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Regulation of bone and cartilage metabolism by nucleotide pyrophosphatase (NPPS) -skeletal analysis of ttw mice and its contribution to the human npps gene SNPs -

Research Project

Project/Area Number 13470303
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

NAKAGAWA Takumi (2003)  The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (90338385)

五嶋 孝博 (2001-2002)  東京大学, 医学部附属病院, 講師 (20272544)

Co-Investigator(Kenkyū-buntansha) NAKAMURA Kozo  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60126133)
HIRAOKA Hisatada  The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (10262007)
KAWAGUCHI Hiroshi  The University of Tokyo, Faculty of Medicine, Lecture, 医学部附属病院, 講師 (40282660)
KADOWAKI Takashi  The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (30185889)
阿久根 徹  東京大学, 医学部附属病院, 医員 (60282662)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥14,200,000 (Direct Cost: ¥14,200,000)
Fiscal Year 2003: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2002: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2001: ¥5,100,000 (Direct Cost: ¥5,100,000)
Keywordsnucleotide pyrophosphatase(NPPS) / ttw / cytatin 10 / OPLL / polymorphism / bone / PPARγ / 老化 / 骨粗鬆症 / 脂肪 / ノックアウトマウス / ES細胞 / ゲノム / PPAR-γ / 骨芽細胞 / 骨髄 / 破骨細胞
Research Abstract

Based on the facts that ageing is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow, and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ, a key regulator of adipocyte differentiation, in bone metabolism from the reverse and forward genetic approaches. Homozygous PPARγ-deficient embryonic stem cells failed to differentiate into adipocytes but spontaneously differentiated into osteoblasts, and these were restored by the PPARγ gene reintroduction. Heterozygous PPARγ-deficient mice. exhibited high bone mass with increased osteoblastogenesis but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ haploinsufficiency became prominent with ageing, but was not changed with ovariectomy. The PPARγ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture, but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ-dependent regulation of bone metabolism in vivo, in that PPARγ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors. However, our preliminary studies failed to reveal the osteogenic action of a synthetic antagonist of RXR that forms the hererodimer with PPARγ-in several culture systems. In addition, human genomic analyses did not show the significant association between the SNPs of the PPARγ gene and bone density in postmenopausal women. Possible involvement of PPARγ in the pathophysiology of age-realted osteoporosis and its application to the novel treatment of these diseases will be next tasks to be done.

Report

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

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Yu Koshizuka: "Nucleotide pyrophosphatase gene polymorphism associated with OPLL of the spine"J.Bone Miner.Res.. 17. 138-144 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yu Koshizuka: "Cystatin 10, a novel clindrocyte-specificprotein, may promote the last step of the chondroyte differentiation"J.Biol.Chem.. 278. 48259-48266 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 川口 浩: "骨軟骨再生研究の分子生物学的展望"Molecular Medicine. 40. 702-710 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 川口 浩: "骨髄間葉系細胞を用いた骨再生"関節外科. 22. 1250-1256 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yu Koshizuka, Hiroshi Kawaguchi, Naoshi Ogata, Toshiyuki Ikeda, Akihiko Mabuchi, Atsushi Seichi, Yusuke Nakamura, Kozo Nakamura, Shiro Ikegawa: "Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine."J Bone Miner Res. 17. 138-144 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yu Koshizuka, Takashi Yamada, Kazuto Hoshi, Toru Ogasawara, Ung-il Chung, Hirotaka Kawano, Yusuke Nakamura, Kozo Nakamura, Shiro Ikegawa, Hiroshi Kawaguchi: "Cystatin 10, a novel chondrocyte-specific protein, may promote the last steps of the chondrocyte differentiation pathway."J Biol Chem. 278. 48259-48266 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hiroshi Kawaguchi: "Molecular approaches to bone and cartilage regeneration (in Japanese)"Molecular Medicine. 40(6). 702-710 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Hiroshi Kawaguchi: "Bone regeneration from bone marrow mesenchymal cells (in Japanese)"Kansetsu-geka. 22(10). 1250-1256 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Toru Akune: "PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors"J.Clin.Invest.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "骨粗鬆症の病型と病態"Pharma Medica. 21・6. 21-27 (2003)

    • 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. 919-926 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "加齢と骨"CLINICAL CALCIUM. 14・2. 275-283 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "骨・関節疾患"朝倉書店. 370 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 川口 浩: "老化による骨粗鬆化の分子メカニズム"生体の科学. 53(5). 490-496 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川口 浩: "Reverse & forward genetics からの骨軟骨二疾患へのアプローチ"整形外科. 53(12). 1569-1579 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川口 浩: "骨粗鬆症と老化"医学のあゆみ. 198. 559-562 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 阿久根 徹: "骨を構成する細胞群とその起源についての理解の進歩"内分泌・糖尿病科. 13(3). 226-230 (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:骨軟骨代謝と注目の骨症例. (単行本). 96-104 (2002)

    • Related Report
      2001 Annual Research Report

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

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