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Elucidation of molecular mechanisms of osteoclastogenesis and its application for bone disease therapy

Research Project

Project/Area Number 16390428
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionThe University of Tokyo

Principal Investigator

INOUE Jun-ichiro  The University of Tokyo, Institute of Medical Science, Professor, 医科学研究所, 教授 (70176428)

Co-Investigator(Kenkyū-buntansha) GOHDA Jin  The University of Tokyo, Institute of Medical Science, Assistant Professor, 医科学研究所, 助手 (90361617)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2005: ¥6,900,000 (Direct Cost: ¥6,900,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
KeywordsRANK / CD40 / TRAF6 / osteoclast / NFAT / リウマチ / 骨粗鬆症 / 創薬
Research Abstract

RANK and CD40 activate NF-kB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK-specific activity in osteoclastogenesis, we created an osteoclast formation system driven by antihuman CD40 antibody-mediated stimulation of a chimeric receptor, h40/mRK, which consists of the extra cellular domain of human CD40 and the transmembrane and cytoplasmic domains of mouse RANK. By introducing mutations into three TRAF6-binding sites of RANK, we found that h40/mRK with a single TRAF6-binding site efficiently induced Ca2+ oscillation and expression of NFATc1, a master switch in osteoclastogenesis, whereas CD40 carrying a single TRAF6-binding site did not. However, expression of CD40 that was approximately 100 times greater than that of h40/mRK resulted in osteoclast formation, indicating that the RANK-TRAF6 signal is more potent than the CD40-TRAF6 signal in terms of NFATc1 activation and osteoclastogenesis. These results suggest that RANK may harbor a specific domain that amplifies TRAF6 signaling. To identify the specific domain, we have introduced various deletion into the cytoplasmic domain of RANK. We found a deletion mutant that can activate NF-kB and MAPKs but can not generate ostesoclasts. The domain missing in this mutant is highly conserved among various species, suggesting that the domain could be critical in TRAF6 activation required for osteoclastogenesis. We are currently focusing on this domain.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (12 results)

All 2006 2005 2004

All Journal Article (12 results)

  • [Journal Article] Involvement of TNF Receptor-associaetd Factor (TRAF) 6 in IL-25 Receptor Signaling2006

    • Author(s)
      Maezawa, Y.
    • Journal Title

      J Immunol. 176

      Pages: 1013-1018

    • Related Report
      2005 Annual Research Report
  • [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis2005

    • Author(s)
      Gohda, J, et al.
    • Journal Title

      EMBO J 24

      Pages: 790-799

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.2005

    • Author(s)
      Gohda, J., Akiyama, T., Koga, T., Takayanagi, H., Tanaka, S., Inoue, J.
    • Journal Title

      EMBO J 24

      Pages: 790-799

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dependence of Self-tolerance on TRAF6-directed Development of Thymic Stroma2005

    • Author(s)
      Akiyama, T
    • Journal Title

      Science 308

      Pages: 248-251

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification and characterization of Xenopus laevis homologs of mammalian TRAF6 and its binding protein TIFA2005

    • Author(s)
      Inoue, J.
    • Journal Title

      Gene 358

      Pages: 53-59

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Recruitment of TRAF family protein to The ASK1 signalosome is essential for oxidative stress-induced cell death2005

    • Author(s)
      Noguchi, T.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 37033-37040

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification of DRG family regulatory proteins (DFRPs) : specific regulation of DRG1 and DRG2.2005

    • Author(s)
      Ishikawa, K. et al.
    • Journal Title

      Genes Cells 10

      Pages: 139-150

    • Related Report
      2004 Annual Research Report
  • [Journal Article] RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.2005

    • Author(s)
      Gohda, J. et al.
    • Journal Title

      EMBO J 24

      Pages: 790-799

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Dependence of Self-tolerance on TRAF6-directed Development of Thymic Stroma.2005

    • Author(s)
      Akiyama, T. et al.
    • Journal Title

      Science Feb.10(Epub ahead of print)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] TIFAB inhibits TIFA, TRAF-interacting protein with a forkhead-associated domain2004

    • Author(s)
      Matsumura, T. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 317

      Pages: 230-234

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cutting Edge : TNF Receptor-Associated Factor (TRAF) 6 is Essential for Myeloid Differentiation Factor (MyD) 88-Dependent Pathway but Not Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-β (TRIF)-Dependent Pathway in Toll-like Receptor Signaling2004

    • Author(s)
      Gohda, J. et al.
    • Journal Title

      J.Immunol. 173

      Pages: 2913-2917

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF62004

    • Author(s)
      Kawai, T. et al.
    • Journal Title

      Nat.Immunol. 10

      Pages: 1061-1068

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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