycation, we used an in vitro glycation approach. Within two weeks, our glycation procedures led to the formation of advanced glycation end products (AGEs at the levels that corresponded to approx. 25-30 years of the natural in vivo glycation. Cortical and cancellous bones from human tibias were glycated in vitro using either glucose (glucosylation or ribose (ribosylation. Both glucosylation and ribosylation led to the formation of higher levels of AGEs and pentosidine (PEN in cancellous than cortical bone dissected from all tested donors (young, middle-age and elderly men and women. More efficient glycation of bone matrix proteins in cancellous bone most likely depended on the higher porosity of this tissue, which facilitated better accessibility of the sugars to the matrix proteins. Notably, glycation of cortical bone from older donors led to much higher AGEs levels as compared to young donors. Such efficient in vitro glycation of older cortical bone could result from aging-related increase in porosity caused by the loss of mineral content. In addition, more pronounced glycation in vivo would be driven by elevated oxidation processes. Interestingly, the levels of PEN formation differed pronouncedly between glucosylation and ribosylation. Ribosylation generated very high levels of PEN (approx. 6- vs. 2.5-fold higher PEN level than in glucosylated samples. Kinetic studies of AGEs and PEN formation in human cortical and cancellous bone matrix confirmed higher accumulation of fluorescent crosslinks for ribosylation. Our results suggest that in vitro glycation of bone using glucose leads to the formation of lower levels of AGEs including PEN, whereas ribosylation appears to support a pathway toward PEN formation. Our studies may help to understand differences in the progression of bone pathologies related to protein glycation by different sugars, and raise awareness for excessive sugar

  18. A novel mouse model for the study of the inhibitory effects of chronic ethanol exposure on direct bone formation

    Science.gov (United States)

    Excessive alcohol consumption has been reported to interfere with human bone homeostasis and repair in multiple ways. Previous studies have demonstrated that chronic ethanol exposure in the rat via an intragastric dietary delivery system inhibits direct bone formation during distraction osteogenesis...

  19. Formation of Cell-To-Cell Connection between Bone Marrow Cells and Isolated Rat Cardiomyocytes in a Cocultivation Model

    Czech Academy of Sciences Publication Activity Database

    Skopalík, J.; Pásek, Michal; Rychtárik, M.; Koristek, Z.; Gabrielová, E.; Sheer, P.; Matejovič, P.; Modrianský, M.; Klabusay, M.

    2014-01-01

    Roč. 5, č. 5 (2014), s. 1000185. ISSN 2157-7013 Institutional support: RVO:61388998 Keywords : bone marrow * mononuclear cells * isolated cardiomyocytes * cocultivation Subject RIV: BO - Biophysics http://omicsonline.org/ open - access /formation-of-celltocell-connection-between-bone-marrow-cells- and -isolated-rat-cardiomyocytes-2157-7013.1000185.php?aid=33364

  20. Bone resorption facilitates osteoblastic bone metastatic colonization by cooperation of insulin-like growth factor and hypoxia

    OpenAIRE

    Kuchimaru, Takahiro; Hoshino, Takuya; Aikawa, Tomoya; Yasuda, Hisataka; KOBAYASHI, Tatsuya; Kadonosono, Tetsuya; Kizaka-Kondoh, Shinae

    2014-01-01

    Bone metastasis is a multistep process that includes cancer cell dissemination, colonization, and metastatic growth. Furthermore, this process involves complex, reciprocal interactions between cancer cells and the bone microenvironment. Bone resorption is known to be involved in both osteolytic and osteoblastic bone metastasis. However, the precise roles of the bone resorption in the multistep process of osteoblastic bone metastasis remain unidentified. In this study, we show that bone resorp...

  1. Bone morphogenetic protein-2 gene controls tooth root development in coordination with formation of the periodontium

    Institute of Scientific and Technical Information of China (English)

    Audrey Rakian; Wu-Chen Yang; Jelica Gluhak-Heinrich; Yong Cui; Marie A Harris; Demitri Villarreal; Jerry Q Feng; Mary MacDougall; Stephen E Harris

    2013-01-01

    Formation of the periodontium begins following onset of tooth-root formation in a coordinated manner after birth. Dental follicle progenitor cells are thought to form the cementum, alveolar bone and Sharpey’s fibers of the periodontal ligament (PDL). However, little is known about the regulatory morphogens that control differentiation and function of these progenitor cells, as well as the progenitor cells involved in crown and root formation. We investigated the role of bone morphogenetic protein-2 (Bmp2) in these processes by the conditional removal of the Bmp2 gene using the Sp7-Cre-EGFP mouse model. Sp7-Cre-EGFP first becomes active at E18 in the first molar, with robust Cre activity at postnatal day 0 (P0), followed by Cre activity in the second molar, which occurs after P0. There is robust Cre activity in the periodontium and third molars by 2 weeks of age. When the Bmp2 gene is removed from Sp71 (Osterix1) cells, major defects are noted in root, cellular cementum and periodontium formation. First, there are major cell autonomous defects in root-odontoblast terminal differentiation. Second, there are major alterations in formation of the PDLs and cellular cementum, correlated with decreased nuclear factor IC (Nfic), periostin and a-SMA1 cells. Third, there is a failure to produce vascular endothelial growth factor A (VEGF-A) in the periodontium and the pulp leading to decreased formation of the microvascular and associated candidate stem cells in the Bmp2-cKOSp7-Cre-EGFP. Fourth, ameloblast function and enamel formation are indirectly altered in the Bmp2-cKOSp7-Cre-EGFP. These data demonstrate that the Bmp2 gene has complex roles in postnatal tooth development and periodontium formation.

  2. Multiple myeloma presenting as plasmacytoma of the jaws showing prominent bone formation during chemotherapy.

    Science.gov (United States)

    An, S-Y; An, C-H; Choi, K-S; Heo, M-S

    2013-01-01

    A 65-year-old female visited our hospital complaining of a swelling on the left cheek area of 2 years' duration. A panoramic radiograph revealed an ill-defined osteolytic radiolucent bony lesion involving the left mandibular angle, ascending ramus, coronoid process and condylar process. Histological examination showed the mandibular lesion to be a plasmacytoma, and a systemic work-up was obtained to rule out multiple myeloma. Contrast-enhanced CT images showed a well-defined and slightly enhanced round mass on the left ramal area, accompanied by the destruction of the left ramus and posterior maxilla. An (18)F-fluorodeoxy-glucose positron emission tomography CT ((18)F-FDG PET/CT) scan revealed a hypermetabolic mass extending from the left mandible to the left maxillary sinus. The patient had M-protein in serum and urine, plasma cells up to 36.5% on bone marrow biopsy and anaemia as a clinical complication. The patient was diagnosed with multiple myeloma and received chemotherapy with thalidomide, cyclophosphamide and dexamethasone. A PET/CT scan taken 6 months later revealed that the hypermetabolic mass had disappeared and there was remarkable bone formation on the left mandible compared with a previous PET/CT scan. A panoramic radiograph taken 8 months later also demonstrated a prominent bone formation of the affected site. To the best of our knowledge, the current case is the first report of multiple myeloma presenting as plasmacytoma of the mandible with an FDG PET/CT scan. The lesion was solitary at diagnosis, and remarkable bone formation was newly observed on the radiographic examination during chemotherapy. PMID:23520399

  3. A truncated phosphorylated p130Cas substrate domain is sufficient to drive breast cancer growth and metastasis formation in vivo.

    Science.gov (United States)

    Kumbrink, Joerg; de la Cueva, Ana; Soni, Shefali; Sailer, Nadja; Kirsch, Kathrin H

    2016-08-01

    Elevated p130Cas (Crk-associated substrate) levels are found in aggressive breast tumors and are associated with poor prognosis and resistance to standard therapeutics in patients. p130Cas signals majorly through its phosphorylated substrate domain (SD) that contains 15 tyrosine motifs (YxxP) which recruit effector molecules. Tyrosine phosphorylation of p130Cas is important for mediating migration, invasion, tumor promotion, and metastasis. We previously developed a Src*/SD fusion molecule approach, where the SD is constitutively phosphorylated. In a polyoma middle T-antigen (PyMT)/Src*/SD double-transgenic mouse model, Src*/SD accelerates PyMT-induced tumor growth and promotes a more aggressive phenotype. To test whether Src*/SD also drives metastasis and which of the YxxP motifs are involved in this process, full-length and truncated SD molecules fused to Src* were expressed in breast cancer cells. The functionality of the Src*/SD fragments was analyzed in vitro, and the active proteins were tested in vivo in an orthotopic mouse model. Breast cancer cells expressing the full-length SD and the functional smaller SD fragment (spanning SD motifs 6-10) were injected into the mammary fat pads of mice. The tumor progression was monitored by bioluminescence imaging and caliper measurements. Compared with control animals, the complete SD promoted primary tumor growth and an earlier onset of metastases. Importantly, both the complete and truncated SD significantly increased the occurrence of metastases to multiple organs. These studies provide strong evidence that the phosphorylated p130Cas SD motifs 6-10 (Y236, Y249, Y267, Y287, and Y306) are important for driving mammary carcinoma progression. PMID:26867768

  4. Value of Radiological Imaging on Detecting Bone Metastasis in Pediatric Neuroblastoma%小儿成神经细胞瘤骨转移影像学特征及诊断价值

    Institute of Scientific and Technical Information of China (English)

    徐燕清; 乔中伟; 李国平; 施莺燕

    2011-01-01

    Purpose: To compare the diagnostic value of X - ray computed tomography(CT) and magnetic resonance image(MRI) on detecting bone metastasis in pediatric neuroblastoma.Methods: Forty seven neuroblastoma with bone metastasis cases were evaluated and analyzed respectively on plain X - ray, CT and MRI.Results: In all the 47 cases with bone metastases, 89.2% metastatic lesions were located in long tubular bones, iliac, cranium and vertebrae.Morphologically, the percentages of osteolytic and mixed pattern were 71.4% and 28.6% respectively, there was no sclerotic pattern in all the 47 cases.The features on plain X - ray and CT were moth - eaten, irregular and tiny lesions, part of the cases were with peripheral sclerosis or periosteal reactions.CT showed more tiny changes at cranium, vertebra and pelvis.It was low signal intensity on T1 WI, high signal intensity on T2 WI.The MR images showed the infiltration earlier and further than CT.Conclusions: X- ray is mainly used for detecting bone metastasis in pediatric neuroblastoma, which especially demonstrates the lesions in long tubular bones.CT provides a detailed image, particularly in cranium, vertebra and pelvis.MRI is used for detecting bone marrow and intraspinal metastasis at an earlier stage.%目的:分析小儿成神经细胞瘤骨转移的影像学特征,并探讨X线平片、CT和MRI的诊断价值.方法:收集小儿成神经细胞瘤骨转移患者47例,分析骨转移在X线平片、CT和MRI上的特征,并比较其诊断价值.结果:成神经细胞瘤骨转移89.2%位于长管状骨、骨盆、头颅和脊柱.形态上包括溶骨型(71.4%)、混合型(28.6%)和单纯成骨型.X线和CT表现为虫蚀样、不规则、极小透光区,部分伴有硬化边缘或骨膜反应.CT在头颅、骨盆、椎体等部位显示更细微、更广泛的病变.MRI骨髓侵犯表现为T1WI低信号,T2WI高信号,MRI发现髓内转移的时间早于CT和X线,显示病变范围更大.结论:X线平片是诊断成神

  5. Effects of soccer vs swim training on bone formation in sedentary middle-aged women

    DEFF Research Database (Denmark)

    Mohr, Magni; Helge, Eva Wulff; Petersen, Liljan F;

    2015-01-01

    PURPOSE: The present study examined the effects of 15 weeks of soccer training and two different swimming training protocols on bone turnover in sedentary middle-aged women. METHODS: Eighty-three premenopausal mildly hypertensive women [age: 45 ± 6 (±SD) years, height: 165 ± 6 cm, weight: 80.0 ± 14.......7 ± 1.9 and 2.4 ± 2.9 %, respectively, in SOC, with a greater (P < 0.05) change in SOC than in MS and C, whereas total body and total leg BMD did not change in any of the groups. CONCLUSION: In conclusion, 15 weeks of soccer training with sedentary middle-aged women caused marked increases in bone...... turnover markers, with concomitant increases in leg bone mass. No changes in bone formation and resorption markers were seen after prolonged submaximal or high-intensity intermittent swimming training. Thus, soccer training appears to provide a powerful osteogenic stimulus in middle-aged women....

  6. 双侧乳腺癌伴骨及宫颈转移一例报告并文献复习%A Case Report and a Review of the Literature of Bilateral Breast Cancer with Bone and Cervical Metastasis

    Institute of Scientific and Technical Information of China (English)

    陆晓峰; 苏磊; 王雪晨

    2015-01-01

    Objective To study the clinical diagnosis and treatment of bilateral breast cancer with bone and cervical metastasis. Methods We retrospectively analyzed the clinical data of a case of bilateral breast cancer with bone and cervical metastasis in our hospital. Results The patient was a 52-year-old female,admitted for the right breast mass, which had been found more than one month before. Breast ultrasound showed substantial occupying lesions of bilateral breasts. The pathologic results of bilateral breast mass indicated all invasive lobular carcinoma. ECT of the whole body bone scanning showed systemic multiple bone metastases. B ultrasound in gynecology showed cervical hypoechoic occupying lesion. After the neoadjuvant chemotherapy, we performed operations of bilateral breast modified radical mastectomy and cervical neoplasm electrotomy. The postoperative pathological results showed that the bilateral breast tumors were invasive lobular carcinoma associated with axilla-ry lymph node metastasis. The pathological staging was IV( T1b ,N3 ,M1 ) . The result of immunohistochemistry showed that CK, S100, Mummaglobin and GCDFP-15 were positive, Ki67 was about 3% positive,ER was about 40% positive,PR was about 20% positive,while CerbB2 was negative. Then, the patient accepted the postoperative systemic treatment,such as chemother-apy, and endocrine therapy. The patient was checked every three months with a stable condition, and continued endocrine therapy. Conclusion The bone metastasis from breast cancer is a common condition,while the occurrence of metastasis to the neck of uterus is rare. The histopathological analysis combined with immunohistochemical detection is of great value in diagno-sis and treatment.%目的:探讨双侧乳腺癌伴骨及宫颈转移的临床诊治要点。方法对我院收治的双侧乳腺癌伴骨及宫颈转移1例的临床资料进行回顾性分析。结果本例52岁,因发现右乳腺包块1月余入院。乳腺彩色多普勒超声

  7. Long-Term Symptoms Onset and Heterotopic Bone Formation around a Total Temporomandibular Joint Prosthesis: a Case Report

    OpenAIRE

    Luca Guarda-Nardini; Daniele Manfredini; Marco Olivo; Giuseppe Ferronato

    2014-01-01

    Background: The literature on total alloplastic temporomandibular joint (TMJ) reconstructions is encouraging, and studies on total alloplastic TMJ replacements outcomes showed acceptable improvements in terms of both pain levels and jaw function. Nevertheless, some adverse events, such as heterotopic bone formation around the implanted prosthesis, may occur. In consideration of that, the present manuscript describes a case of heterotopic bone formation around a total temporomandibular joint p...

  8. Long-Term Symptoms Onset and Heterotopic Bone Formation around a Total Temporomandibular Joint Prosthesis: a Case Report

    OpenAIRE

    Guarda-Nardini, Luca; Manfredini, Daniele; Olivo, Marco; Ferronato, Giuseppe

    2014-01-01

    ABSTRACT Background The literature on total alloplastic temporomandibular joint (TMJ) reconstructions is encouraging, and studies on total alloplastic TMJ replacements outcomes showed acceptable improvements in terms of both pain levels and jaw function. Nevertheless, some adverse events, such as heterotopic bone formation around the implanted prosthesis, may occur. In consideration of that, the present manuscript describes a case of heterotopic bone formation around a total temporomandibular...

  9. Structure and formation of the twisted plywood pattern of collagen fibrils in rat lamellar bone.

    Science.gov (United States)

    Yamamoto, Tsuneyuki; Hasegawa, Tomoka; Sasaki, Muneteru; Hongo, Hiromi; Tabata, Chihiro; Liu, Zhusheng; Li, Minqi; Amizuka, Norio

    2012-04-01

    This study was designed to elucidate details of the structure and formation process of the alternate lamellar pattern known to exist in lamellar bone. For this purpose, we examined basic internal lamellae in femurs of young rats by transmission and scanning electron microscopy, the latter employing two different macerations with NaOH at concentrations of 10 and 24%. Observations after the maceration with 10% NaOH showed that the regular and periodic rotation of collagen fibrils caused an alternation between two types of lamellae: one consisting of transversely and nearly transversely cut fibrils, and the other consisting of longitudinally and nearly longitudinally cut fibrils. This finding confirms the consistency of the twisted plywood model. The maceration method with 24% NaOH removed bone components other than cells, thus allowing for three-dimensional observations of osteoblast morphology. Osteoblasts extended finger-like processes paralleling the inner bone surface, and grouped in such a way that, within a group, the processes arranged in a similar direction. Transmission electron microscopy showed that newly deposited fibrils were arranged alongside these processes. For the formation of the alternating pattern, our findings suggest that: (1) osteoblasts control the collagen fibril arrangement through their finger-like process position; (2) osteoblasts behave similarly within a group; (3) osteoblasts move their processes synchronously and periodically to promote alternating different fibril orientation; and (4) this dynamic sequential deposition of fibrils results in the alternate lamellar (or twisted plywood) pattern. PMID:22362877

  10. Nanoscale control of silica particle formation via silk-silica fusion proteins for bone regeneration.

    Science.gov (United States)

    Mieszawska, Aneta J; Nadkarni, Lauren D; Perry, Carole C; Kaplan, David L

    2010-10-26

    The biomimetic design of silk/silica fusion proteins was carried out, combining the self assembling domains of spider dragline silk (Nephila clavipes) and silaffin derived R5 peptide of Cylindrotheca fusiformis that is responsible for silica mineralization. Genetic engineering was used to generate the protein-based biomaterials incorporating the physical properties of both components. With genetic control over the nanodomain sizes and chemistry, as well as modification of synthetic conditions for silica formation, controlled mineralized silk films with different silica morphologies and distributions were successfully generated; generating 3D porous networks, clustered silica nanoparticles (SNPs), or single SNPs. Silk serves as the organic scaffolding to control the material stability and multiprocessing makes silk/silica biomaterials suitable for different tissue regenerative applications. The influence of these new silk-silica composite systems on osteogenesis was evaluated with human mesenchymal stem cells (hMSCs) subjected to osteogenic differentiation. hMSCs adhered, proliferated, and differentiated towards osteogenic lineages on the silk/silica films. The presence of the silica in the silk films influenced osteogenic gene expression, with the upregulation of alkaline phosphatase (ALP), bone sialoprotein (BSP), and collagen type 1 (Col 1) markers. Evidence for early bone formation as calcium deposits was observed on silk films with silica. These results indicate the potential utility of these new silk/silica systems towards bone regeneration. PMID:20976116

  11. Kartogenin induces cartilage-like tissue formation in tendon–bone junction

    Science.gov (United States)

    Zhang, Jianying; Wang, James H-C

    2014-01-01

    Tendon–bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs. PMID:25419468

  12. Kartogenin induces cartilage-like tissue formation in tendon-bone junction

    Institute of Scientific and Technical Information of China (English)

    Jianying Zhang; James H-C Wang

    2014-01-01

    Tendon-bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs.

  13. Kartogenin induces cartilage-like tissue formation in tendon-bone junction.

    Science.gov (United States)

    Zhang, Jianying; Wang, James H-C

    2014-01-01

    Tendon-bone junctions (TBJs) are frequently injured, especially in athletic settings. Healing of TBJ injuries is slow and is often repaired with scar tissue formation that compromises normal function. This study explored the feasibility of using kartogenin (KGN), a biocompound, to enhance the healing of injured TBJs. We first determined the effects of KGN on the proliferation and chondrogenic differentiation of rabbit bone marrow stromal cells (BMSCs) and patellar tendon stem/progenitor cells (PTSCs) in vitro. KGN enhanced cell proliferation in both cell types in a concentration-dependent manner and induced chondrogenic differentiation of stem cells, as demonstrated by high expression levels of chondrogenic markers aggrecan, collagen II and Sox-9. Besides, KGN induced the formation of cartilage-like tissues in cell cultures, as observed through the staining of abundant proteoglycans, collagen II and osteocalcin. When injected into intact rat patellar tendons in vivo, KGN induced cartilage-like tissue formation in the injected area. Similarly, when KGN was injected into experimentally injured rat Achilles TBJs, wound healing in the TBJs was enhanced, as evidenced by the formation of extensive cartilage-like tissues. These results suggest that KGN may be used as an effective cell-free clinical therapy to enhance the healing of injured TBJs. PMID:25419468

  14. Development of a bone tissue-engineered construct to enhance new bone formation in revision total hip replacement

    OpenAIRE

    García Gareta, E.

    2012-01-01

    The main issue associated with revision total hip replacements (rTHRs) is how to generate new bone and restore bone stock for fixation of the revision stem. Bone tissue engineering (BTE) seeks the generation of constructs ex vivo in order to replace damaged or lost bone. The aim of this thesis was to develop a bone tissue-engineered construct with a calcium-phosphate (CaP) coated porous metal scaffold seeded throughout its structure with mesenchymal stem cells (MSCs) in order to enhance new b...

  15. EFFECTS OF XW630 ON BONE FORMATION IN OVARIECTOMIZED RATS AND IN HUMAN OSTEOBLAST-LIKE CELLS

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective. To study the effects of XW630 on bone formation in overiectomized(OVX) rats and in human osteoblast-like cell line TE85.Method. Bone histomorphometric analysis was performed with undecalcified bone sections and tetracycline intraperitoneally labeling.Results. Compared with that of OVX rats, the static data of trabecular bone volume(TBV)/ total tissue volume(TTV), TBV/sponge bone volume(SBV) and mean trabecular plate density (MTPD) were enhanced while mean trabecular plate spacing(MTPS) decreased after treated with XW630 for 13w. The dynamic data of single-labeled surface [Sfract(s)], double-labeled surface[Sfract(d)],Sfract(d+1/2s),trabecular osteoid surface(TOS), and bone formation rate in tissue level (Svf) were increased and osteoid maturation period (OMP) shortened in XW630 group. In osteoblast-like cells, both 3H-thymidine incorporation and cell count increased after treated with XW630 for 48. Treated with XW630 for 12~18h,inducible nitric oxide synthase(iNOS) activity and cGMP content increased in time-dependent manners.Conclusions. XW630 enhanced bone activation frequency and increased trabecular connectivity, stability, and strength. The cellular mechanism related to effects of XW630 on bone formation in ovariectomized rats.

  16. Radiation-blocking shields to localize periarticular radiation precisely for prevention of heterotopic bone formation around uncemented total hip arthroplasties

    International Nuclear Information System (INIS)

    Sixteen patients (18 hips) were treated with localized radiation therapy limited to periarticular regions surrounding the femoral neck by shielding the prosthesis and the adjacent regions to prevent heterotopic bone formation around the uncemented prosthesis. All hips received 1500 rads. Eight of these hips were irradiated after excising severe heterotopic bone, five because they developed extensive heterotopic ossification in the opposite hip, and five others because they were considered to be at high risk for developing heterotopic ossification. Only two of the 18 hips developed a small amount of heterotopic bone after localized periarticular radiation. All wounds healed primarily. No progressive radiolucencies developed at the bone-prosthesis interface. There was only one trochanteric nonunion of six trochanteric osteotomies. Localized periarticular radiation therapy with precision shielding of the prosthetic components and adjacent skeletal structures is an effective means to prevent heterotopic bone formation around cementless total hip arthroplasties. It also has the advantage of not adversely affecting the healing of the trochanteric osteotomy

  17. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase

    Science.gov (United States)

    Cox, Thomas R.; Rumney, Robin M.H.; Schoof, Erwin M.; Perryman, Lara; Høye, Anette M.; Agrawal, Ankita; Bird, Demelza; Latif, Norain Ab; Forrest, Hamish; Evans, Holly R.; Huggins, Iain D; Lang, Georgina; Linding, Rune

    2016-01-01

    Tumour metastasis is a complex process involving reciprocal interplay between cancer cells and host stroma at both primary and secondary sites, and is strongly influenced by microenvironmental factors such as hypoxia1. Tumour-secreted proteins play a crucial role in these interactions2–5 and present strategic therapeutic potential. Metastasis of breast cancer to the bone affects approximately 85% of patients with advanced disease and renders them largely untreatable6. Specifically, osteolytic bone lesions, where bone is destroyed, lead to debilitating skeletal complications and increased patient morbidity and mortality6,7. The molecular interactions governing the early events of osteolytic lesion formation are currently unclear. Here we show hypoxia to be specifically associated with bone relapse in ER-negative breast cancer patients. Global quantitative analysis of the hypoxic secretome identified Lysyl Oxidase (LOX) as significantly associated with bone-tropism and relapse. High expression of LOX in primary breast tumours or systemic delivery of LOX leads to osteolytic lesion formation whereas silencing or inhibition of LOX activity abrogates tumour-driven osteolytic lesion formation. We identify LOX as a novel regulator of NFATc1-driven osteoclastogenesis, independent of RANK Ligand, which disrupts normal bone homeostasis leading to the formation of focal pre-metastatic lesions. We show that these lesions subsequently provide a platform for circulating tumour cells to colonise and form bone metastases. Our study identifies a novel mechanism of regulation of bone homeostasis and metastasis, opening up opportunities for novel therapeutic intervention with important clinical implications. PMID:26017313

  18. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss.

    Science.gov (United States)

    Raghu Nadhanan, Rethi; Abimosleh, Suzanne M; Su, Yu-Wen; Scherer, Michaela A; Howarth, Gordon S; Xian, Cory J

    2012-06-01

    Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day(-1)·rat(-1)) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H(2)O + Sal, H(2)O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H(2)O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFα, osteoclast marker receptor activator of nuclear factor-κB, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss. PMID:22436700

  19. Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization.

    Science.gov (United States)

    Azuma, Kotaro; Shiba, Sachiko; Hasegawa, Tomoka; Ikeda, Kazuhiro; Urano, Tomohiko; Horie-Inoue, Kuniko; Ouchi, Yasuyoshi; Amizuka, Norio; Inoue, Satoshi

    2015-07-01

    Vitamin K is a fat-soluble vitamin that is necessary for blood coagulation. In addition, it has bone-protective effects. Vitamin K functions as a cofactor of γ-glutamyl carboxylase (GGCX), which activates its substrates by carboxylation. These substrates are found throughout the body and examples include hepatic blood coagulation factors. Furthermore, vitamin K functions as a ligand of the nuclear receptor known as steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR). We have previously reported on the bone-protective role of SXR/PXR signaling by demonstrating that systemic Pxr-knockout mice displayed osteopenia. Because systemic Ggcx-knockout mice die shortly after birth from severe hemorrhage, the GGCX-mediated effect of vitamin K on bone metabolism has been difficult to evaluate. In this work, we utilized Ggcx-floxed mice to generate osteoblast-specific GGCX-deficient (Ggcx(Δobl/Δobl)) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of Ggcx(Δobl/Δobl) mice was significantly higher than that of control Col1-Cre (Ggcx(+/+)) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in Ggcx(Δobl/Δobl) mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in Ggcx(Δobl/Δobl) mice. The mechanical properties of bones from Ggcx(Δobl/Δobl) mice tended to be stronger than those from control Ggcx(+/+) mice. These results suggest that GGCX in osteoblasts functions to prevent abnormal mineralization in bone formation, although this function may not be a prerequisite for the bone-protective effect of vitamin K. PMID:25600070

  20. Free Radicals Formation of Irradiated Lyophilized Can-Cellous Human and Bovine Bone

    International Nuclear Information System (INIS)

    Radiation sterilization of lyophilized human and bovine bone as allograft and xenograft have been produced and used in orthopaedic practice in Indonesia routinely. It is well known from radio biologic studies that one of the most pronounce effects of ionizing radiation on biologic species produced the free radicals that influence the physico-chemical as well as the mechanical properties of irradiated bone. The aim of our study is to investigate the free radicals formation of irradiated lyophilized cancellous triple A bone (Autolyzed Antigen-Extracted Allograft) produced by Batan Research Tissue Bank in Jakarta. The cancellous triple A were prepared according to AATB (American Association of Tissue Bank) method. Gamma Irradiations was done at doses of 10, 20 and 30 kGy with a dose rate of 7,5 kGy/h at room temperature (30oC± 2oC). Measurements of free radicals was done at 24oC ±1oC within 30 minutes after irradiational and measurement were continued up to 9 months of storage using a JES-REIX ESR Spectrophotometer (JEOL) with Mn exp. ++ standard. Parameters measured, were the effects of mechanical grinding, water immersion and irradiation dose on free radicals formation in the bone. Results show that the signal area of ESR spectra from irradiated bovine bone of 30 kGy was higher than those of human bone I.e. 1,4 x 10 exp. 7 dan 6,4 x 10 exp. 6 Au (arbitrary unit)/g samples respectively. The signal of ESR spectra increased linearly with increasing dose in the range of 10-30 kGy and it will reduce about 30% caused by water immersion. The ESR signal reduced sharply after 2 days and gradually decreased up to 14 days and then became constant up to 9 months of storage at room temperature. A certain method of crushing can produce free radicals. Key Words: free radical, irradiation, allograft, xenograft, mechanical-grinding

  1. The effects of 3D bioactive glass scaffolds and BMP-2 on bone formation in rat femoral critical size defects and adjacent bones

    International Nuclear Information System (INIS)

    Reconstruction of critical size defects in the load-bearing area has long been a challenge in orthopaedics. In the past, we have demonstrated the feasibility of using a biodegradable load-sharing scaffold fabricated from poly(propylene fumarate)/tricalcium phosphate (PPF/TCP) loaded with bone morphogenetic protein-2 (BMP-2) to successfully induce healing in those defects. However, there is limited osteoconduction observed with the PPF/TCP scaffold itself. For this reason, 13-93 bioactive glass scaffolds with local BMP-2 delivery were investigated in this study for inducing segmental defect repairs in a load-bearing region. Furthermore, a recent review on BMP-2 revealed greater risks in radiculitis, ectopic bone formation, osteolysis and poor global outcome in association with the use of BMP-2 for spinal fusion. We also evaluated the potential side effects of locally delivered BMP-2 on the structures of adjacent bones. Therefore, cylindrical 13-93 glass scaffolds were fabricated by indirect selective laser sintering with side holes on the cylinder filled with dicalcium phosphate dehydrate as a BMP-2 carrier. The scaffolds were implanted into critical size defects created in rat femurs with and without 10 μg of BMP-2. The x-ray and micro-CT results showed that a bridging callus was found as soon as three weeks and progressed gradually in the BMP group while minimal bone formation was observed in the control group. Degradation of the scaffolds was noted in both groups. Stiffness, peak load and energy to break of the BMP group were all higher than the control group. There was no statistical difference in bone mineral density, bone area and bone mineral content in the tibiae and contralateral femurs of the control and BMP groups. In conclusion, a 13-93 bioactive glass scaffold with local BMP-2 delivery has been demonstrated for its potential application in treating large bone defects. (paper)

  2. Metastasis Suppressor Genes

    OpenAIRE

    Yan, Jinchun; Yang, Qin; Huang, Qihong

    2013-01-01

    Metastasis is a major cause of cancer mortality. Metastasis is a complex process that requires the regulation of both metastasis-promoting and metastasis suppressor genes. The discovery of metastasis suppressor genes contributes significantly to our understanding of metastasis mechanisms and provides prognostic markers and therapeutic targets in clinical cancer management. In this review, we summarize the methods that have been used to identify metastasis suppressors and the potential clinica...

  3. The frequency of osteolytic bone metastasis is determined by conditions of the soil, not the number of seeds; evidence from in vivo models of breast and prostate cancer

    OpenAIRE

    Wang, N; Reeves, K.J.; Brown, H.K.; Fowles, A.C.M.; Docherty, F.E.; Ottewell, P.D.; Croucher, P.I.; Holen, I; Eaton, C.L.

    2015-01-01

    Background While both preclinical and clinical studies suggest that the frequency of growing skeletal metastases is elevated in individuals with higher bone turnover, it is unclear whether this is a result of increased numbers of tumour cells arriving in active sites or of higher numbers of tumour cells being induced to divide by the bone micro-environment. Here we have investigated how the differences in bone turnover affect seeding of tumour cells and/or development of overt osteolytic b...

  4. Human Osteoblast Differentiation and Bone Formation: Growth Factors, Hormones and Regulatory Networks

    OpenAIRE

    Eijken, Marco

    2007-01-01

    textabstractOsteoporosis is the most common bone disease and is characterized by low bone mass, micro architectural deterioration and decreased bone quality resulting in increased risk of fractures. Osteoblasts, the bone forming cells, play a crucial role in the regulation of bone mass and bone quality. Osteoblasts are of mesenchymal origin and undergo a complex differentiation process regulated by many endocrine and autocrine factors. In order to develop novel bone anabolic drugs, more knowl...

  5. 18F]fluoride PET indicates reduced bone formation in severe glucocorticoid-induced osteoporosis

    International Nuclear Information System (INIS)

    A 61-year-old female patient presenting with mixed connective tissue disease (Sharp syndrome), underwent a long-term high dose glucocordicoid treatment because of multiple organ manifestations. Under steroid therapy she developed severe osteoporosis resulting in multiple fractures. A dynamic [18F]fluoride PET study in this patient revealed reduced fluoride influx in non-fractured vertebrae. This finding corresponds to pathogenetic concepts which propose an inhibition of bone formation as major cause of glucocorticoid-induced osteoporosis. In the light of the presented case it seems to be promising to evaluate the diagnostic benefit of [18F]fluoride PET in osteoporosis. (orig.)

  6. X-ray studies on the change in bone formation in fractures following laser treatment

    International Nuclear Information System (INIS)

    An important problem, associated with the X-ray studies of the changes in bone formation in fractures following laser treatment, is dicussed. Results are reported on laser therapy of 30 patients with fractures of the radius in loco typico and compared with a control group of 30 patients, who were treated with ordinary (laboratory) lamp with a side light beam. It was found that laser biostimulation activated callus development in fractures and speeded their complete consolidation. In laser-treated patients osteoporosis occured more seldom and had predominantly limited and patchy appearance, while Sudek's osteoporosis was seen mainly in the control group

  7. Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

    Directory of Open Access Journals (Sweden)

    Jodi A. Carlson Scholz

    2012-12-01

    Full Text Available Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH. Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture.

  8. Complexation and sequestration of BMP-2 from an ECM mimetic hyaluronan gel for improved bone formation.

    Directory of Open Access Journals (Sweden)

    Marta Kisiel

    Full Text Available Bone morphogenetic protein-2 (BMP-2 is considered a promising adjuvant for the treatment of skeletal non-union and spinal fusion. However, BMP-2 delivery in a conventional collagen scaffold necessitates a high dose to achieve an efficacious outcome. To lower its effective dose, we precomplexed BMP-2 with the glycosaminoglycans (GAGs dermatan sulfate (DS or heparin (HP, prior to loading it into a hyaluronic acid (HA hydrogel. In vitro release studies showed that BMP-2 precomplexed with DS or HP had a prolonged delivery compared to without GAG. BMP-2-DS complexes achieved a slightly faster release in the first 24 h than HP; however, both delivered BMP-2 for an equal duration. Analysis of the kinetic interaction between BMP-2 and DS or HP showed that HP had approximately 10 times higher affinity for BMP-2 than DS, yet it equally stabilized the protein, as determined by alkaline phosphatase activity. Ectopic bone formation assays at subcutaneous sites in rats demonstrated that HA hydrogel-delivered BMP-2 precomplexed with GAG induced twice the volume of bone compared with BMP-2 delivered uncomplexed to GAG.

  9. Local Controlled Release of Polyphenol Conjugated with Gelatin Facilitates Bone Formation

    Directory of Open Access Journals (Sweden)

    Yoshitomo Honda

    2015-06-01

    Full Text Available Catechins are extensively used in health care treatments. Nevertheless, there is scarce information about the feasibility of local administration with polyphenols for bone regeneration therapy, possibly due to lack of effective delivery systems. Here we demonstrated that the epigallocatechin-3-gallate-conjugated gelatin (EGCG/Gel prepared by an aqueous chemical synthesis using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl-4-morpholinium chloride (DMT-MM gradually disintegrated with time and facilitated bone formation in a critical size defect of a mouse calvaria. Conjugation of EGCG with the Gel generated cross-linking between the two molecules, thereby leading to a retardation of the degradation of the EGCG/Gel and to a delayed release of EGCG. The prepared EGCG/Gels represented significant osteogenic capability compared with that of the uncross-linked Gel and the cross-linked Gel with uncombined-EGCG. In vitro experiments disclosed that the EGCG/Gel induced osteoblastogenesis of a mouse mesenchymal stem cell line (D1 cells within 14 days. Using fluorescently-labeled EGCG/Gel, we found that the fraction of EGCG/Gel adsorbed onto the cell membrane of the D1 cells possibly via a Gel-cell interaction. The interaction might confer the long-term effects of EGCG on the cells, resulting in a potent osteogenic capability of the EGCG/Gel in vivo. These results should provide insight into local controlled release of polyphenols for bone therapy.

  10. 肺癌骨转移同期放化疗临床疗效分析%Prospective clinical study of chemotherapy combined with radiotherapy in treatment of lung cancer patients with bone metastasis

    Institute of Scientific and Technical Information of China (English)

    韩萍

    2011-01-01

    目的 探讨同期放、化疗治疗肺癌骨转移临床疗效.方法 分析我院2004年1月~2008年1月收治的63例肺癌骨转移患者,A组同期放、化疗+帕米膦酸二钠;B组序贯放、化疗+帕米膦酸二钠.结果 A、B组治疗疼痛缓解率86.7%、39.4%,差异有统计学意义A、B组治疗局部病灶的总有效率60.0%、33.3%,差异有统计学意义;两个组2年生存率的差异有统计学意义;A、B组治疗前后生存质量比较及A、B组之间生存质量比较无统计学意义.结论 肺癌骨转移后采取同期放、化疗为主的综合治疗可明显减轻症状,延长患者生存时间.%Objective To research the clinical efficacy of simultaneous radiotherapy and chemotherapy for lung cancer with bone metastasis. Methods Analyzing 63 cases of lung cancer with bone metastasis in our hospital from January 2004 to January 2008. Group A : simultaneous radiotherapy and chemotherapy + pamidronate disodium; Group B : sequential radiotherapy and chemotherapy + pamidronate disodium. Results The pain relief rate was 86. 7% in group A and 39. 4% in group B. There was a statistical difference between group A and group B. The total effective rate of partial focus was 60. 0% in group A and 33. 3% in group B. There was a statistical difference hetween group A and group B ; There was a statistical difference between group A and group B;In the 2-year survival rate , There was no a statistical difference between group A and group B in the quality of life before and after the treatment. Conclusion The comprehensive treatment of simultaneous radiotherapy and chemotherapy for lung cancer with bone metastasis can noticeably alleviate the symptoms, extend the survival time of patients.

  11. A comparison of osteoclast-rich and osteoclast-poor osteopetrosis in adult mice sheds light on the role of the osteoclast in coupling bone resorption and bone formation

    DEFF Research Database (Denmark)

    Thudium, Christian S; Moscatelli, Ilana; Flores, Carmen; Thomsen, Jesper Skovhus; Brüel, Annemarie; Gudmann, Natasja Stæhr; Hauge, Ellen Margrethe; Karsdal, Morten A; Richter, Johan; Henriksen, Kim

    2014-01-01

    formation rate (54 %) in trabecular bone, while RANK KO recipients showed only minor trends compared to control recipients. We here show that maintaining non-resorbing osteoclasts, as opposed to reducing the osteoclasts, leads to increased bone formation, bone volume, and ultimately higher bone strength in......Osteopetrosis due to lack of acid secretion by osteoclasts is characterized by abolished bone resorption, increased osteoclast numbers, but normal or even increased bone formation. In contrast, osteoclast-poor osteopetrosis appears to have less osteoblasts and reduced bone formation, indicating......-poor adult osteopetrosis model. We used fetal liver HSCs from (1) oc/oc mice, (2) RANK KO mice, and (3) compared these to wt control cells. TRAP5b activity, a marker of osteoclast number and size, was increased in the oc/oc recipients, while a significant reduction was seen in the RANK KO recipients. In...

  12. The role of 1,25-dihydroxyvitamin D in the inhibition of bone formation induced by skeletal unloading

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Wronski, T. J.; GLOBUS. R.; Levens, M. J.; Morey-Holton, E.

    1983-01-01

    Skeletal unloading results in osteopenia. To examine the involvement of vitamin D in this process, the rear limbs of growing rats were unloaded and alterations in bone calcium and bone histology were related to changes in serum calcium (Ca), inorganic phosphorus (P sub i), 25-hydroxyvitamin D (25-OH-D), 24,25-dihydroxyvitamin D (24,25(OH)2D and 1,25-dihydroxyvitamin D (1,25(OH)2D. Acute skeletal unloading induced a transitory inhibition of Ca accumulation in unloaded bones. This was accompanied by a transitory rise in serum Ca, a 21% decrease in longitudinal bone growth (P 0.01), a 32% decrease in bone surface lined with osteoblasts (P .05), no change in bone surface lined with osteoclasts and a decrease in circulating (1,25(OH)2D. No significant changes in the serum concentrations of P sub i, 25-OH-D or 24,25(OH)2D were observed. After 2 weeks of unloading, bone Ca stabilized at approximately 70% of control and serum Ca and 1,25(OH)2D returned to control values. Maintenance of a constant serum 1,25(OH)2D concentration by chronic infusion of 1,25(OH)2D (Alza osmotic minipump) throughout the study period did not prevent the bone changes induced by acute unloading. These results suggest that acute skeletal unloading in the growing rat produces a transitory inhibition of bone formation which in turn produces a transitory hypercalcemia.

  13. NADH-Cytochrome b5 Reductase 3 Promotes Colonization and Metastasis Formation and Is a Prognostic Marker of Disease-Free and Overall Survival in Estrogen Receptor-Negative Breast Cancer

    DEFF Research Database (Denmark)

    Lund, Rikke R; Leth-Larsen, Rikke; Caterino, Tina Di;

    2015-01-01

    (NRH2). The altered expression levels were validated at the protein and transcriptional levels, and analysis of breast cancer biopsies from two cohorts of patients demonstrated a significant correlation between high CYB5R3 expression and poor disease-free and overall survival in patients with estrogen......Metastasis is the main cause of cancer-related deaths and remains the most significant challenge to management of the disease. Metastases are established through a complex multistep process involving intracellular signaling pathways. To gain insight to proteins central to specific steps in...... metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using stable isotopic labeling by amino acids in cell culture and subcellular fractionation, the nuclear, cytosol, and mitochondria proteomes...

  14. Influence of B-lymphocytes from various organs on hemopoietic colony formation in the spleen by bone marrow cells

    International Nuclear Information System (INIS)

    The influence of B-lymphocytes from various sources on splenic colony formation was studied in the syngeneic system. Splenic, but not bone marrow and lymph node B-cells inhibited colony formation by combination of Sc-1- and Sc-1+ cells. All effects of Ig+ cells were abolished by treatment of cells with rabbit anti-MBLA serum. Thus, B-cells of various origin can either enhance or inhibit colony formation. The enhancing of inhibitory effect after B (MBLA+)-cells elimination from suspension of bone marrow and lymph node (but not spleen) Ig+-cells resulted from the activity of B-contrasuppressors

  15. Association between in vivo bone formation and ex vivo migratory capacity of human bone marrow stromal cells

    DEFF Research Database (Denmark)

    Andersen, Rikke K; Zaher, Walid; Larsen, Kenneth H;

    2015-01-01

    by bioluminescence imaging (BLI). In order to identify the molecular phenotype associated with enhanced migration, we carried out comparative DNA microarray analysis of gene expression of hBMSC-derived high bone forming (HBF) clones versus low bone forming (LBF) clones. RESULTS: HBF clones were exhibited higher ex...

  16. Ectopic bone formation using an injectable biphasic calcium phosphate/Si-HPMC hydrogel composite loaded with undifferentiated bone marrow stromal cells.

    Science.gov (United States)

    Trojani, Christophe; Boukhechba, Florian; Scimeca, Jean-Claude; Vandenbos, Fanny; Michiels, Jean-François; Daculsi, Guy; Boileau, Pascal; Weiss, Pierre; Carle, Georges F; Rochet, Nathalie

    2006-06-01

    We have used a new synthetic injectable composite constituted of hydroxyapatite/tricalcium phosphate (HA/TCP) particles in suspension in a self-hardening Si-hydroxypropylmethylcellulose (HPMC) hydrogel. The aim of this study was to evaluate in vivo the biocompatibility and the new bone formation efficacy of this scaffold loaded with undifferentiated bone marrow stromal cells (BMSCs). This biomaterial was mixed extemporaneously with BMSCs prepared from C57BL/6 mice, injected in subcutaneous and intramuscular sites and retrieved 4 and 8 weeks after implantation. Dissection of the implants revealed a hard consistency and the absence of a fibrous capsule reflecting a good integration into the host tissues. Histological analysis showed mineralized woven bone in the granule inter-space with numerous active osteoclasts attached to the particles as assessed by the presence of multinucleated cells positively stained for TRAP activity and for the a3 subunit of the V-ATPase. Small vessels were homogenously distributed in the whole implants. Similar results were obtained in SC and IM sites and no bone formation was observed in the control groups when cell-free and particle-free transplants were injected. These results indicate that this injectable biphasic calcium phosphate-hydrogel composite mixed with undifferentiated BMSCs is a new promising osteoinductive bone substitute. It also provides with an original in vivo model of osteoclast differentiation and function. PMID:16510180

  17. cAMP/PKA signaling inhibits osteogenic differentiation and bone formation in rodent models.

    Science.gov (United States)

    Siddappa, Ramakrishnaiah; Mulder, Winfried; Steeghs, Ilse; van de Klundert, Christine; Fernandes, Hugo; Liu, Jun; Arends, Roel; van Blitterswijk, Clemens; de Boer, Jan

    2009-08-01

    We previously demonstrated that cAMP-mediated protein kinase A (PKA) activation induces in vitro osteogenesis and in vivo bone formation by human mesenchymal stem cells (hMSCs). To analyze the species-specific response of this phenomenon and to translate our findings into a clinical trial, suitable animal models and cell lines are desirable. In this report, we assessed whether PKA plays a similar proosteogenic role played by two commonly used PKA activators-N6,2'-O-dibutyryl-cAMP (db-cAMP) and 8-bromo cAMP (8b-cAMP)-in a number of model systems. To this end, we treated MC3T3-E1 cells, mouse calvarial osteoblasts, mouse MSCs, and rat MSCs with cAMP. We demonstrate that cAMP inhibits osteogenesis in rodent cell types, evidenced by inhibition of osteogenic markers such as alkaline phosphatase (ALP), osteocalcin (BGLAP), and collagen type 1 (COL1A1). In support of this, ex vivo-cultured mouse calvaria exposed to db-cAMP showed a reduction in bone volume. Interestingly, cAMP even stimulated adipogenic differentiation in rat MSCs. Taken together, our data demonstrate that cAMP inhibits osteogenesis in vitro and bone formation ex vivo in rodent models in contrast to our earlier findings in hMSCs. The species discrepancy in response to various osteogenic signals is a critical need to be tested in clinically relevant models to translate the fundamental findings in lower species level to clinical applications. PMID:19231969

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

    Science.gov (United States)

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

    2016-01-01

    Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)-expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)-JAK-STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development. PMID:27507649

  19. Contemporary approaches for imaging skeletal metastasis

    Institute of Scientific and Technical Information of China (English)

    David Ulmert; Lilja Solnes; Daniel LJ Thorek

    2015-01-01

    The skeleton is a common site of cancer metastasis. Notably high incidences of bone lesions are found for breast, prostate, and renal carcinoma. Malignant bone tumors result in significant patient morbidity. Identification of these lesions is a critical step to accurately stratify patients, guide treatment course, monitor disease progression, and evaluate response to therapy. Diagnosis of cancer in the skeleton typically relies on indirect bone-targeted radiotracer uptake at sites of active bone remodeling. In this manuscript, we discuss established and emerging tools and techniques for detection of bone lesions, quantification of skeletal tumor burden, and current clinical challenges.

  20. The remodeling pattern of human mandibular alveolar bone during prenatal formation from 19 to 270mm CRL.

    Science.gov (United States)

    Radlanski, Ralf J; Renz, Herbert; Tsengelsaikhan, Nyamdorj; Schuster, Felix; Zimmermann, Camilla A

    2016-05-01

    The underlying mechanisms of human bone morphogenesis leading to a topologically specific shape remain unknown, despite increasing knowledge of the basic molecular aspects of bone formation and its regulation. The formation of the alveolar bone, which houses the dental primordia, and later the dental roots, may serve as a model to approach general questions of bone formation. Twenty-five heads of human embryos and fetuses (Radlanski-Collection, Berlin) ranging from 19mm to 270mm (crown-rump-length) CRL were prepared as histological serial sections. For each stage, virtual 3D-reconstructions were made in order to study the morphogenesis of the mandibular molar primordia with their surrounding bone. Special focus was given to recording the bone-remodeling pattern, as diagnosed from the histological sections. In early stages (19-31mm CRL) developing bone was characterized by appositional only. At 41, in the canine region, mm CRL bony extensions were found forming on the bottom of the trough. Besides general apposition, regions with resting surfaces were also found. At a fetal size of 53mm CRL, septa have developed and led to a compartment for canine development. Furthermore, one shared compartment for the incisor primordia and another shared compartment for the molars also developed. Moreover, the inner surfaces of the dental crypts showed resorption of bone. From this stage on, a general pattern became established such that the compartmentalizing ridges and septa between all of the dental primordia and the brims of the crypts were noted, and were due to appositional growth of bone, while the crypts enlarged on their inner surfaces by resorption. By 160mm CRL, the dental primordia were larger, and all of the bony septa had become reduced in size. The primordia for the permanent teeth became visible at 225mm CRL and shared the crypts of their corresponding deciduous primordia. PMID:26921449

  1. Stereotactic body radiotherapy for solitary spine metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sun Young [Dept. of Radiation Oncology, Sun Medical Center, Daejeon (Korea, Republic of); Chun, Mison [Dept. of Radiation Oncology, Ajou University School of Medicine, Suwon (Korea, Republic of); Lee, Mi Jo [Dept. of Radiation Oncology, Eulji Universtiy School of Medicine, Daejeon (Korea, Republic of)

    2013-12-15

    A clear consensus has not been established regarding the best treatment for solitary bone metastasis. Here, we reviewed the medical records of patients with a controlled primary malignancy who had only solitary spine metastasis without metastasis to the extraspinal bone or viscera and underwent treatment between April 2007 and December 2012 with stereotactic body radiosurgery using CyberKnife, with a total dose of 24 Gy in three to four fractions. During that time, there were only four cases. This was effective in each case, and all the four patients had no local failure and remained alive at a median follow-up of 68 months (range, 64 to 80 months). Although our experience is limited, this study suggests that stereotactic body radiotherapy could be a feasible, safe, effective, and noninvasive alternative treatment for solitary spine metastasis in patients who are medically inoperable or unsuitable for surgery.

  2. A primary phosphorus-deficient skeletal phenotype in juvenile Atlantic salmon Salmo salar: the uncoupling of bone formation and mineralization.

    Science.gov (United States)

    Witten, P E; Owen, M A G; Fontanillas, R; Soenens, M; McGurk, C; Obach, A

    2016-02-01

    To understand the effect of low dietary phosphorus (P) intake on the vertebral column of Atlantic salmon Salmo salar, a primary P deficiency was induced in post-smolts. The dietary P provision was reduced by 50% for a period of 10 weeks under controlled conditions. The animal's skeleton was subsequently analysed by radiology, histological examination, histochemical detection of minerals in bones and scales and chemical mineral analysis. This is the first account of how a primary P deficiency affects the skeleton in S. salar at the cellular and at the micro-anatomical level. Animals that received the P-deficient diet displayed known signs of P deficiency including reduced growth and soft, pliable opercula. Bone and scale mineral content decreased by c. 50%. On radiographs, vertebral bodies appear small, undersized and with enlarged intervertebral spaces. Contrary to the X-ray-based diagnosis, the histological examination revealed that vertebral bodies had a regular size and regular internal bone structures; intervertebral spaces were not enlarged. Bone matrix formation was continuous and uninterrupted, albeit without traces of mineralization. Likewise, scale growth continues with regular annuli formation, but new scale matrix remains without minerals. The 10 week long experiment generated a homogeneous osteomalacia of vertebral bodies without apparent induction of skeletal malformations. The experiment shows that bone formation and bone mineralization are, to a large degree, independent processes in the fish examined. Therefore, a deficit in mineralization must not be the only cause of the alterations of the vertebral bone structure observed in farmed S. salar. It is discussed how the observed uncoupling of bone formation and mineralization helps to better diagnose, understand and prevent P deficiency-related malformations in farmed S. salar. PMID:26707938

  3. The p38α MAPK function in osteoprecursors is required for bone formation and bone homeostasis in adult mice.

    Directory of Open Access Journals (Sweden)

    Edgardo Rodríguez-Carballo

    Full Text Available p38 MAPK activity plays an important role in several steps of the osteoblast lineage progression through activation of osteoblast-specific transcription factors and it is also essential for the acquisition of the osteoblast phenotype in early development. Although reports indicate p38 signalling plays a role in early skeletal development, its specific contributions to adult bone remodelling are still to be clarified.We evaluated osteoblast-specific deletion of p38α to determine its significance in early skeletogenesis, as well as for bone homeostasis in adult skeleton. Early p38α deletion resulted in defective intramembranous and endochondral ossification in both calvaria and long bones. Mutant mice showed reduction of trabecular bone volume in distal femurs, associated with low trabecular thickness. In addition, knockout mice also displayed decreased femoral cortical bone volume and thickness. Deletion of p38α did not affect osteoclast function. Yet it impaired osteoblastogenesis and osteoblast maturation and activity through decreased expression of osteoblast-specific transcription factors and their targets. Furthermore, the inducible Cre system allowed us to control the onset of p38α disruption after birth by removal of doxycycline. Deletion of p38α at three or eight weeks postnatally led to significantly lower trabecular and cortical bone volume after 6 or 12 months.Our data demonstrates that, in addition to early skeletogenesis, p38α is essential for osteoblasts to maintain their function in mineralized adult bone, as bone anabolism should be sustained throughout life. Moreover, our data also emphasizes that clinical development of p38 inhibitors should take into account their potential bone effects.

  4. Efficacy of a small cell-binding peptide coated hydroxyapatite substitute on bone formation and implant fixation in sheep

    DEFF Research Database (Denmark)

    Ding, Ming; Andreasen, Christina Møller; Dencker, Mads L.;

    2015-01-01

    hydroxyapatite (ABM/P-15); hydroxyapatite + βtricalciumphosphate+ Poly-Lactic-Acid (HA/βTCP-PDLLA); or ABM/P-15+HA/βTCP-PDLLA. After nine weeks, bone-implant blocks were harvested and sectioned for micro-CT scanning, push-out test, and histomorphometry. Significant bone formation and implant fixation could...... implant were not significantly different among the four groups. The ABM/P-15 group had similar shear mechanical properties on implant fixation as the allograft group. Adding HA/βTCP-PDLLA to ABM/P-15 did not significantly change these parameters. This study revealed that ABM/P-15 had significantly bone...

  5. Conditional Deletion of BMP7 from the Limb Skeleton Does Not Affect Bone Formation or Fracture Repair

    OpenAIRE

    Tsuji, Kunikazu; Cox, Karen; Gamer, Laura; Graf, Daniel; Economides, Aris; Rosen, Vicki

    2010-01-01

    While the osteoinductive activity of recombinant bone morphogenetic protein 7 (BMP7) is well established, evaluation of the role of endogenous BMP7 in bone formation and fracture healing has been hampered by perinatal lethality in BMP7 knockout mice. Here we employ conditional deletion of BMP7 from the embryonic limb prior to the onset of skeletogenesis to create limb bones lacking BMP7. We find that the absence of locally produced BMP7 has no effect on postnatal limb growth, articular cartil...

  6. Effect of xenograft (ABBM) particle size on vital bone formation following maxillary sinus augmentation: a multicenter, randomized, controlled, clinical histomorphometric trial.

    Science.gov (United States)

    Testori, Tiziano; Wallace, Stephen S; Trisi, Paolo; Capelli, Matteo; Zuffetti, Francesco; Del Fabbro, Massimo

    2013-01-01

    The purpose of this study was a histomorphometric comparison of vital bone formation following maxillary sinus augmentation with two different particle sizes of anorganic bovine bone matrix (ABBM). Bilateral sinus floor augmentations were performed in 13 patients. Trephine bone cores were taken from the lateral window areas of 11 patients 6 to 8 months after augmentation for histologic and histomorphometric analysis. Bone samples from both the large and small particle size groups showed evidence of vital bone formation similar to that seen in previous studies, confirming the osteoconductivity of ABBM. Significant bone bridging was seen creating new trabeculae composed of the newly formed bone and residual ABBM particles. Histologic evaluation revealed the newly formed bone to be mostly woven bone with some remodeling to lamellar bone. Osteocytes were seen within the newly formed bone as well as osteoblast seams with recently formed osteoid. Isolated osteoclasts were observed on the ABBM surfaces. Vital bone formation (primary outcome measure) was more extensive in the large particle grafts compared with the small particle grafts (26.77% ± 9.63% vs 18.77% ± 4.74%, respectively). The histologic results reaffirm the osteoconductive ability of ABBM when used as the sole grafting material in maxillary sinus augmentation. The histomorphometric results at 6 to 8 months revealed a statistically significant increase (P = .02) in vital bone formation when the larger particle size was used. Additional studies should be performed to confirm these results. PMID:23820706

  7. Class I PI-3-Kinase Signaling Is Critical for Bone Formation Through Regulation of SMAD1 Activity in Osteoblasts.

    Science.gov (United States)

    Gámez, Beatriz; Rodríguez-Carballo, Edgardo; Graupera, Mariona; Rosa, José Luis; Ventura, Francesc

    2016-08-01

    Bone formation and homeostasis is carried out by osteoblasts, whose differentiation and activity are regulated by osteogenic signaling networks. A central mediator of these inputs is the lipid kinase phosphatidylinositol 3-kinase (PI3K). However, at present, there are no data on the specific role of distinct class IA PI3K isoforms in bone biology. Here, we performed osteoblast-specific deletion in mice to show that both p110α and p110β isoforms are required for survival and differentiation and function of osteoblasts and thereby control bone formation and postnatal homeostasis. Impaired osteogenesis arises from increased GSK3 activity and a depletion of SMAD1 protein levels in PI3K-deficient osteoblasts. Accordingly, pharmacological inhibition of GSK3 activity or ectopic expression of SMAD1 or SMAD5 normalizes bone morphogenetic protein (BMP) transduction and osteoblast differentiation. Together, these results identify the PI3K-GSK3-SMAD1 axis as a central node integrating multiple signaling networks that govern bone formation and homeostasis. © 2016 American Society for Bone and Mineral Research. PMID:26896753

  8. Contiguous spinal metastasis mimicking infectious spondylodiscitis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chul Min; Lee, Seung Hun [Dept. of Radiology, Hanyang University Hospital, Seoul (Korea, Republic of); Bae, Ji Yoon [Dept. of Pathology, National Police Hospital, Seoul (Korea, Republic of)

    2015-12-15

    Differential diagnosis between spinal metastasis and infectious spondylodiscitis is one of the occasional challenges in daily clinical practice. We encountered an unusual case of spinal metastasis in a 75-year-old female breast cancer patient that mimicked infectious spondylodiscitis. Magnetic resonance imaging (MRI) showed diffuse bone marrow infiltrations with paraspinal soft tissue infiltrative changes in 5 contiguous cervical vertebrae without significant compression fracture or cortical destruction. These MRI findings made it difficult to differentiate between spinal metastasis and infectious spondylodiscitis. Infectious spondylodiscitis such as tuberculous spondylodiscitis was regarded as the more appropriate diagnosis due to the continuous involvement of > 5 cervical vertebrae. The patient's clinical presentation also supported the presumptive diagnosis of infectious spondylodiscitis rather than spinal metastasis. Intravenous antibiotics were administered, but clinical symptoms worsened despite treatment. After pathologic confirmation by computed tomography-guided biopsy, we were able to confirm a final diagnosis of spinal metastasis.

  9. TEI-3313, a novel prostaglandin A1 derivative, prevents bone loss and enhances bone formation in immobilized male rats.

    Science.gov (United States)

    Ohta, T; Azuma, Y; Kanatani, H; Kiyoki, M; Koshihara, Y

    1995-10-01

    The effect of a novel prostaglandin A1 derivative, TEI-3313, with the chemical structure 5-[(Z,2E)-4,7-dihydroxy-2-heptenyridene]-4-hydroxy- 2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone, on bone mineral content was investigated. Seven-week-old Sprague-Dawley rats in which the right hindlimbs were immobilized by sciatic nerve dissection received 1, 10, 100 or 500 micrograms of TEI-3313/kg/day, i.p., for 6 weeks. Control animals were operated on but received vehicle only. Bone mineral content of the femur was measured by single-photon absorptiometry, and biochemical parameters were analyzed. Histomorphometric observations were performed on the proximal metaphysial sections of the tibiae. The administration of up to 500 micrograms/kg of TEI-3313 to rats had no effect on body weight or on serum calcium, inorganic phosphorus and 1 alpha,25 dihydroxy vitamin D3 levels. Immobilization decreased the ash content, calcium content and total bone mineral content of the femur compared with nonimmobilization (unoperated femur). With TEI-3313 administration, changes in these parameters in the immobilized femur were prevented almost to the levels of the nonimmobilized femur, in a dose-dependent manner. The enhancement of bone mineral content was remarkable in the midshaft of the femur. TEI-3313 enhanced ash and calcium content and total bone mineral content in nonimmobilized femurs. Microradiograms showed that TEI-3313, unlike pamidronate and 17 beta-estradiol, had little inhibitory effect on trabecular bone resorption in the proximal portion of the tibia. TEI-3313 not only prevented the bone loss induced by immobilization but also increased bone mass in the nonimmobilized femurs without affecting the levels of 1 alpha,25 dihydroxy vitamin D3.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7562584

  10. Utility of the dimercapto succinic acid pentavalent (99m Tc- DMSA V) in the diagnostic of secondary bone leisure at metastasis of diverse primary tumours. Preliminary study

    International Nuclear Information System (INIS)

    The more used method in the diagnosis of secondary bone lesions to become cancerous it is by means of having derived of phosphates like it is the 99mTc- MDP. The reason of acquiring searching with the radiopharmaceutical 99mTc- DMSA V is with the purpose to find other bone lesions that are not visualized with the gammagraphy with diphosphonate and therefore to increase the specificity of the study. (Author)

  11. Sternal metastasis as an initial presentation of renal cell carcinoma: a case report

    OpenAIRE

    Batista, Raquel Ribeiro; Marchiori, Edson; Takayassu, Tatiana Chinem; Cabral, Fernanda Caseira; Cabral, Rafael Ferracini; Zanetti, Gláucia

    2009-01-01

    Renal cell carcinoma accounts for 85% of all solid renal tumors in adults. Nearly one quarter of patients has distant metastasis at presentation while another 50% develop metastasis during follow-up. A small percentage of these are solitary metastasis. We report here a case of solitary bone sternal metastasis as an initial presentation of clear-cell renal cell carcinoma in a 56-year-old woman. The prognosis for patients with metastasized renal cell carcinoma is poor; treatment of metastasis i...

  12. The combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells.

    Science.gov (United States)

    Bolander, J; Ji, W; Geris, L; Bloemen, V; Chai, Y C; Schrooten, J; Luyten, F P

    2016-01-01

    When combining osteogenic progenitor cells such as human periosteum derived cells (hPDCs) with osteoconductive biomaterials like calcium phosphate (CaP)-scaffolds, in vivo bone formation can be achieved. This process is dependent on the early activation of Bone morphogenetic protein (BMP)-signalling. However, the bone forming process is slow and routinely only a limited amount of bone and bone marrow is formed. Therefore, we hypothesised that a robust clinically relevant outcome could be achieved by adding more physiological levels of potent BMP-ligands to these cell- and CaP-based constructs. For this, hPDCs were characterised for their responsiveness to BMP-ligands upon in vitro 2D stimulation. BMP-2, -4, -6 and -9 robustly induced osteochondrogenic differentiation. Subsequently, these ligands were coated onto clinically approved CaP-scaffolds, BioOss® and CopiOs®, followed by hPDC-seeding. Protein lysates and conditioned media were investigated for activation of BMP signalling pathways. Upon in vivo implantation, the most abundant bone formation was found in BMP-2 and BMP-6-coated scaffolds. Implanted cells actively contributed to the newly formed bone. Remnants of cartilage could be observed in BMP-coated CopiOs®-constructs. Computational analysis displayed that the type of BMP-ligand as well as the CaP-scaffold affects skeletal tissue formation, observed in a qualitative as well as quantitative manner. Furthermore, the in vitro mechanism appears to predict the in vivo outcome. This study presents further evidence for the potential of BMP-technology in the development of clinically relevant cell-based constructs for bone regenerative strategies. PMID:26728496

  13. Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

    International Nuclear Information System (INIS)

    The anabolic effect of intermittent parathyroid hormone (PTH) on bone is variable depending on the species studied, duration/mode of administration, and location of skeletal response investigated. We tested the hypothesis that low dose, short term, intermittent PTH 1-34 administration is sufficient to enhance bone formation without altering bone resorption. To test our hypothesis, mice were treated intermittently with one of three concentrations of PTH 1-34 (1 μg/kg, low; 10μg/kg or 20 μg/kg, high) for three weeks. The skeletal response was identified by quantifying: serum markers of bone turnover, cancellous bone parameters in distal femur, proximal tibia, and lumbar vertebrae by μCT, and number of osteoblasts and osteoclasts in distal femur. Mice receiving 20 μg/kg of PTH 1-34 demonstrated a 30% increase in serum osteocalcin, but no differences in serum calcium, type I collagen teleopeptides, or tartrate resistant acid phosphatase (TRACP) 5b. For all bones, μCT analysis suggested mice receiving 20 μg/kg of PTH 1-34 had increased cancellous bone mineral density, trabecular thickness and spacing, but decreased trabecular number. A 60% increase in the number of alkaline phosphatase positive osteoblasts in the distal femur was also observed in tissue sections; however, the number of TRAP positive osteoclasts was not different between test and control groups. While animals administered 10 μg/kg demonstrated similar trends for all bone turnover indices, such alterations were not observed in animals administered PTH 1-34 at 1 μg/kg per day. Thus, PTH 1-34, administered intermittently for three weeks at 20 μg/kg is sufficient to enhance bone formation without enhancing resorption. (author)

  14. Generation of an rhBMP-2-loaded beta-tricalcium phosphate/hydrogel composite and evaluation of its efficacy on peri-implant bone formation

    International Nuclear Information System (INIS)

    Dental implant insertion on a site with low bone quality or bone defect should be preceded by a bone graft or artificial bone graft insertion to heal the defect. We generated a beta-tricalcium phosphate (β-TCP) and poloxamer 407-based hydrogel composite and penetration of the β-TCP/hydrogel composite into the peri-implant area of bone was evaluated by porous bone block experiments. The maximum penetration depth for porous bone blocks and dense bone blocks were 524 μm and 464 μm, respectively. We report the in-vivo performance of a composite of β-TCP/hydrogel composite as a carrier of recombinant human bone morphogenetic protein (rhBMP-2), implanted into a rabbit tibial defect model. Three holes drilled into each tibia of eight male rabbits were (1) grafted with dental implant fixtures; (2) filled with β-TCP/hydrogel composite (containing 5 μg of rhBMP-2), followed by grafting of the dental implant fixtures. Four weeks later, bone-implant contact ratio and peri-implant bone formation were analyzed by radiography, micro-CT and histology of undecalcified specimens. The micro-CT results showed a significantly higher level of trabecular thickness and new bone and peri-implant new bone formation in the experimental treatment compared to the control treatment. Histomorphometry revealed a significantly higher bone-implant contact ratio and peri-implant bone formation with the experimental treatment. The use of β-TCP/poloxamer 407 hydrogel composite as a carrier of rhBMP-2 significantly promoted new bone formation around the dental implant fixture and it also improved the quality of the new bone formed in the tibial marrow space. (paper)

  15. Calcium Plasma Implanted Titanium Surface with Hierarchical Microstructure for Improving the Bone Formation.

    Science.gov (United States)

    Cheng, Mengqi; Qiao, Yuqin; Wang, Qi; Jin, Guodong; Qin, Hui; Zhao, Yaochao; Peng, Xiaochun; Zhang, Xianlong; Liu, Xuanyong

    2015-06-17

    Introducing hierarchical microstructure and bioactive trace elements simultaneously onto the surface of titanium implant is a very effective way to improve the osseointegration between bone and implant. In this work, hierarchical topography was prepared on Ti surface via acid etching and sandblasting (SLA) to form micropits and microcavities then underwent Ca plasma immersion ion implantation (Ca-PIII) process. The surface wettability and roughness did not change obviously before and after Ca-PIII process. The in vitro evaluations including cell adhesion, activity, alkaline phosphatase (ALP), osteogenic genes (Runx2, OSX, ALP, BSP, Col1a1, OPN, and OC), and protein (BSP, Col1a1, OPN, and OC) expressions revealed that the introduction of Ca ions onto the surface of SLA-treated Ti can promote greater osteoblasts adhesion, spread and proliferation, which in return further accelerated the maturation and mineralization of osteoblasts. More importantly, in vivo evaluations including Micro-CT evaluation, histological observations, push-out test, sequential fluorescent labeling and histological observations verified that Ca-SLA-treated Ti implants could efficiently promote new bone formation in early times. These promising results suggest that Ca-SLA-treated Ti has the potential for future application in orthopedic field. PMID:26020570

  16. Periostin action in bone.

    Science.gov (United States)

    Bonnet, Nicolas; Garnero, Patrick; Ferrari, Serge

    2016-09-01

    Periostin is a highly conserved matricellular protein that shares close homology with the insect cell adhesion molecule fasciclin 1. Periostin is expressed in a broad range of tissues including the skeleton, where it serves both as a structural molecule of the bone matrix and a signaling molecule through integrin receptors and Wnt-beta-catenin pathways whereby it stimulates osteoblast functions and bone formation. The development of periostin null mice has allowed to elucidate the crucial role of periostin on dentinogenesis and osteogenesis, as well as on the skeletal response to mechanical loading and parathyroid hormone. The use of circulating periostin as a potential clinical biomarker has been explored in different non skeletal conditions. These include cancers and more specifically in the metastasis process, respiratory diseases such as asthma, kidney failure, renal injury and cardiac infarction. In postmenopausal osteoporosis, serum levels have been shown to predict the risk of fracture-more specifically non-vertebral- independently of bone mineral density. Because of its preferential localization in cortical bone and periosteal tissue, it can be speculated that serum periostin may be a marker of cortical bone metabolism, although additional studies are clearly needed. PMID:26721738

  17. The synergistic induction of bone formation by the osteogenic proteins of the TGF-β supergene family.

    Science.gov (United States)

    Ripamonti, Ugo; Parak, Ruqayya; Klar, Roland M; Dickens, Caroline; Dix-Peek, Thérèse; Duarte, Raquel

    2016-10-01

    The momentum to compose this Leading Opinion on the synergistic induction of bone formation suddenly arose when a simple question was formulated during a discussion session on how to boost the often limited induction of bone formation seen in clinical contexts. Re-examination of morphological and molecular data available on the rapid induction of bone formation by the recombinant human transforming growth factor-β3 (hTGF-β3) shows that hTGF-β3 replicates the synergistic induction of bone formation as invocated by binary applications of hOP-1:hTGF-β1 at 20:1 by weight when implanted in heterotopic sites of the rectus abdominis muscle of the Chacma baboon, Papio ursinus. The rapid induction of bone formation in primates by hTGF-β3 may stem from bursts of cladistic evolution, now redundant in lower animal species but still activated in primates by relatively high doses of hTGF-β3. Contrary to rodents, lagomorphs and canines, the three mammalian TGF-β isoforms induce rapid and substantial bone formation when implanted in heterotopic rectus abdominis muscle sites of P. ursinus, with unprecedented regeneration of full thickness mandibular defects with rapid mineralization and corticalization. Provocatively, thus providing potential molecular and biological rationales for the apparent redundancy of osteogenic molecular signals in primates, binary applications of recombinant human osteogenic protein-1 (hOP-1) with low doses of hTGF-β1 and -β3, synergize to induce massive ossicles in heterotopic rectus abdominis, orthotopic calvarial and mandibular sites of P. ursinus. The synergistic binary application of homologous but molecularly different soluble molecular signals has indicated that per force several secreted molecular signals are required singly, synchronously and synergistically to induce optimal osteogenesis. The morphological hallmark of the synergistic induction of bone formation is the rapid differentiation of large osteoid seams enveloping

  18. Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone implant contact formation

    Science.gov (United States)

    Strnad, Jakub; Strnad, Zdeněk; Šesták, Jaroslav; Urban, Karel; Povýšil, Ctibor

    2007-05-01

    This study was carried out to quantify the effect of an alkali-modified surface on the bone implant interface formation during healing using an animal model. A total of 24 screw-shaped, self-tapping, (c.p.) titanium dental implants, divided into test group B—implants with alkali-modified surface (Bio surface) and control group M—implants with turned, machined surface, were inserted without pre-tapping in the tibiae of three beagle dogs. The animals were sacrificed after 2, 5 and 12 weeks and the bone implant contact (BIC%) was evaluated histometrically. The surface characteristics that differed between the implant surfaces, i.e. specific surface area, contact angle, may represent factors that influence the rate of osseointegration and the secondary implant stability. The alkali-treated surface enhances the BIC formation during the first 2 5 weeks of healing compared to the turned, machined surface.

  19. Unusual presentation of glomus tympanicum tumour: New bone formation in the middle ear.

    Science.gov (United States)

    Kumar, Gaurav; Andreou, Zenon; Virk, Jagdeep Singh; Owa, Anthony

    2014-09-16

    The objective of this study is to increase awareness of the rare presentation, diagnostic difficulties and management of glomus tympanicum of the middle ear. A 49 years old male, with a background of hypertension and epilepsy, presented with a two month history of left sided conductive hearing loss, pulsatile tinnitus and headache. Clinically and radiologically a diagnosis of glomus tympanicum was made. Intraoperatively, extensive osteogenesis of the middle ear resulting in ossicular fixation and erosion was found. This patient required a two stage operation for full clearance of disease. A stapedectomy drill was used to drill off the bony overgrowth surrounding the ossicles resulting in improved hearing thresholds and full clearance of the disease at two year follow up. Glomus tympanicum can result in new bone formation in the middle ear with resultant ossicular fixation and conductive hearing loss. This can be effectively treated surgically with restoration of hearing. PMID:25232551

  20. Radiotherapy of heterotopic bone formation in patients with paraplegia. Preliminary results

    International Nuclear Information System (INIS)

    In 20 patients with paralysis, 25 regions were irradiated with (mostly) 10 Gy in single fractions of 2 to 2.5 Gy using 8 MW photons. In 15 patients radiotherapy was performed as a primary treatment in the status of myositis; 7 patients were treated after (subtotal) resection of already manifest ossifications (2 patients were treated twice, primarily and postoperatively). In a minimum follow-up 12 weeks, none of the 20 irradiated patients showed any progression of the developing or already manifest ossification; thus mobilisation and rehabilitation could be carried out as desired. No side effects occurred. The preliminary results of the present study suggest that radiotherapy is an effective local treatment with minimal side effects for the prevention of heterotopic bone formation in patients with paraplegia. (orig.)

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

    DEFF Research Database (Denmark)

    Chen, Li; Shi, Kaikai; Frary, Charles Edward;

    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...

  2. Platelet P2Y12 is involved in murine pulmonary metastasis.

    Directory of Open Access Journals (Sweden)

    Yanhua Wang

    Full Text Available The involvement of platelets in tumor progression is well recognized. The depletion of circulating platelets or pharmacologic inhibitors of platelet activation decreases the metastatic potential of circulating tumor cells in metastasis mouse models. The platelet ADP receptor P2Y12 amplifies the initial hemostatic responses activated by a variety of platelet agonists and stabilizes platelet aggregation, playing a crucial role in granule secretion, integrin activation and thrombus formation. However, the relationship between P2Y12 and tumor progression is not clear. In our study, the Lewis Lung Carcinoma (LLC spontaneous metastatic mouse model was used to evaluate the role of P2Y12 in metastasis. The results demonstrated that P2Y12 deficiency significantly reduced pulmonary metastasis. Further studies indicated that P2Y12 deficiency diminished the ability of LLC cells to induce platelet shape change and release of active TGFβ1 by a non-contact dependent mechanism resulting in a diminished, platelet-induced EMT-like transformation of the LLC cells, and that transformation probably is a prerequisite of LLC cell metastasis. Immunohistochemical analyses indicated an obvious P2Y12 deficiency related attenuation of recruitment of VEGFR1+ bone marrow derived cell clusters, and extracellular matrix fibronectin deposition in lungs, which presumably are required for pre-metastatic niche formation. In contrast to the LLC cells, non-epithelial melanoma B16 cells induced platelet aggregation in a cell number and P2Y12-dependent manner. Also, a platelet induced EMT-like transformation of B16 cells is dependent on P2Y12. In agreement with the LLC cell model, platelet P2Y12 deficiency also results in significantly less lung metastasis in the B16 melanoma experimental metastasis model. These results demonstrate that P2Y12 is a safe drug target for anti-thrombotic therapy, and that P2Y12 may serve as a new target for inhibition of tumor metastasis.

  3. Expression of Preprotachykinin-I(PPT-I), Neurokinin-1(NK-1) and Neurokinin-2(NK-2) in Breast Cancer Cells Improves Tumor Cell Survival in Bone Marrow in the Early Stage of Metastasis

    Institute of Scientific and Technical Information of China (English)

    Huilai Zhang; Huaqing Wang; Pengfei Liu; Zhi Yao; Xishan Hao

    2009-01-01

    OBJECTIVE To study the potential relationship between the expression of PPT-I, NK-1, NK2 and the development of breast cancer cells in bone marrow stroma and to provide evidence of potential molecular mechanisms of bone metastasis in early stage of breast cancer patients.METHODS The cocultures of breast cancer cell line T-47D and marrow-derived mesenchymal stem cells (MSC) were established with equal numbers. T-47D cells were separated from the coculture system at 48 h and 96 h after coculture by MACS magnetic cell sorting (MicroBeads). The expression of PPT-I, NK-1, NK-2 in T-47D was then examined before and after coculture by real-time PCR and by Western blot. Alterations in cellular ultrastructure of T-47D cells were detected before and after coculture under electron microscope. Finally, changes in cell cycle distribution were examined by flow cytometry, and growth curves from before and after coculture were drawn and analyzed. RESULTS Following coculture of T-47D and MSC, the expression of PPT-I mRNA and protein was significantly upregulated, while the expression of NK-1 and NK-2 mRNA and protein was greatly downregulated. The analysis of cell cycle distribution by flow cytometry showed that the proportion of T-47D during S phase was increased, and the duration of the G2/M phase was sharply decreased. Under electron microscope, we observed that the synthesis of hereditary material was increased, but the hepatin granules were shown prominent stacking in T-47D cells. These results suggest that although the synthesis of DNA was increased, the proliferation of cells was inhibited after coculture. The cellgrowth curve confirmed the findings from the observation under the electron microscope and flow cytometry. CONCLUSION Tumor cells could survive through the upregulation in expression of preprotachykinin-I gene during early bone metastasis in breast cancer. The phenomenon of growth suppression in breast cancer cells after coculture in the current study could be

  4. Bevacizumab Inhibits Breast Cancer-Induced Osteolysis, Surrounding Soft Tissue Metastasis, and Angiogenesis in Rats as Visualized by VCT and MRI

    Directory of Open Access Journals (Sweden)

    Tobias Bäuerle

    2008-05-01

    Full Text Available The aim of this study was to evaluate the effect of an antiangiogenic treatment with the vascular endothelial growth factor antibody bevacizumab in an experimental model of breast cancer bone metastasis and to monitor osteolysis, soft tissue tumor, and angiogenesis in bone metastasis noninvasively by volumetric computed tomography (VCT and magnetic resonance imaging (MRI. After inoculation of MDA-MB-231 human breast cancer cells into nude rats, bone metastasis was monitored with contrast-enhanced VCT and MRI from day 30 to day 70 after tumor cell inoculation, respectively. Thereby, animals of the treatment group (10 mg/kg bevacizumab IV weekly, n = 15 were compared with sham-treated animals (n = 17. Treatment with bevacizumab resulted in a significant difference versus control in osteolytic as well as soft tissue lesion sizes (days 50 to 70 and 40 to 70 after tumor cell inoculation, respectively; P < .05. This observation was paralleled with significantly reduced vascularization in the treatment group as shown by reduced increase in relative signal intensity in dynamic contrast-enhanced MRI from days 40 to 70 (P < .05. Contrast-enhanced VCT and histology confirmed decreased angiogenesis as well as new bone formation after application of bevacizumab. In conclusion, bevacizumab significantly inhibited osteolysis, surrounding soft tissue tumor growth, and angiogenesis in an experimental model of breast cancer bone metastasis as visualized by VCT and MRI.

  5. Magnetic nanocomposite scaffolds combined with static magnetic field in the stimulation of osteoblastic differentiation and bone formation.

    Science.gov (United States)

    Yun, Hyung-Mun; Ahn, Su-Jin; Park, Kyung-Ran; Kim, Mi-Joo; Kim, Jung-Ju; Jin, Guang-Zhen; Kim, Hae-Won; Kim, Eun-Cheol

    2016-04-01

    Magnetism has recently been implicated to play significant roles in the regulation of cell responses. Allowing cells to experience a magnetic field applied externally or scaffolding them in a material with intrinsic magnetic properties has been a possible way of utilizing magnetism. Here we aim to investigate the combined effects of the external static magnetic field (SMF) with magnetic nanocomposite scaffold made of polycaprolactone/magnetic nanoparticles on the osteoblastic functions and bone formation. The SMF synergized with the magnetic scaffolds in the osteoblastic differentiation of primary mouse calvarium osteoblasts, including the expression of bone-associated genes (Runx2 and Osterix) and alkaline phosphatase activity. The synergism was demonstrated in the activation of integrin signaling pathways, such as focal adhesion kinase, paxillin, RhoA, mitogen-activated protein kinase, and nuclear factor-kappaB, as well as in the up-regulation of bone morphogenetic protein-2 and phosphorylation of Smad1/5/8. Furthermore, the SMF/magnetic scaffold-stimulated osteoblasts promoted the angiogenic responses of endothelial cells, including the expression of vascular endothelial growth factor and angiogenin-1 genes and the formation of capillary tubes. When the magnetic scaffolds were implanted in mouse calvarium defects, the application of SMF significantly enhanced the new bone formation at 6 weeks, as revealed by the histological and micro-computed tomographic analyses. Current findings suggest that the combinatory application of external (SMF) and internal (scaffold) magnetism can be a promising tool to regenerative engineering of bone. PMID:26854394

  6. In Vivo Static Creep Loading of the Rat Forelimb Reduces Ulnar Structural Properties at Time-Zero and Induces Damage-Dependent Woven Bone Formation

    OpenAIRE

    Lynch, Jennifer A.; Silva, Matthew J.

    2008-01-01

    Periosteal woven bone forms in response to stress fractures and pathological overload. The mechanical factors that regulate woven bone formation are poorly understood. Fatigue loading of the rat ulna triggers a woven bone response in proportion to the level of applied fatigue displacement. However, because fatigue produces damage by application of cyclic loading it is unclear if the osteogenic response is due to bone damage (injury response) or dynamic strain (adaptive response). Creep loadin...

  7. Bone-like apatite formation on HA/316L stainless steel composite surface in simulated body fluid

    Institute of Scientific and Technical Information of China (English)

    FAN Xin; CHEN Jian; ZOU Jian-peng; WAN Qian; ZHOU Zhong-cheng; RUAN Jian-ming

    2009-01-01

    HA/316L stainless steel(316L SS) biocomposites were prepared by hot-pressing technique. The formation of bone-like apatite on the biocomposite surfaces in simulated body fluid(SBF) was analyzed by digital pH meter, plasma emission spectrometer, scanning electron microscope(SEM) and energy dispersive X-ray energy spectrometer(EDX). The results indicate that the pH value in SBF varies slightly during the immersion. It is a dynamic process of dissolution-precipitation for the formation of apatite on the surface. With prolonging immersion time, Ca and P ion concentrations increase gradually, and then approach equilibrium. The bone-like apatite layer forms on the composites surface, which possesses benign bioactivity and favorable biocompatibility and achieves osseointegration, and can provide firm fixation between HA60/316L SS composite implants and human body bone.

  8. Mice deficient in 11beta-hydroxysteroid dehydrogenase type 1 lack bone marrow adipocytes, but maintain normal bone formation

    DEFF Research Database (Denmark)

    Justesen, Jeannette; Mosekilde, Lis; Holmes, Megan;

    2004-01-01

    marrow composition revealed a total absence of marrow adipocytes in HSD1(-/-) mice. Cells from Wt and HSD1(-/-) mice exhibited similar growth rates as well as similar levels of production of osteoblastic markers. The adipocyte-forming capacity of in vitro cultured bone marrow stromal cells and trabecular...

  9. Collagen immobilization of multi-layered BCP-ZrO2 bone substitutes to enhance bone formation

    International Nuclear Information System (INIS)

    Graphical abstract: - Highlights: • Col-BCP-ZrO. • Collagen fibers were formed and attached firmly on the surface of BCP-ZrO. • Highly interconnected but uniform porosity were obtained. • High biocompatible, strength scaffolds and new bone were evident in Col-BCP-ZrO2. - Abstract: A porous microstructure of multi-layered BCP-ZrO2 bone substitutes was fabricated using the sponge replica method in which the highly interconnected structure was immobilized with collagen via ethyl(dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide crosslinking. Their struts are combined with a three-layered BCP/BCP-ZrO2/ZrO2 microstructure. Collagen fibers were firmly attached to the strut surface of the BCP-ZrO2 scaffolds. With control of the three-layered microstructure and collagen immobilization, the compressive strength of the scaffolds increased significantly to 6.8 MPa compared to that of the monolithic BCP scaffolds (1.3 MPa). An in vitro study using MTT, confocal observation, and real-time polymer chain reaction analysis demonstrated that the proliferation and differentiation of the pre-osteoblast-like MC3T3-E1 cells was improved due to the collagen incorporation. Remarkable enhancement of bone regeneration was observed without any immunological reaction in the femurs of rabbits during 1 and 5 months of implantation. Furthermore, the interfaces between new bone and the scaffold struts bonded directly without any gaps

  10. Collagen immobilization of multi-layered BCP-ZrO{sub 2} bone substitutes to enhance bone formation

    Energy Technology Data Exchange (ETDEWEB)

    Linh, Nguyen Thuy Ba [Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 330-090 (Korea, Republic of); Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, 330-090 (Korea, Republic of); Jang, Dong-Woo [Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 330-090 (Korea, Republic of); Lee, Byong-Taek, E-mail: lbt@sch.ac.kr [Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, Cheonan, 330-090 (Korea, Republic of); Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, 330-090 (Korea, Republic of)

    2015-08-01

    Graphical abstract: - Highlights: • Col-BCP-ZrO. • Collagen fibers were formed and attached firmly on the surface of BCP-ZrO. • Highly interconnected but uniform porosity were obtained. • High biocompatible, strength scaffolds and new bone were evident in Col-BCP-ZrO{sub 2}. - Abstract: A porous microstructure of multi-layered BCP-ZrO{sub 2} bone substitutes was fabricated using the sponge replica method in which the highly interconnected structure was immobilized with collagen via ethyl(dimethylaminopropyl)carbodiimide/N-hydroxysuccinimide crosslinking. Their struts are combined with a three-layered BCP/BCP-ZrO{sub 2}/ZrO{sub 2} microstructure. Collagen fibers were firmly attached to the strut surface of the BCP-ZrO{sub 2} scaffolds. With control of the three-layered microstructure and collagen immobilization, the compressive strength of the scaffolds increased significantly to 6.8 MPa compared to that of the monolithic BCP scaffolds (1.3 MPa). An in vitro study using MTT, confocal observation, and real-time polymer chain reaction analysis demonstrated that the proliferation and differentiation of the pre-osteoblast-like MC3T3-E1 cells was improved due to the collagen incorporation. Remarkable enhancement of bone regeneration was observed without any immunological reaction in the femurs of rabbits during 1 and 5 months of implantation. Furthermore, the interfaces between new bone and the scaffold struts bonded directly without any gaps.

  11. Ectopic bone formation cannot occur by hydroxyapatite/β-tricalcium phosphate bioceramics in green fluorescent protein chimeric mice

    International Nuclear Information System (INIS)

    Highlights: ► Firstly, chimeric mouse model could be established successfully by bone marrow transplantation after irradiation. ► Secondly, bone induction can occur in wild-type mice 90 days after implantation, but not occur in chimeric mice. ► Thirdly, destruction of immune function will block osteoinduction by calcium phosphate ceramics. - Abstract: Many studies have shown that calcium phosphate ceramics (CP) have osteoconductive and osteoinductive properties; however, the exact mechanism of bone induction has not yet been reported. This study was performed to investigate if destroying immunological function will influence osteogenesis, to explain the mechanism which is unclear. In this study, twenty C57BL/6 mice were divided into two groups (n = 10), in group 1, a hydroxyapatite/β-tricalcium phosphate (HA/β-TCP) ceramic was implanted into both the left and right leg muscles of each mouse; in group 2, ten mice experienced lethal irradiation, then were injected bone marrow (BM) cells from green fluorescent protein (GFP) transgenic mice by tail veil, after bone marrow transplantation (BMT), heart, liver, spleen, lung, kidney, and muscle were harvested for biological analysis, after the GFP chimera model was established successfully, the same HA/β-TCP ceramic was implanted into both leg muscles of each mouse immediately after irradiation. 45 and 90 days after implantation, the ceramics of the two groups were harvested to perform with hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining; the results showed that there was no bone formation in group 2, while new bone tissues were detected in group 1. Our findings suggest that the BM cell from GFP transgenic mice is a good biomarker and it could set a good platform for chimera model; it also shows that BM cell is one of cell resources of bone induction, and destruction of immune function will impede osteoinduction by CP. Overall, our results may shed light on clear mechanism study of bone

  12. Ectopic bone formation cannot occur by hydroxyapatite/{beta}-tricalcium phosphate bioceramics in green fluorescent protein chimeric mice

    Energy Technology Data Exchange (ETDEWEB)

    Cheng Lijia [Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu (China); Duan Xin [Department of Orthopaedics, Chengdu Second People' s Hospital, Chengdu (China); Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu (China); Xiang Zhou [Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu (China); Shi Yujun; Lu Xiaofeng; Ye Feng [Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu (China); Bu Hong, E-mail: hongbu@scu.edu.cn [Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu (China); Department of Pathology, West China Hospital, Sichuan University, Chengdu (China)

    2012-12-01

    Highlights: Black-Right-Pointing-Pointer Firstly, chimeric mouse model could be established successfully by bone marrow transplantation after irradiation. Black-Right-Pointing-Pointer Secondly, bone induction can occur in wild-type mice 90 days after implantation, but not occur in chimeric mice. Black-Right-Pointing-Pointer Thirdly, destruction of immune function will block osteoinduction by calcium phosphate ceramics. - Abstract: Many studies have shown that calcium phosphate ceramics (CP) have osteoconductive and osteoinductive properties; however, the exact mechanism of bone induction has not yet been reported. This study was performed to investigate if destroying immunological function will influence osteogenesis, to explain the mechanism which is unclear. In this study, twenty C57BL/6 mice were divided into two groups (n = 10), in group 1, a hydroxyapatite/{beta}-tricalcium phosphate (HA/{beta}-TCP) ceramic was implanted into both the left and right leg muscles of each mouse; in group 2, ten mice experienced lethal irradiation, then were injected bone marrow (BM) cells from green fluorescent protein (GFP) transgenic mice by tail veil, after bone marrow transplantation (BMT), heart, liver, spleen, lung, kidney, and muscle were harvested for biological analysis, after the GFP chimera model was established successfully, the same HA/{beta}-TCP ceramic was implanted into both leg muscles of each mouse immediately after irradiation. 45 and 90 days after implantation, the ceramics of the two groups were harvested to perform with hematoxylin and eosin (HE) and immunohistochemistry (IHC) staining; the results showed that there was no bone formation in group 2, while new bone tissues were detected in group 1. Our findings suggest that the BM cell from GFP transgenic mice is a good biomarker and it could set a good platform for chimera model; it also shows that BM cell is one of cell resources of bone induction, and destruction of immune function will impede

  13. Unusual Presentation of Renal Cell Carcinoma: Gluteal Metastasis

    OpenAIRE

    Yunus Emre Goger; Mehmet Mesut Piskin; Mehmet Balasar; Mehmet Kilinc

    2013-01-01

    Renal cell carcinoma (RCC) has widespread and unpredictable metastatic potential. The most common sites of metastatic RCC are the lungs, lymph nodes, bones, liver, and brain; however the soft tissue metastasis is rare (2,3). Here we report a 76-year-old male patient who had renal cell carcinoma presented with gluteal metastasis. To our knowledge this is the first renal cell cancer case with gluteal metastasis at the initial diagnosis.

  14. Long-Term Symptoms Onset and Heterotopic Bone Formation around a Total Temporomandibular Joint Prosthesis: a Case Report

    Directory of Open Access Journals (Sweden)

    Luca Guarda-Nardini

    2014-04-01

    Full Text Available Background: The literature on total alloplastic temporomandibular joint (TMJ reconstructions is encouraging, and studies on total alloplastic TMJ replacements outcomes showed acceptable improvements in terms of both pain levels and jaw function. Nevertheless, some adverse events, such as heterotopic bone formation around the implanted prosthesis, may occur. In consideration of that, the present manuscript describes a case of heterotopic bone formation around a total temporomandibular joint prosthesis, which occurred several years after the implant. Methods: The present manuscript describes a case of heterotopic bone formation around a total TMJ prosthesis, which occurred several years after the implant in patients, who previously underwent multiple failed TMJ surgeries. Results: Ten years after the surgical TMJ replacement to solve an ankylotic bone block, the patient came to our attention again referring a progressive limitation in mouth opening. A computerized tomography showed evidence of marked heterotopic bone formation in the medial aspects of the joint, where a new-born ankylotic block occupied most part of the gap created by resecting the coronoid process at the time of the TMJ prosthesis insertion. Conclusions: Despite this adverse event has been sometimes described in the literature, this is the first case in which its occurrence happened several years after the temporomandibular joint replacement. It can be suggested that an accurate assessment of pre-operative risk factors for re-ankylosis (e.g., patients with multiple failed temporomandibular joint surgeries and within-intervention prevention (e.g., strategies to keep the bone interfaces around the implant separated should be better standardized and define in future studies.

  15. Monotropein isolated from the roots of Morinda officinalis increases osteoblastic bone formation and prevents bone loss in ovariectomized mice.

    Science.gov (United States)

    Zhang, Zhiguo; Zhang, Qiaoyan; Yang, Hua; Liu, Wei; Zhang, Naidan; Qin, Luping; Xin, Hailiang

    2016-04-01

    Monotropein is a natural iridoid glycoside enriched in Morinda officinalis and has been used for medicinal purposes in China. In the present study, we systematically examined its effects on ovariectomy (OVX)-induced osteoporosis in mice and osteoblastic MC3T3-E1 cells for the first time. Eight-week-old female C57/BL6 mice were used to evaluate the osteoprotective effect of monotropein. Results showed that administration of monotropein (40 or 80mg/kg/day) for four weeks exerted good bone protective effects as evidenced by the increase of bone mineral content (BMC), bone mineral density (BMD), bone volume fraction (BVF) and improvement of bone microstructure. Monotropein also enhanced the parameters of biomechanical properties, including maximum load, maximum stress and elastic modulus of femur in OVX mice. In addition, monotropein treatment decreased the serum levels of interleukin 1 (IL-1), interleukin 6 (IL-6) and soluble receptor activator of NF-κB ligand (sRANKL) in OVX mice. In this study, we also assessed the effects of monotropein on the proliferation and differentiation of osteoblastic MC3T3-E1 cells in vitro. After incubation for 48h, the cell proliferation was increased at the concentration of 10μM, 25μM, 50μM and 100μM. ALP activities were significantly increased after treatment with monotropein for 72h. Quantitative analyses with alizarin red staining showed significantly increased mineralization of MC3T3-E1 cells after treatment with monotropein for 28days. Based on these results, monotropein may serve as a new candidate or a leading compound for antiosteoporosis. PMID:26996879

  16. Effect of enamel matrix derivative and parathyroid hormone on bone formation in standardized osseous defects: an experimental study in minipigs

    DEFF Research Database (Denmark)

    Jensen, Simon S; Chen, B; Bornstein, Michael M; Bosshardt, Dieter D; Buser, Daniel

    2011-01-01

    Previous experimental studies have indicated that locally administered enamel matrix derivative (EMD) and parathyroid hormone (PTH) may have a stimulatory effect on bone formation. However, it is not clear if the positive effect of EMD is related to its effect on the periodontium as a whole or...

  17. In vitro and in vivo evaluation of bone formation using solid freeform fabrication-based bone morphogenic protein-2 releasing PCL/PLGA scaffolds

    International Nuclear Information System (INIS)

    The aim of this study was to develop novel polycaprolactone/poly(lactic-co-glycolic acid) (PCL/PLGA) scaffolds with a heparin–dopamine (Hep–DOPA) conjugate for controlled release of bone morphogenic protein-2 (BMP-2) to enhance osteoblast activity in vitro and also bone formation in vivo. PCL/PLGA scaffolds were prepared by a solid freeform fabrication method. The PCL/PLGA scaffolds were functionalized with Hep–DOPA and then BMP-2 was sequentially coated onto the Hep–DOPA/PCL/PLGA scaffolds. The characterization and surface elemental composition of all scaffolds were evaluated by scanning electron microscope and x-ray photoelectron spectroscopy. The osteoblast activities on all scaffolds were assessed by cell proliferation, alkaline phosphatase (ALP) activity and calcium deposition in vitro. To demonstrate bone formation in vivo, plain radiograph, micro-computed tomography (micro-CT) evaluation and histological studies were performed after the implantation of all scaffolds on a rat femur defect. Hep–DOPA/PCL/PLGA had more controlled release of BMP-2, which was quantified by enzyme-linked immunosorbent assay, compared with Hep/PCL/PLGA. The in vitro results showed that osteoblast-like cells (MG-63 cells) grown on BMP-2/Hep–DOPA/PCL/PLGA had significantly enhanced ALP activity and calcium deposition compared with those on BMP-2/Hep/PCL/PLGA and PCL/PLGA. In addition, the plain radiograph, micro-CT evaluation and histological studies demonstrated that the implanted BMP-2/Hep–DOPA/PCL/PLGA on rat femur had more bone formation than BMP-2/Hep/PCL/PLGA and PCL/PLGA in vivo. (paper)

  18. Icariin attenuates titanium-particle inhibition of bone formation by activating the Wnt/β-catenin signaling pathway in vivo and in vitro

    OpenAIRE

    Junhua Wang; Yunxia Tao; Zichuan Ping; Wen Zhang; Xuanyang Hu; Yijun Wang; Liangliang Wang; Jiawei Shi; Xiexing Wu; Huilin Yang; Yaozeng Xu; Dechun Geng

    2016-01-01

    Wear-debris-induced periprosthetic osteolysis (PIO) is a common clinical condition following total joint arthroplasty, which can cause implant instability and failure. The host response to wear debris promotes bone resorption and impairs bone formation. We previously demonstrated that icariin suppressed wear-debris-induced osteoclastogenesis and attenuated particle-induced osteolysis in vivo. Whether icariin promotes bone formation in a wear-debris-induced osteolytic site remains unclear. Her...

  19. Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells

    OpenAIRE

    Seo, Hyun-Ju; Cho, Young-Eun; Kim, Taewan; Shin, Hong-In; Kwun, In-Sook

    2010-01-01

    Zinc is an essential trace element required for bone formation, however not much has been clarified yet for its role in osteoblast. We hypothesized that zinc would increase osteogenetic function in osteoblasts. To test this, we investigated whether zinc treatment enhances bone formation by stimulating osteoblast proliferation, bone marker protein alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells. MC3T3-E1 cells were cultured and treated with various concentra...

  20. Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation

    OpenAIRE

    N C Rivron; Raiss, C.C.; Liu, J.; Nandakumar, A.; Sticht, C; Gretz, N; Truckenmuller, R.K.; Rouwkema, J.; Blitterswijk, van, W.J.

    2012-01-01

    Large bone defects naturally regenerate via a highly vascularized tissue which progressively remodels into cartilage and bone. Current approaches in bone tissue engineering are restricted by delayed vascularization and fail to recapitulate this stepwise differentiation toward bone tissue. Here, we use the morphogen Sonic Hedgehog (Shh) to induce the in vitro organization of an endothelial capillary network in an artificial tissue. We show that endogenous Hedgehog activity regulates angiogenic...

  1. Use of postoperative irradiation for the prevention of heterotopic bone formation after total hip replacement

    Energy Technology Data Exchange (ETDEWEB)

    Sylvester, J.E.; Greenberg, P.; Selch, M.T.; Thomas, B.J.; Amstutz, H.

    1988-03-01

    Formation of heterotopic bone (HTB) following total hip replacement may partially or completely ankylose the joint space, causing pain and/or limiting the range of motion. Patients at high risk for formation of HTB postoperatively include those with previous HTB formation, heterotopic osteoarthritis, and active rheumatoid spondylitis. Patients in these high risk groups have a 63-69% incidence of post-operative HTB formation, usually seen radiographically by 2 months post-operation. From 1980-1986 twenty-nine hips in 28 consecutively treated patients were irradiated post-operatively at the UCLA Center for the Health Sciences. The indication for irradiation was documented HTB formation previously in 26 of the 27 hips presented below. From 1980-1982 patients received 20 Gray (Gy) in 2 Gy fractions; from 1982-1986 the dose was reduced to 10 Gy in 2 Gy fractions. Twenty-seven hips in 26 patients completed therapy and were available for evaluation, with a minimum of 2 month follow-up, and a median follow-up of 12 months. Three of 27 hips developed significant HTB (Brooker grade III or IV) post-operatively, whereas 5 of 27 hips developed minor, nonsymptomatic HTB (Brooker grade I). When irradiation was begun by postoperative day 4, 0 of 17 hips formed significant HTB. If irradiation began after post-operative day 4, 3 of 10 hips formed significant HTB (Brooker grade III or IV). These 3 hips received doses of 10 Gy in one hip and 20 Gy in the other 2 hips. There were no differences in the incidence or severity of side effects in the 10 Gy vs. the 20 Gy treatment groups. Eighteen hips received 10 Gy, 8 hips 20 Gy and, 1 hip 12 Gy. In conclusion, 10 Gy in 5 fractions appears as effective as 20 Gy in 10 fractions at preventing post-operative formation of HTB. For optimal results, treatment should begin as early as possible prior to post-operative day 4.

  2. Skeletal Self-Repair: Stress Fracture Healing by Rapid Formation and Densification of Woven Bone