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

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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