TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage.
TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage.
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DOI：
10.1083/jcb.153.1.35
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发表时间：
2001-04-02
期刊：
影响因子：
--
通讯作者：
Deng CX
中科院分区：
文献类型：
--
作者：
Yang X;Chen L;Xu X;Li C;Huang C;Deng CX
软骨内骨化开始于间充质细胞向软骨的凝聚和分化。软骨然后经历细胞增殖、肥大分化、钙化、凋亡的程序，并最终被骨取代。与大多数软骨不同，关节软骨在终末肥大分化之前被阻止。在这项研究中，我们发现TGF-β/Smad 3信号抑制软骨细胞的终末肥大分化，并对维持关节软骨至关重要。靶向破坏Smad 3外显子8的纯合突变小鼠（Smad 3 ex 8/ex 8）出现了类似于人类骨关节炎的退行性关节疾病，其特征是关节软骨进行性丧失、形成大骨赘、蛋白聚糖产量减少以及数量异常增加。X型胶原表达的软骨细胞在滑液关节中。增强终末分化的骺生长板软骨细胞也观察到突变小鼠断奶后不久。在体外胚胎跖骨原基培养体系中，我们发现TGF-β1显著抑制了野生型跖骨原基软骨细胞的分化。然而，这种抑制作用在从Smad 3 ex 8/ex 8小鼠分离的跖骨中减弱。这些数据表明，TGF-β/Smad 3信号是抑制关节软骨细胞分化所必需的。如果没有这些抑制信号，软骨细胞打破静止状态并经历异常的终末分化，最终导致骨关节炎。
Endochondral ossification begins from the condensation and differentiation of mesenchymal cells into cartilage. The cartilage then goes through a program of cell proliferation, hypertrophic differentiation, calcification, apoptosis, and eventually is replaced by bone. Unlike most cartilage, articular cartilage is arrested before terminal hypertrophic differentiation. In this study, we showed that TGF-β/Smad3 signals inhibit terminal hypertrophic differentiation of chondrocyte and are essential for maintaining articular cartilage. Mutant mice homozygous for a targeted disruption of Smad3 exon 8 (Smad3 ex8/ex8) developed degenerative joint disease resembling human osteoarthritis, as characterized by progressive loss of articular cartilage, formation of large osteophytes, decreased production of proteoglycans, and abnormally increased number of type X collagen–expressing chondrocytes in synovial joints. Enhanced terminal differentiation of epiphyseal growth plate chondrocytes was also observed in mutant mice shortly after weaning. In an in vitro embryonic metatarsal rudiment culture system, we found that TGF-β1 significantly inhibits chondrocyte differentiation of wild-type metatarsal rudiments. However, this inhibition is diminished in metatarsal bones isolated from Smad3 ex8/ex8 mice. These data suggest that TGF-β/Smad3 signals are essential for repressing articular chondrocyte differentiation. Without these inhibition signals, chondrocytes break quiescent state and undergo abnormal terminal differentiation, ultimately leading to osteoarthritis.
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