Research for the elucidation of bone formation signals applied to the development of bone-forming agents
| Project/Area Number |
18591025
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Shimane University |
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Principal Investigator |
SUGIMOTO Toshitsugu Shimane University, Department of Medicine, Professor (00226458)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAGUCHI Toru Shimane University, Department of Medicine, Associate Professor (00239899)
YANO Shozo Shimane University, Department of Medicine, Associate Professor (80403450)
YAMAUCHI Mika Shimane University, Department of Medicine, Assistant Professor (40379681)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,730,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Parathyroid hormone / Bisohosohonate / Stalin / strontium / Osteoblast / Bone formation / Smart / Wnt / Smad / Smad3 / Lunt / グルココルチコイド / TGFβ / アポトーシス |
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| Research Abstract |
Parathyroid hormone (PTH) exerts anabolic action on bone and the canonical Wnt as well as TGFβ-smad3 pathways are important in bone formation. We demonstrated that PTH activates Wnt-β-catenin signal through Smad3, resulting in the inhibition of osteoblast apoptosis. Next, we examined how Smad3 affects osteoblast at the different differentiation stage. Smad3 inhibits osteoblastic commitment of multipotential mesenchymal cells, while it promotes early stage of differentiation and maturation of osteoblastic committed cells. On the other hand, statins possess pleiotropic effects and among them, their bone anabolic action's have been noted. We examined whether statins would affect TGF-β-Smad3 pathway and apoptosis in osteoblasts. Pitavastatin suppressed osteoblast apoptosis through Smad3.
Glucocorticoid (GC)-induced osteoporosis (GIO) is caused by the suppression of osteogenesis, and effectively treated by bisphosphonate (BP) and PTH. However, the exact mechanisms by which GC suppresses oste
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oblast functions, or BP and PTH alleviate GIO are still unclear. The present study indicates that GC inhibits osteoblastic differentiation by suppressing BMP and Wnt signaling pathways through enhanced expressions of their antagonists, follistatin/Dan and sFRP, respectively, and that the effectiveness of BP and PTH may be partly explained by the cancellation of these processes. Our recent study indicates that adiponectin stimulates the proliferation, differentiation and mineralization of osteoblasts via the AdipoR1 and AMP kinase (AMPK) signaling pathway in autocrine and/or paracrine fashions. Both AMPK and Rho-kinase (ROK) are known to modulate mevalonate pathway. Inhibition of HMG-CoA reductase by AICAR and that of ROK by hydroxyfasudil stimulated the differentiation and mineralization of osteoblasts, indicating that agents modulating the mevalonate pathway might be candidate drugs that promote bone formation. Strontium stimulates osteoblast differentiation and mineralization via the activation of Ca-sensing receptor (CaSR). The present findings provide the rationale for the therapeutic usefulness of PTH,BP, statin as well as CaSR agonist as bone-forming agents for senile osteoporosis Less
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Report
(3 results)
Research Products
(24 results)
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[Journal Article] The combination of high glucose and advanced glycation end-products (AGEs) unhibit the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs2007
Author(s)
Ogawa, N., Yamaguchi, N., Yano, S., Yamauchi, M., Yamamoto, M., Sugimoto, T
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Journal Title
Horm Metab Res 39
Pages: 871-875
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Parathyroid hormone increases b-catenin levels through smad3 in mouse osteoblastic cells in osteoblasts2006
Author(s)
Tobimatsu, T., Kaji, H., Sowa, H., Naito, J., Hendy, GN.,Sugimoto, T.,Chihara, K
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[Journal Article] Adiponectin and AMP kinase activator stimulates proliferation, differtentiation and mineralization of osteonlastic MC3T3-E1 cells
Author(s)
Kanazawa, I., Yamaguchi, T., Yano, S., Yamauchi, M., Yamamoto, M., Sugimolto, T
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Glucocorticoid suppresses the differentiation of osteoblasts by enhancing the expression of BMP antagonists, follistatin and danm and pretreatment with alendronate and PTH abolish this process2007
Author(s)
Hayashi, K., Yamaguchi, T., Yano, S., Yamauchi, M., Yamamoito, M., The, Sugimoto, T
Organizer
The American Society for Bone Mineral Research
Place of Presentation
Hawaii USA
Year and Date
2007-09-29
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Presentation] AMP kinase activator (AICAR) and Rho-kinasse inhibitor (hydroxyfasudil) induce the differentiation and mineralization of osteoblastic MC3T3-E1 cells via inhibiting the mavalonate pathway and enhancing BMP-2 expression2007
Author(s)
Kanazawa, I., Yamaguchi, T., Yano, S., yamauchi, M., Yamamoto, M., Sugimoto, T
Organizer
The American Society for Bone Mineral Research
Place of Presentation
Hawaii USA
Year and Date
2007-09-29
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Role of TGF-b-independent smad3 action in FTH-induced Wnt-b-catenin signaling in osteoblastic cells2006
Author(s)
Kaji, H., Tobimatsu, T., Inoue, Y., Sowa, H., Naito, J., Canaff, L., Hendy, GN., Sugimoto, T., Chihgara, K
Organizer
The American Society for Bone Mineral Research
Place of Presentation
Phyradelphia USA
Year and Date
2006-09-28
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Adiponectin stimulates the proliferation, differentiation and mineralization of osteoblastic MC3T3-E1 cells via the adiponectin receptor typel and AMMP signaling pathway2006
Author(s)
Kanazawa, I., Yamaguchi, T., Yano, S., Yamauchi, M., Yamamoto, M., Sugimoto, T
Organizer
3rd International Osteoporosis Foundation Asia-Pacific Regional Conference onn Osteoporosis & 16th Annual Meeting of the Australian and New Zealand Bone and Mineral Society
Place of Presentation
Port Douglas, Australia
Description
「研究成果報告書概要(欧文)」より
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