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

核苷酸焦磷酸酶 (NPPS) 对骨骼和软骨代谢的调节 - ttw 小鼠的骨骼分析及其对人类 npps 基因 SNP 的贡献 -

基本信息

批准号：
13470302
负责人：
TAKESHITA Katsushi
金额：
$ 8.7万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

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 … More 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

本项目研究了TTW小鼠矿化诱导的分子机制以及人类NPPS基因在临床骨骼疾病中的作用。首先，我们在TTW小鼠的耳软骨中发现了一个软骨特异性基因Cstatin 10(Cst10)，该基因是由高磷饮食诱导的。使用小鼠软骨细胞系ATDC5进行的体外分析表明，Cst10可能在软骨细胞分化途径的最后一步发挥重要作用，诱导软骨细胞成熟，继而诱导软骨细胞凋亡。为了进一步研究Cst10在体内的生理作用，我们建立了缺乏Cst10的小鼠(Cst10^&lt；-/-&gt；小鼠)。Cst10^&lt；-/-&gt；小鼠发育正常，主要脏器未见异常，Cst10^&lt；-/-&gt；小鼠在观察期内的生长和周转情况与WT小鼠相似，直至52周龄。我们正在计划研究是否可以通过与Cst1…杂交来挽救TTW小鼠的异常表型基于核苷酸焦磷酸酶NPPS基因导致OPLL模型小鼠TTW异位骨化的事实，探讨了人类NPPS基因是否与OPLL的易感性和严重程度有关。首先，我们筛查了人类NPPS基因座的单核苷酸多态SNPs和该基因座的14个SNPs。对180OPLL患者和265例非OPLL对照的病例对照研究表明，IVS15-14T-&GT；C替换在OPLL患者中更常见，P=0.022。一项对OPLL患者骨化椎体数量的分层研究显示，IVS15-14T-&GT；C替换(p=0.013)、年轻发病p=0.046和女性(p=0.006)与严重骨化有关。虽然病例对照研究和分层研究未能发现SNPs与骨质疏松症和骨性关节炎的关联，但我们得出结论，人类NPPS基因中IVS15-14T-&GT；C替换不仅与OPLL的易感性有关，而且与OPLL的严重程度有关。较少

项目成果

期刊论文数量（32）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hiroshi Kawaguchi: "Molecular mechanism of osteoporosis by ageing (in Japanese)"Seitai-no-kagaku. 53(5). 490-496 (2002)

川口博：“衰老引起的骨质疏松症的分子机制（日语）”Seitai-no-kagaku。

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通讯作者：

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

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不足通过成骨细胞增强成骨作用