Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis.
Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis.
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DOI：
10.1002/art.34566
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发表时间：
2012-10
影响因子：
--
通讯作者：
Alliston, Tamara
中科院分区：
文献类型：
--
作者：
Chen, Carol G.;Thuillier, Daniel;Chin, Emily N.;Alliston, Tamara
确定Smad 3维持关节软骨和预防骨关节炎的机制。使用体内和体外方法的组合来测试Smad 3抑制Runx 2诱导基因表达以防止关节软骨退变的假设。Col 2-Cre; Smad 3fl/fl小鼠允许研究Smad 3的软骨细胞内在作用，独立于其在软骨膜或其他组织中的作用。采用原代Smad 3fl/fl关节软骨细胞和ATDC 5软骨祖细胞来评估Smad 3和Runx 2对基质金属蛋白酶-13（MMP-13）mRNA和蛋白表达的调节。由于软骨基质合成和降解不平衡，Smad 3的软骨细胞特异性减少导致进行性关节软骨退化。除了胶原II mRNA表达减少之外，Col 2-Cre; Smad 3fl/fl关节软骨严重缺乏胶原II和聚集蛋白聚糖蛋白，这是由于这些关键软骨基质成分的过度MMP-13介导的蛋白水解。正常情况下，TGF-β通过Smad 3发出信号，以快速和动态地抑制Runx 2诱导的MMP-13表达。然而，在不存在Smad 3的情况下，TGF-β通过p38和Runx 2信号传导以诱导MMP-13表达。这项工作阐明了人类和小鼠中Smad 3突变导致软骨退化和骨关节炎的机制。具体而言，Smad 3通过诱导胶原II表达和抑制Runx 2诱导的MMP-13表达来维持软骨基质合成和降解之间的平衡。通过Smad 3而不是p38选择性激活TGF-β信号可能有助于恢复骨关节炎中失去的基质合成和蛋白水解之间的平衡。
To identify mechanisms by which Smad3 maintains articular cartilage and prevents osteoarthritis. A combination of in vivo and in vitro approaches was used to test the hypothesis that Smad3 represses Runx2-inducible gene expression to prevent articular cartilage degeneration. Col2-Cre;Smad3fl/fl mice allowed study of the chondrocyte-intrinsic role of Smad3, independently of its role in the perichondrium or other tissues. Primary Smad3fl/fl articular chondrocytes and ATDC5 chondroprogenitors were employed to evaluate Smad3 and Runx2 regulation of matrix metalloproteinase-13 (MMP-13) mRNA and protein expression. Chondrocyte-specific reduction of Smad3 causes progressive articular cartilage degeneration due to imbalanced cartilage matrix synthesis and degradation. In addition to reduced collagen II mRNA expression, Col2-Cre;Smad3fl/fl articular cartilage is severely deficient in collagen II and aggrecan protein, due to excessive MMP-13-mediated proteolysis of these key cartilage matrix constituents. Normally, TGF-β signals through Smad3 to confer a rapid and dynamic repression of Runx2-inducible MMP-13 expression. However, in the absence of Smad3, TGF-β signals through p38 and Runx2 to induce MMP-13 expression. This work elucidates a mechanism by which Smad3 mutations in humans and mice cause cartilage degeneration and osteoarthritis. Specifically, Smad3 maintains the balance between cartilage matrix synthesis and degradation by inducing collagen II expression and repressing Runx2-inducible MMP-13 expression. Selective activation of TGF-β signaling through Smad3, rather than p38, may help to restore the balance between matrix synthesis and proteolysis that is lost in osteoarthritis.
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