2003 Fiscal Year Final Research Report Summary
Regulation of bona and cartilage metabolism by nucleotide pyrophosphatase (NPPS) -skeletal analysis of ttw mice and its contribution to the human npps gene SNPs -
| Project/Area Number |
13470302
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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 |
TAKESHITA Katsushi The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (30262009)
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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)
IKEGAWA Shiro Riken, SNP Research Center, Chief, 理化学研究所・遺伝子多型センター, チームリーダー(研究職) (30272496)
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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 |
This project investigated the molecular mechanism of mineralization induction in project ttw mice and the contribution of the human npps gene to clinical skeletal disorders.
First, we identified a cartilage specific gene cystatin 10 (Cst10 that was induced in the auricular cartilage by a high phosphate diet in ttw mice. In vitro analyses using a mouse chondrogenic cell line, ATDC5, suggested that Cst10 may play an important role in the last steps of the chondrocyte differentiation pathway as an induces of maturation followed by apoptosis of chondrocytes.
To further investigate the physiological role of Cst10 in vivo, we created mice lacking the Cst10 one Cst10^<-/-> mice). Cst10^<-/-> mice developed normally without abnormalities of major organs, and bane growth and turnover of Cst10^<-/-> mice remained similar to those of WT during the observation period up to 52 weeks of age. We are now planning examine whether the abnormal phenotype of ttw mice can be rescued by crossing with the Cst1
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0^<-/-> mice.
Based on the fact that the nucleotide pyrophosphatase Npps gene is responsible for ectopic ossification in ttw, an OPLL model mouse, the possibility was explored whether the human NPPS gene is associated with susceptibility to and severity of OPLL. First we screened for single-nucleotide Polymorphisms SNPs in the human NPPS locus and 14 SNPs in the locus. A case-control association study between 180 OPLL patients and 265 non-OPLL controls showed that one of these SNPs, IVS15-14T->C substitution was more frequently seen in OPLL, Patients p=0.022 than in controls. A stratified study with the number of ossified vertebrae in OPLL patients revealed that IVS15-14T->C substitution (p=0.013), as well as young onset p=0.046 And female sex (p=0.006), were associated with severe ossification. Although the case-control stud ann the stratified study failed to fond association of the SNPs with osteoporosis and osteoarthritis, we conclude that the IVS15-14T->C substitution in the human NPPS gene is associated not only with susceptibility to but also with severity of OPLL. Less
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Research Products
(10 results)
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[Publications] Toru Akune, Shinsuke Ohba, Satoru Kamekura, Masayuki Yamaguchi, Ung-il Chung, Naoto Kubota, Yasuo Terauchi, Yoshifumi Harada, Yoshiaki Azuma, Kozo Nakamura, Takashi Kadowaki, Hiroshi Kawaguchi: "PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors."J Clin Invest. (in press).
Description
「研究成果報告書概要(欧文)」より
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