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A STUDY ON THE CONTROL OF BONE DESTRUCTION USING OSTEOCLAST DIFFERENTIATION FACTOR AS A TARGET

Research Project

Project/Area Number 13480205
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionTHE UNIVERSITY OF TOKYO

Principal Investigator

YASUDA Hisataka  THE UNIVERSITY OF TOKYO, INSTITUTE of MEDICAL SCIENCE, LECTURER, 医科学研究所, 講師 (90323641)

Co-Investigator(Kenkyū-buntansha) SUDO Katsuko  THE UNIVERSITY OF TOKYO, INSTITUTE OF MEDICAL SCIENCE, RESEARCH ASSOCIATE, 医科学研究所, 助手 (50126091)
IWAKURA Yoichiro  THE UNIVERSITY OF TOKYO, INSTITUTE OF MEDICAL SCIENCE, PROFESSOR, 医科学研究所, 教授 (10089120)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2003: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2002: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2001: ¥6,200,000 (Direct Cost: ¥6,200,000)
KeywordsBONE DESTRUCTION / OSTEOCLASTS / OSTEOCLAST DIFFERENTIATION FACTOR / OSTEOCLASTOGENESIS INHIBITORY FACTOR / TRANSGENIC MICE
Research Abstract

Osteoclast differentiation factor, RANKL, is a membrane-bound protein. It is thought that RANKL functions as a membrane-form because osteoclast differentiation requires the interaction between osteoclast progenitors and osteoblasts. Although it is reported that soluble RANKL (sRANKL) is produced by activated T -cells and sRANKL is involved in the inflammatory bone destruction, the function of sRANKL is unknown. We generated transgenic (TG) mice overexpressing sRANKL to investigate the physiological roles of sRANKL. The TG mice as well as osteoclastogenesis inhibitory factor, osteoprotegerin (OPG)-deficient (KO) mice exhibited severe osteoporosis. These results suggest that overexpresssion of sRANKL in vivo due to pathological conditions such as inflammation results in bone destruction. The number of osteoclasts increases in both sRANKL-TG nice and OPG-KO mice by the similar mechanism that the increase of the ratio of RANKL and OPG in bone causes osteoclast differentiation. The coupling between bone formation and bone resorption observed in OPG-KO mice was not observed in sRANKL-TG mice. The detailed comparison of the phenotypes of the two types of mice will facilitate the identification of the coupling mechanism and coupling factors involved in the process.
Runx2 is the transcription factor essential for osteoblast differentiation. Runx2-KO mice have cartridge but lack osteoblasts and bone. Runx2-KO mice almost lack osteoclasts probably due to the absence of osteoblasts. We mated Runx2-KO mice and sRANKL-TG mice to investigate the mechanism by which Runx2-KO mice lack osteoclasts. The number of osteoclasts increased in Runx2-KO/sRANKL-TG mice, suggesting that the osteoclast differentiation in Runx2-KO/sRANKL-TG mice was restored by sRANKL and that osteoblasts differentiated by Runx2 was the source of RANKL.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Enomoto, H. et al.: "Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-/- mice by RANKL transgene"J Biol Chem. 278. 23971-23977 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice."J Immunol. 171. 6173-6177 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist."Proc Natl Acad Sci USA. 100. 5986-5990 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizuno, A. et al.: "Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis"J Bone Miner Metab. 20. 337-344 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saijo, S. et al.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaire due to low levels of CD40L and OX40 expression on T cells"Arth Rheum. 46. 533-544 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, resulting in the suppression of allergic cellular and humoral responses"Immunity. 17. 375-387 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yasuda, H. et al.: "Vitamin D, Second Edition, Vitamin D and Osteoclastogenesis"Academic Press(In press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Enomoto, H. et al.: "Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-/-mice by RANKL transgene"J Biol Chem. 278. 23971-23977 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice."J Immunol,. 171. 6173-6177 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist."Proc Natl Acad Sci USA. 100. 5986-5990 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Mizuno, A. et al.: "Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis"J Bone Miner Metab. 20. 337-344 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Saijo, S. et al.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells"Arth Rheum. 46. 533-544 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nakae, S. et al.: "Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, resulting in the suppression of allergic cellular and humoral responses"Immunity. 17. 375-387 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yano, K. et al.: "Synovial cells from a patient with rheumatoid arthritis produce osteoclastogenesis inhibitory factor/osteoprotegerin : reciprocal regulation of the production by inflammatory cytokine and basic fibroblast growth factor"J Bone Miner Metab. 19. 365-372 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Quinn, J.M.W.et al.: "Transforming growth factor affects osteoclast differentiation via direct and indirect action"J Bone Miner Res. 16. 1787-1794 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Itoh K.et al.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand"Endocrinology. 142. 3656-3662 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yasuda, H. et al.: "Vitamin D and Osteoclastogenesis"Vitamin D, Second Edition (Academic Press). (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Enomoto, H. et al.: "Induction of osteoclast differentiation by Runx2 through receptor activator of nuclear factor-kappa B ligand (RANKL) and osteoprotegerin regulation and partial rescue of osteoclastogenesis in Runx2-/- mice by RANKL transgene"J Biol Chem. 278. 23971-23977 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakae, S. et al.: "Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice."J Immunol. 171. 6173-6177 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakae, S. et al.: "IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist."Proc Natl Acad Sci USA. 100. 5986-5990 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yasuda, H., et al.: "Vitamin D, Second Edition, Vitamin D and Osteoclastogenesis"Academic Press (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mizuno, A.: "Transgenic mice overexpressing soluble osteoclast differentiation factor (sODF) exhibit severe osteoporosis"J. Bone Miner. Metab.. 20. 337-344 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells"Arth. Rheum.. 46. 533-544 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakae, S.: "Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, resulting in the suppression of allergic cellular and humoral responses"Immunity. 17. 375-387 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yano, K.: "Synovial cells from a patient with rheumatoid arthritis produce osteoclastogenesis inhibitory factor/osteoprotegerin : reciprocal regulation of the production by inflammatory cytokine and basic fibroblast growth factor"J Bone Miner. Metab. 19. 365-372 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Quinn, J.M.W.: "Transforming growth factor β affects osteoclast differentiation via direct and indirect actions"J.Bone Miner.Res.. 16. 1787-1794 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh K.: "Bone morphogenetic protein 2 stimulates osteoclast differentiation and survival supported by receptor activator of nuclear factor-kappaB ligand"Endocrinology. 142. 3656-3662 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD40L and OX40 expression on T cells"Arth.Rheum.. 46. 533-544 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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