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Analysis of regulatory mechanisms of bone metabolism utilizing TAK1-conditional knockout mice

Research Project

Project/Area Number 16390434
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionSaitama Medical University (2006)
Tokyo Medical and Dental University (2004-2005)

Principal Investigator

SATO Kojiro  Saitama Medical University, Faculty of Medicine, Assistant professor, 医学部, 講師 (10372434)

Co-Investigator(Kenkyū-buntansha) TAKAYANAGI Hiroshi  Tokyo Medical and Dental University, Graduate School, Professor, 大学院医歯学総合研究科, 教授 (20334229)
ASAGIRI Masataka  Tokyo Medical and Dental University, Graduate School, Assistant professor, 大学院医歯学総合研究科, 特任講師 (20372435)
Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥12,800,000 (Direct Cost: ¥12,800,000)
Fiscal Year 2006: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
Fiscal Year 2004: ¥5,200,000 (Direct Cost: ¥5,200,000)
Keywordsosteoclast / bone metabolism / kinase / transcription factor / immunology / osteoporosis / rheumatoid arthritis / T cell / 骨芽細胞 / 骨免疫学 / ホスファターゼ / コンディショナルノックアウト / TAK1 / 質量分析 / コンディショナルノックアウトマウス / MAPキナーゼ / レトロウイルスベクター
Research Abstract

Osteoclasts are specially differentiated multinucleated macrophages that resorb bone matrix. Their function is essential for normal bone metabolism ; their dysfunction causes osteopetrosis and their hyper-function can lead to osteoporosis or bone destruction observed in rheumatoid arthritis. Thus, it is important to understand the mechanisms of their differentiation and functions.
We previously reported that a transcription factor NFATc1 is strongly induced in the course of osteoclastogenesis in vitro. During the period covered by this grant, we showed that (1) NFATc1 is indeed required for osteoclastogenesis in vivo and that (2) one of immunoreceptors, OSCAR, is a target of NFATc1 whilst it is involved in activation of NFATc1, thus constituting a novel positive feedback system. We also discovered a novel T helper cell subset, now called Th17 cells, which can enhance osteoclastogenesis. Th1 and Th2 cells strongly suppressed osteoclastogenesis, casting doubt on the notion that rheumatoid … More arthritis (RA), in which bone destruction is one of the characteristics, is a Th1 disease. IL-17 that is produced by Th17 cells and IL-23 that is required for Th17 cell expansion could be promising targets for the treatment of RA. Finally, we found that calcium/calmodulin-dependent kinases (CaMKs) are involved in osteoclastogenesis. Among them, we showed through knockdown experiments that CaMKIV is especially important. In fact, CaMKIV KO mice showed increased bone mass (osteopetrosis) because of reduced osteoclastogenesis. The molecular target of CaMKIV seems to be a transcription factor CREB, which is required for NFATc1 induction, because forced expression of constitutive active CREB can rescue osteoclast differentiation in the presence of CaMK inhibitor in vitro. In mouse models bone destruction (an LPS injection model) and osteoporosis (an ovariectomy model), the CaMK inhibitor ameriolated both of the diseases. Thus, CaMK-CREB pathway is also a promising target in the treatment of bone diseases. Less

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (38 results)

All 2006 2005 2004 Other

All Journal Article (38 results)

  • [Journal Article] Osteoclasts, rheumatoid arthritis, and osteoimmunology.2006

    • Author(s)
      Sato Kojiro
    • Journal Title

      Current Opinion of Rheumatology 18(4)

      Pages: 419-426

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction.2006

    • Author(s)
      Sato Kojiro
    • Journal Title

      Journal of Experimental Medicine 203(12)

      Pages: 2673-2682

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Regulation of osteoclast differentiation and function by the CaMK-CREB pathway.2006

    • Author(s)
      Sato Kojiro
    • Journal Title

      Nature Medicine 12(12)

      Pages: 1410-1416

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] 破骨細胞分化第3シグナルの発見-骨免疫学の視点から2006

    • Author(s)
      佐藤 浩二郎
    • Journal Title

      実験医学増刊号 24(5)

      Pages: 764-769

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction2006

    • Author(s)
      Sato Kojiro
    • Journal Title

      Journal of Experimental Medicine 203(12)

      Pages: 2673-82

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Regulation of osteoclast differentiation and function by the CaMK-CREB pathway2006

    • Author(s)
      Sato Kojiro
    • Journal Title

      Nature Medicine 12(12)

      Pages: 1410-6

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Downregulation of IL-12 and a novel negative feedback system mediated by CD25+CD4+ T cells.2005

    • Author(s)
      Sato Kojiro
    • Journal Title

      Biochem Biophys Res Commun. 330(1)

      Pages: 226-232

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis.2005

    • Author(s)
      Kim Yoonji
    • Journal Title

      Journal of Biological Chemistry 280(38)

      Pages: 32905-32913

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Autoamplification of NFATc1 expression determines its essential role in bone homeostasis.2005

    • Author(s)
      Asagiri Masataka
    • Journal Title

      Journal of Experimental Medicine 202(9)

      Pages: 1261-1269

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Interplay between interferon and other cytokine systems in bone metabolism.2005

    • Author(s)
      Takayanagi Hiroshi
    • Journal Title

      Immunology Review 208

      Pages: 181-193

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] T細胞と骨破壊2005

    • Author(s)
      佐藤 浩二郎
    • Journal Title

      炎症と免疫 24(5)

      Pages: 441-446

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 活性化T細胞による破骨細胞分化制御2005

    • Author(s)
      佐藤 浩二郎
    • Journal Title

      日本臨床 63(9)

      Pages: 1529-1532

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Downregulation of IL-12 and a novel negative feedback system mediated by CD25+CD4+ T cells2005

    • Author(s)
      Sato Kojiro
    • Journal Title

      Biochem Biophys Res Commun 330(1)

      Pages: 226-32

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis2005

    • Author(s)
      Kim Yoonji
    • Journal Title

      Journal of Biological Chemistry 280(38)

      Pages: 32905-13

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Autoamplification of NFATc1 expression determines its essential role in bone homeostasis2005

    • Author(s)
      Asagiri Masataka
    • Journal Title

      Journal of Experimental Medicine 202(9)

      Pages: 1261-9

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Interplay between interferon and other cytokine systems in bone metabolism2005

    • Author(s)
      Takayanagi Hiroshi
    • Journal Title

      Immunology Review 208

      Pages: 181-93

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Osteoclasts, rheumatoid arthritis, and osteoimmunology2005

    • Author(s)
      Sato Kojiro
    • Journal Title

      Current Opinion of Rheumatology 18(4)

      Pages: 419-26

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Autoamplification of NFATc1 determines its essential role in bone homeostasis.2005

    • Author(s)
      Asagiri, M. et al.
    • Journal Title

      J Exp Med 202・9

      Pages: 1261-1269

    • Related Report
      2005 Annual Research Report
  • [Journal Article] NFAT and Osterix cooperatively regulate bone formation.2005

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

      Nat Med 11・8

      Pages: 880-885

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Contribution of NFATc1 to the transcriptional control of immunoreceptor OSCAR but not TREM-2 during osteoclastogenesis.2005

    • Author(s)
      Kim, Y.et al.
    • Journal Title

      J Biol Chem 280・38

      Pages: 32905-32913

    • Related Report
      2005 Annual Research Report
  • [Journal Article] μ-calpain regulates RANKL-supported osteoclastogenesis via NF-kB activation in raw 264.7 cells.2005

    • Author(s)
      Lee, F.Y.et al.
    • Journal Title

      J Biol Chem 280・33

      Pages: 29929-29936

    • Related Report
      2005 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 24・4

      Pages: 790-799

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition of RANKL-induced Osteoclastogenesis by (-)-DHMEQ, a Novel NF-κB Inhibitor, through Downregulation of NFATc1.2005

    • Author(s)
      Takatsuna, H. et al.
    • Journal Title

      J Bone Mineral Res 20・4

      Pages: 653-662

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Interplay between interferon and other cytokine systems in bone metabolism.2005

    • Author(s)
      Takayanagi, H. et al.
    • Journal Title

      Immunol Rev 208

      Pages: 181-193

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Osteoimmunological insight into bone damage in rheumatoid arthritis.2005

    • Author(s)
      Takayanagi, R.
    • Journal Title

      Mod Rheumatol 15・4

      Pages: 225-231

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inflammatory bone destruction and osteoimmunology.2005

    • Author(s)
      Takayanagi, H.
    • Journal Title

      J Periodontal Res 40・4

      Pages: 287-293

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Mechanistic insight into osteoclast differentiation in osteoimmunology.2005

    • Author(s)
      Takayanagi, H.
    • Journal Title

      J Mol Med 83・3

      Pages: 170-179

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Stat1-mediated cytoplasmic attenuation in osteoimmunology.2005

    • Author(s)
      Takayanagi, H. et al.
    • Journal Title

      J Cell Biochem 94・2

      Pages: 232-240

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

    • Author(s)
      Gohda, J., Akiyama, T., Koga, T., Takayanagi, H., 他2名
    • Journal Title

      EMBO 24・4

      Pages: 790-799

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions.2004

    • Author(s)
      Sato Kojiro
    • Journal Title

      Biochem Biophys Res Commun. 318(4)

      Pages: 935-940

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 多腺性自己免疫症候群2004

    • Author(s)
      佐藤 浩二郎
    • Journal Title

      臨床看護増刊号 30(6)

      Pages: 831-834

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] CD25^+CD4^+T細胞によるCD4^+T細胞の増殖抑制機構2004

    • Author(s)
      佐藤 浩二郎
    • Journal Title

      臨床免疫 42(4)

      Pages: 421-426

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions2004

    • Author(s)
      Sato Kojiro
    • Journal Title

      Biochem Biophys Res Commun 318(4)

      Pages: 935-40

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Essential role of p38 MAP kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1.2004

    • Author(s)
      Matsumoto, M., Kogawa, M., Wada, S., Takayanagi, H., 他4名
    • Journal Title

      J Biol Chem. 279・44

      Pages: 45969-45979

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.2004

    • Author(s)
      Koga, I., Inui, M., Inoue, K., Kim, S., Suematsu.A., 他8名
    • Journal Title

      Nature 428

      Pages: 758-763

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF-κB ligand-stimulated induction of nuclear factor of activated T cells c1.2004

    • Author(s)
      Urushibara, M., Takayanagi, H.^*, Koga, T., Kim, S., 他7名
    • Journal Title

      Arthritis Rheum 50(3)

      Pages: 794-804

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Aire downregulates multiple molecules that have contradicting immune-enhancing and immune-suppressive functions.2004

    • Author(s)
      Sato, K., Sato, U., Tateishi, S., Horikawa.R., 他3名
    • Journal Title

      Biochem Biophys Res Commun. 318(4)

      Pages: 935-940

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibition of RANKL-induced Osteoclastogenesis by (-)-DHMEQ, a Novel NF-κB Inhibitor. through Downregulation of NFATc1.

    • Author(s)
      Takatsuna, H., Asagiri, M., Kubota, T., Oka, K., 他7名
    • Journal Title

      J Bone Mineral Res (in press)

    • Related Report
      2004 Annual Research Report

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

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