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Research for the elucidation of bone formation signals applied to the development of bone-forming agents

Research Project

Project/Area Number 18591025
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionShimane University

Principal Investigator

SUGIMOTO Toshitsugu  Shimane University, Department of Medicine, Professor (00226458)

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)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
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)
KeywordsParathyroid 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
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 … More 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

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (24 results)

All 2007 2006 Other

All Journal Article (16 results) (of which Peer Reviewed: 6 results) Presentation (6 results) Book (2 results)

  • [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
    • Journal Title

      Horm Metab Res 39

      Pages: 871-875

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] The uraemic toxin phenylacetic acid inhibits osteoblastic proliferation and differentiation2007

    • Author(s)
      Yano S
    • Journal Title

      Nephrol Dial Transplant 22

      Pages: 3160-3165

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The combination of high glucose and advanced glycation end-products. (AGEs) inhibits the mineralization of osteoblastic MC3T3-E1 cells through glucose-induced increase in the receptor for AGEs2007

    • Author(s)
      Ogawa N
    • Journal Title

      Horm Metab Res 39

      Pages: 871-875

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Parathyroid hormone increases β-catenin levels through smad3 in mouse osteoblastis colls2006

    • Author(s)
      Tobimatsu T
    • Journal Title

      Endocrinology 147

      Pages: 2583-2590

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Smad3 directly affects osteoblast differetiation in amanner dependent upon differentiation stase2006

    • Author(s)
      Kaji H
    • Journal Title

      Horm Metab Res 38

      Pages: 740-745

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [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
    • Journal Title

      Endocrinology

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Smad3 differently affects osteoblast differentiation in amanner dependent upon its differentiation stage2006

    • Author(s)
      Kaji, H., Naito, J., Sowa, H., Sugimoto, T., Chihara, K
    • Journal Title

      Horm Metab Res

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Body composition and ventebral tractures in female patients treated with osteoporosis2006

    • Author(s)
      Kaji H
    • Journal Title

      Osteoporosis Int 17・4

      Pages: 627-633

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Parathyroid hormone increases β-catenin leuels through smad 3 in mouse osteoblastic cells2006

    • Author(s)
      Tobinatsu T
    • Journal Title

      Endocrinology 147・5

      Pages: 2583-2590

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Theusefulness of bone metabolic indices for the prediction of changes in bone mineral density after parethyroidectomy2006

    • Author(s)
      Kaji H
    • Journal Title

      Horm Metab Res 38・6

      Pages: 411-416

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Exporession and functional analysis of menin in new patient with somatic loss of heterozygosity in chronosome 11g132006

    • Author(s)
      Natio J
    • Journal Title

      Endocrine 29・3

      Pages: 485-490

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Senim soluble factors induces the proliferation, ALP activity and TGFA signal in osteoblastic cells.2006

    • Author(s)
      Kaji H
    • Journal Title

      Exp Clin Endocrinol Diabetes 114・10

      Pages: 599-604

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Smad 3 directly affects osteoblast differentiation in a manner dependent upon its differentiation stage2006

    • Author(s)
      Kaji H
    • Journal Title

      Horm Metab Res 38・11

      Pages: 740-745

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Adiponectin and AMP kinase activator stimulate proliferotion, differentiation and mineralization of osteoblastic MC3T3-E1 cells

    • Author(s)
      Kanazawa I
    • Journal Title

      BMC Cell Biol (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [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
    • Journal Title

      BMC Cell Biol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Adiponectin and AMP kinase activator stimulate prolifera- tion, differentiation, and mineralization of osteoblastic MC3T3-E1 cells.

    • Author(s)
      Kanazawa I
    • Journal Title

      BMC Cell Biol (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [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
      2007 Final Research Report Summary
  • [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
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Glucocorticoid suppresses the differentiation of osteobl asfs by enhancing the expression of BMP antagonists and alendronme and PTH a bolish this press2007

    • Author(s)
      Hayashi K
    • Organizer
      American Society for Bone Mineral Research
    • Place of Presentation
      Hawaii(USA)
    • Year and Date
      2007-09-17
    • Related Report
      2007 Annual Research Report
  • [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
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 骨形成促迫剤の臨床応用への展開2006

    • Author(s)
      杉本利嗣
    • Organizer
      日本骨形態計測学会
    • Place of Presentation
      新潟
    • Year and Date
      2006-07-27
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [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
    • Related Report
      2007 Final Research Report Summary
  • [Book] 内科学、原発性、二次性副甲状腺機能大迫症2007

    • Author(s)
      杉本利嗣
    • Total Pages
      2008
    • Publisher
      朝倉書店
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] 内科学 原発性、二次性副甲状腺機能圧迫症2007

    • Author(s)
      杉本利嗣
    • Total Pages
      2008
    • Publisher
      朝倉書店
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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