2003 Fiscal Year Final Research Report Summary
Regulation of bone and cartilage metabolism by nucleotide pyrophosphatase (NPPS) -skeletal analysis of ttw mice and its contribution to the human npps gene SNPs -
| Project/Area Number |
13470303
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Orthopaedic surgery
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| Research Institution | The University of Tokyo |
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Principal Investigator |
NAKAGAWA Takumi The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (90338385)
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| 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)
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| Project Period (FY) |
2001 – 2003
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| Keywords | nucleotide pyrophosphatase(NPPS) / ttw / cytatin 10 / OPLL / polymorphism / bone |
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| 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.
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[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)
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