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Study of the function of cystatin 10, a novel chondrocyte-specific gene.

研究软骨细胞特异性基因胱抑素 10 的功能。

基本信息

批准号：
14370454
负责人：
TAKESHITA Katsushi
金额：
$ 9.54万
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：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

This study was conducted to elucidate the role and the molecular mechanism of cystatin 10 (Cst10), in the process of endochondral ossification and osteochondral regeneration, and to apply the novel gene, Cst10, to the medical treatment.Cst10 was identified from the mouse auricular cartilage and belongs to the cystatin superfamily, the family of cysteine protease inhibitors. Expression of Cst10 was specific to cartilage, especially to hypertrophic chondrocytes of the growth plate. We found from in vitro studies that Cst10 induced later differentiation and apoptosis of chondrocytes. In order to further investigate the physiological role of Cst10 in vivo, we created mice lacking the Cst10 gene (Cst10KO) and analyzed their bone and cartilage. Cst10KO developed and grew normally without abnormalities of major organs. Radiological and histological analysis revealed an impairment of calcification of the growth plate and a significant decrease in the volume of primary spongiosa adjacent to the … More growth plate by Cst10 deficiency, although bone growth and bone turnover of the Cst10KO remained similar to those of wild type (WT) and heterozygote littermates. In the culture of primary chondrocytes derived from the growth plate, later differentiation of Cst10KO cells was suppressed compared to that of WT cells, which showed the roles of Cst10 expressing in chondrocytes are terminal differentiation and calcification of cartilaginous matrix. In the Cst10KO, calcification was also significantly impaired in other pathological conditions related to endochondral ossification, such as fracture healing and osteophyte formation in osteoarthritis knee model. Furthermore, although WT exhibited calcification of the tendon insertion of patella and calcaneus at 52 weeks of age, these ectopic calcifications were not seen in the Cst10KO. Cst10 was expressed exclusively in type X collagen expressing, matured cells in these calcification regions of WT.These in vitro and in vivo results revealed that Cst10 is an inducer of chondrocyte calcification and contributes to the pathogenesis of osteoarthritis and ectopic calcification without affecting the physiological bone growth or turnover. Less

本研究旨在阐明胱抑素10 （cystatin 10, Cst10）在软骨内成骨和骨软骨再生过程中的作用及其分子机制，并将新基因Cst10应用于医学治疗。Cst10是从小鼠耳软骨中鉴定出来的，属于半胱氨酸蛋白酶抑制剂家族——胱抑素超家族。Cst10的表达是软骨特异性的，尤其是生长板的肥大软骨细胞。我们从体外研究中发现，Cst10诱导软骨细胞后期分化和凋亡。为了进一步研究Cst10在体内的生理作用，我们建立了缺乏Cst10基因的小鼠（Cst10KO），并分析了它们的骨骼和软骨。Cst10KO发育生长正常，主要器官无异常。放射学和组织学分析显示，由于Cst10缺乏，生长板钙化受损，生长板附近的初级海绵体积显著减少，尽管Cst10KO的骨生长和骨转换与野生型（WT）和杂合子幼崽相似。在生长板原代软骨细胞培养中，Cst10KO细胞的后期分化较WT细胞受到抑制，说明Cst10表达在软骨细胞中的作用是终末分化和软骨基质的钙化。在Cst10KO中，与软骨内成骨相关的其他病理情况（如骨关节炎膝关节模型中的骨折愈合和骨赘形成）的钙化也明显受损。此外，尽管WT在52周龄时表现出髌骨和跟骨肌腱止点的钙化，但这些异位钙化在Cst10KO中未见。这些体外和体内实验结果表明，Cst10是软骨细胞钙化的诱导剂，参与骨关节炎和异位钙化的发病，但不影响骨的生理性生长或转换。少

项目成果

期刊论文数量（53）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cystatin 10, a Novel Chondrocyte-specific Protein, May Promote the Last Steps of the Chondrocyte Differentiation Pathway*

DOI：
10.1074/jbc.m211639200
发表时间：
2003-11
期刊：
Journal of Biological Chemistry
影响因子：
4.8
作者：
Y. Koshizuka;Takashi Yamada;K. Hoshi;T. Ogasawara;U. Chung;H. Kawano;Yusuke Nakamura;Kozo Nakamura;S. Ikegawa;H. Kawaguchi
通讯作者：
Y. Koshizuka;Takashi Yamada;K. Hoshi;T. Ogasawara;U. Chung;H. Kawano;Yusuke Nakamura;Kozo Nakamura;S. Ikegawa;H. Kawaguchi

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