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老化関連骨軟骨疾患におけるklotho遺伝子の関与

Research Project

Project/Area Number 12137201
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

川口 浩  東京大学, 医学部附属病院, 助教授 (40282660)

Co-Investigator(Kenkyū-buntansha) 星 和人  東京大学, 医学部附属病院, 寄附講座教員(客員助教授) (30344451)
小崎 慶介  東京大学, 医学部・附属病院, 助手 (60302692)
Project Period (FY) 2000 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥50,000,000 (Direct Cost: ¥50,000,000)
Fiscal Year 2004: ¥11,400,000 (Direct Cost: ¥11,400,000)
Fiscal Year 2003: ¥12,600,000 (Direct Cost: ¥12,600,000)
Fiscal Year 2002: ¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 2001: ¥13,100,000 (Direct Cost: ¥13,100,000)
Keywords老化 / klotho / 副甲状腺ホルモン(PTH) / インスリン受容体基質(IRS) / PPAR-gamma / 骨粗鬆症 / PPARγ / IRS / 骨 / PPAR-γ / 遺伝子解析 / 変形性脊椎症 / 遺伝子多型 / SNP
Research Abstract

本研究の目的は、老化による骨粗鬆化の分子メカニズムを解明することであり、老化抑制全身因子であるklotho、細胞内分子であるPPAR-gamma、局所因子であるインスリン受容体基質(IRS)-1およびIRS-2について、ノックアウトマウス(KO)を用いたreverse genetics、および臨床患者のゲノム解析を用いたforward geneticsの手法を用いて検討することである。
本年度はまず、ヒトPPAR-gamma,IRS-1,IRS-2各遺伝子におけるSNPsのスクリーニングを行い骨密度との相関解析を行ったが、現在のところ有意な相関は認められていない。今後は年齢別の層別化検討を予定している。
また、老化による骨粗鬆症に対する骨形成能を持つ治療薬として注目されているPTHの骨同化シグナルの検討を行った。まず、野生型(WT)マウス頭蓋骨由来の培養骨芽細胞をPTHで刺激したところ、IGF-I mRNAレベルおよびALP活性が上昇することを確認した。そこでIRS-1KOおよびIRS-2KOマウスに対してPTH皮下注射を行い、その効果をWTマウスと比較した。その結果、WTおよびIRS-2KOにおいてPTH投与群では非投与群に比べて大腿骨、脛骨、脊椎(L2-L5)の骨密度が上昇したのに対し、IRS-1KOではPTHの同化効果は見られなかった。以上より、PTHの骨同化作用は、局所で誘導されたIGF-Iがautocrine/paracrineに骨芽細胞に作用して、IRS-2ではなくIRS-1シグナルが活性化されることによるものであることが示された。この結果はEndocrinology誌にて掲載受諾されている。今後は、IRS-1の下流シグナル分子の関与を検討することでPTHの骨同化作用の分子メカニズムが解明されると考えられる。

Report

(5 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report

Research Products

(30 results)

All 2004 Other

All Journal Article Publications

  • [Journal Article] PPAR-gamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors.2004

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

      Journal of Clinical Investigation 113

      Pages: 846-855

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 加齢に伴う骨粗鬆化の分子メカニズム2004

    • Author(s)
      川口 浩
    • Journal Title

      日本老年医学会雑誌 41(6)

      Pages: 612-615

    • NAID

      10014285579

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ヒトklotho遺伝子多型2004

    • Author(s)
      川野健一, 川口浩
    • Journal Title

      日本臨床 62(増刊号2)

      Pages: 190-194

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice.

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

      Endocrinology (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Distinct effects of PPARγ insufficiency on bone marrow cells, osteoblasts, and osteoclastic cells.

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

      Journal of Bone and Joint Metabolism (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reverse and forward genetic approaches to the pathophysiology of osteoporosis.

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

      Geriatrics & Gerontology International (in press)

    • NAID

      10018027199

    • Related Report
      2004 Annual Research Report
  • [Publications] Kazuto Hoshi: "Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage"J.Bone.Miner.Res.. 19. 214-223 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Toru Akune: "PPARγ insufficiency enhances osteogenesis through osteoblast formation from marrow progenitors"J.Clin.Invest.. in press.

    • Related Report
      2003 Annual Research Report
  • [Publications] Takashi Shimoaka: "Impairment of bone healing by insulin receptor substrate -1 deficiency"J.Biol.Chem.. in press.

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "骨粗鬆症の分子生物学的病態"脊椎脊髄ジャーナル. 16・9. 916-926 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "加齢と骨"CLINICAL CALCIUM. 14・1. 275-283 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "骨・関節疾患(分担執筆:骨と老化)"朝倉書店. 380 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ken-ichi Kawano: "Klotho gene polymorphisms associated with bone density of aged postmenopausal women"J Bone Miner Res. 17. 1744-1751 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naoshi Ogata: "Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women"Bone. 31. 37-42 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Toru Akune: "Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts"J Cell Biol. 159. 147-156 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naoshi Ogata: "Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity"Spine. 27. 1765-1771 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Noriyo Manabe: "Connection between B lymphocyte and osteoclast differentiation pathways"J Immunol. 167. 2625-2631 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naoshi Ogata: "A polymorphic variant at the Werner helicase causes decreases in bone formation and resorption"J Bone Miner Metab. 19. 296-301 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Naoshi Ogata: "A polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women"Journal of Bone and Mineral Metabolism. 19. 296-301 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroshi Kawaguchi: "Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse"Cell Mol. Life Sci.. 57. 731-737 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroshi Kawaguchi: "Mutation in Aging Suppressor Gene, Klotho, Causes Decreases in Bone Formation and Resorption in Mice"Connective Tissue. 32. 295-301 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Naoshi Ogata: "Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women"Bone. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] 川口 浩: "骨粗鬆症と老化"医学のあゆみ. 198(9). 559-562 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 川口 浩: "加齢と骨"新臨床医のための分子医学シリーズ(羊土社). 96-104 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hiroshi Kawaguchi: "Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse"Cell Mol.Life Sci.. 57. 731-737 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hiroshi Kawaguchi: "Mutation in aging suppressor gene, klotho, causes' decreases in bone formation and resorption in mice"Connect.Tissue. 32. 295-301 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "老化モデルklotho変異マウスにおける骨代謝異常"整形外科. 51. 90-92,260-207 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "老化抑制遺伝子klothoと骨代謝異常"骨代謝学会雑誌. 17. 110-115 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "klotho遺伝子の骨粗鬆症への関与"ホルモンと臨床. 増刊号. 62-68 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 川口浩: "骨粗鬆症の発症機構-Reverse genetics と forward geneticsからの解明-"組織細胞工学. 26. 553-556 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-03-31   Modified: 2018-03-28  

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