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Study of the molecular targeting therapy for rheumatoid arthritis.

Research Project

Project/Area Number 13307044
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Orthopaedic surgery
Research InstitutionSaitama medical school (2004)
The University of Tokyo (2001-2003)

Principal Investigator

ODA Hiromi  Saitama medical University, Professor, 医学部, 教授 (60101698)

Co-Investigator(Kenkyū-buntansha) TANAKA Sakae  The Univ. of Tokyo Hosp., Assistant Professor, 医学部附属病院, 講師 (50282661)
高柳 広  東京医科歯科大学, 大学院・医歯学総合研究科・分子細胞機能学, 特任教授 (20334229)
AKIYAMA Toru  The Univ. of Tokyo Hosp., Associate, 医学部附属病院, 助手
Project Period (FY) 2001 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000)
Fiscal Year 2004: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2003: ¥13,390,000 (Direct Cost: ¥10,300,000、Indirect Cost: ¥3,090,000)
Fiscal Year 2002: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2001: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
KeywordsOsteoclast / Apoptosis / Bim / Ubiquitination / 滑膜細胞 / ALK3 / 軟骨細胞 / RANKL / インターフェロン / 転写因子 / NFATc1 / 骨破壊 / C-Fos
Research Abstract

Osteoclasts are cells of monocyte/macrophage origin that degrade the bone matrix. They are among the key players in the control of bone metabolism in health and disease. Receptor activator of NF-kappaB ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, induces the differentiation of osteoclasts in the presence of macrophage-colony stimulating factor. RANKL activates TRAF6, c-Fos, and calcium signaling pathways, all of which are indispensable for the induction and activation of nuclear factor of activated T cells (NFAT) c1, the master transcription factor for osteoclastogenesis. The autoamplification of NFATc1 gene results in the efficient induction of osteoclast-specific genes. An AP-1 transcription factor complex containing c-Fos plays a crucial role in these processes, although results in conditional knockout mice show that Jun family members have a redundant role. The immunoreceptor tyrosine-based activation motif (ITAM) is an important signaling component for a number o … More f receptors in the immune system including T-cell, B-cell, NK-cell, and Fc receptors, but its contribution to the skeletal system remains unclarified. In search for the calcium-mobilizing mechanism during osteoclastogenesis we determined that multiple immunoglobulin-like receptors associated with ITAM-harboring adaptors, Fc receptor common gamma chain (FcRgamma), and DNAX-activating protein (DAP) 12, are essential for osteoclastogenesis. In osteoclast precursor cells FcRgamma-associated receptors include osteoclast-associated receptor and paired immunoglobulin-like receptor A, while triggering receptor expressed in myeloid cells 2 and signal-regulatory protein betal preferentially associate with DAP12. In cooperation with RANKL these receptors activate phospholipase Cgamma and calcium signaling essential for the induction of NFATc1 through ITAM phosphorylation. Thus we have established the importance of the ITAM-mediated costimulatory signals in RANKL-induced osteoclast differentiation, which is analogous to the role of costimulatory signals in the immune system. Here we summarize recent advances in the study of signaling mechanism of osteoclast differentiation in the context of osteoimmunology. Less

Report

(5 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (23 results)

All 2004 2003 2002 Other

All Journal Article (11 results) Publications (12 results)

  • [Journal Article] Chondromodulin-I, a cartilage-derived angiogenesis inhibitory factor, suppresses T cell response ; an implication of a therapeutic potential for the treatment of arthritis.2004

    • Author(s)
      Setoguchi K, Misaki Y, Kawahata K, Shimada K, Juji T, Tanaka S, Oda H, Shukunami C, Nishizaki Y, Hiraki Y, Yamamoto K.
    • Journal Title

      Arthritis Rheum 50

      Pages: 828-839

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation.2004

    • Author(s)
      Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hata K, Yamashita K, Hiraga T, Watanabe T, Kukita T, Yoshioka K, Rao A, Yoneda T.
    • Journal Title

      J Clin Invest 114

      Pages: 475-484

    • NAID

      120001106909

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Monokine induced by interferon-gamma is induced by receptor activator of nuclear factor κB ligand and involved in osteoclast adhesion and migration.2004

    • Author(s)
      Kwak HB, Lee SW, Jim HM, Ha H, Lee SH, Takeshita S, Tanaka S, Kim HM, Kim HH, Lee ZH.
    • Journal Title

      Blood. Dec7(Epub ahead of print)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RRANKL for bone homeostasis.2004

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

      Nature 428

      Pages: 758-763

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis2004

    • Author(s)
      Koga T, Inui M, Inoue K, Kim S, Suematsu A, Kobayashi E, Iwata T, Ohnishi H, Matozaki T, Kodama T, Taniguchi T, Takayanagi H, Takai T
    • Journal Title

      Nature 428

      Pages: 758-763

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Chondromodulin-I, a cartilage-derived angiogenesis inhibitory factor, suppresses T cell response ; an implication of a therapeutic potential for the treatment of arthritis.2004

    • Author(s)
      Setoguchi K, Misaki Y, Kawahata K, Shimada K, Juji I, Tanaka S, Oda H, Shukunami C, Nishizaki Y, Hiraki Y, Yamamoto K.
    • Journal Title

      Arthritis Rheum 50

      Pages: 828-839

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. 2004,114:475-484.2004

    • Author(s)
      Ikeda F, Nishimura R, Matsubara T, Tanaka S, Inoue J, Reddy SV, Hta K, Yamashita K, Hiraga T, Watanabe I, Kukita T, Yoshioka K, Rao A, Yoneda T.
    • Journal Title

      J Clin Invest 114

      Pages: 475-484

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Monokine induced by interferon-gamma is induced by receptor activator of nuclear factor κB ligand and involved in osteoclast adhesion and migration.2004

    • Author(s)
      Kwak HB, Lee SW, Jin HM, Ha H, Lee SH, Takeshita S, Tanaka S, Kim HM, Kim RH, Lee ZH.
    • Journal Title

      Blood. 428

      Pages: 758-763

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Signal transduction pathways regulating osteoclast differentiation and function2003

    • Author(s)
      Tanaka, S., Nakamura, I., Inoue, J., Oda, H., Nakamura, K.
    • Journal Title

      J Bone Miner Metab 21

      Pages: 123-133

    • NAID

      10014444230

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Suppression of arthritic bone destruction by adenovirus-mediated dominant negative ras gene transfer to synoviocytes and osteoclasts2003

    • Author(s)
      Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S
    • Journal Title

      Arthritis Rheum 48

      Pages: 2682-2692

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts2002

    • Author(s)
      Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T
    • Journal Title

      Dev Cell 3

      Pages: 889-901

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Yamamoto A, Fukuda A, Seto H, Miyazaki T, Kadono Y, Sawada Y, Nakamura I, Katagiri H, Asano T, Tanaka Y, Oda H, Nakamura K, Tanaka S: "Suppression of arthritic bone destruction by adenovirus-mediated dominant negative ras gene transfer to synoviocytes and osteoclasts."Arthritis Rheum. 48. 2682-2692 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kim H-H, Chung WJ, Lee SW, Chung P-J, You JW, Kwon HJ, Tanaka S, Lee ZH: "Sustained ERK Activity with Integrin β3 Induction during Receptor Activator of Nuclear Factor KappaB Ligand (RANKL)-directed Osteoclast Differentiation."Exp Cell Res. 289. 368-377 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Akiyama T, Bouillet P, Miyazaki T, Kadono Y, Chikuda H, Chung U, Fukuda A, Hikita A, Seto H, Okada T, Inaba T, Sanjay A, Baron R, Kawaguchi H, Oda H, Nakamura K, Strasser A, Tanaka S: "Regulation of Osteoclast Apoptosis by Ubiquitination of Proapoptotic BH3-only Bcl-2 Family Member Bim."Embo J.. 22. 6653-6664 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takayanagi, H., Kim, S., Matsuo, K.他4名: "RANKL maintains bone homeostasis through c-Fos-dependent induction of IFN-β"Nature. 416. 744-749 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takayanagi, H., Kim, S., Koga, T.他11名: "Induction and activation of the transcription factor NFATc1(NFAT2)integrate RANKL signaling for terminal differentiation of osteoclasts"Developmental Cell. 3. 889-901 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takayanagi, H., Kim, S., Taniguchi, T: "Signaling crosstalk between RANKL and interferons in osteoclast differentiation"Arthritis Research. 4. S227-232 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakamura K, Oda, H, Tanaka S, Kuga Y, Yamamoto M, Nishikawa T, juii T Shimizu: "Usefulness of absorbable screws in the Sauve-Kapandji procedure for rheumatoid wrist reconstruction"Mod Rheumatol. 12. 144-147 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokchi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T: "RANKL maintains bone homeostasis thorough c-Fos-dependent induction of IFN-β"Nature. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Sato K, Hida S, Takayanagi H, Yokochi T, Kayagaki N, Takeda K, Yagita H, Okumura K, Tanaka N, Taniguchi T, Ogasawara K: "Antiviral response by natural killer cells through TRAIL gene induction by IFN-α/β"Eur J Immunol. 31. 3138-3146 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yamamoto A, Miyazaki T, Kadono Y, Takayanagi H, Miura T, Wakabayashi K, Nisimura H, Katada T, Oda H, Nakamura K, Tanaka S.: "Requirement of Both NF-B and JNK Pathways for Osteoclastogenesis Induced by Receptor Activator of NF-B Ligand (RANKL)."Journal of Bone and Mineral Research. (In press).

    • Related Report
      2001 Annual Research Report
  • [Publications] 高柳 広: "高柳 広"リウマチ科. 25(5). 461-467 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 高柳 広: "T細胞による破骨細胞制御機構-IFN-γの関与-"臨床免疫. 36(6). 930-936 (2001)

    • Related Report
      2001 Annual Research Report

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

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