Study of the molecular targeting therapy for rheumatoid arthritis.

2004 Fiscal Year Final Research Report Summary

• Project/Area Number: 13307044
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Saitama 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
• Keywords: Osteoclast / Apoptosis / Bim / Ubiquitination

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 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.

Research Products

• [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
• [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
  • Description: 「研究成果報告書概要(和文)」より
• [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
• [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
• [Journal Article] Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis (2004)
  • 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
• [Journal Article] Signal transduction pathways regulating osteoclast differentiation and function (2003)
  • Author(s): Tanaka, S., Nakamura, I., Inoue, J., Oda, H., Nakamura, K.
  • Journal Title: J Bone Miner Metab 21 Pages: 123-133
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Suppression of arthritic bone destruction by adenovirus-mediated dominant negative ras gene transfer to synoviocytes and osteoclasts (2003)
  • 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
• [Journal Article] Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts (2002)
  • 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