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Chondrocyte-intrinsic Smad3 represses Runx2-inducible MMP-13 expression to maintain articular cartilage and prevent osteoarthritis
Arthritis & Rheumatism, 06/08/2012
Clinical Article
Chen CG et al. – 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–(beta) signaling through Smad3, rather than p38, may help to restore the balance between matrix synthesis and proteolysis that is lost in osteoarthritis.
Methods- 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–(beta) signals through Smad3 to confer a rapid and dynamic repression of Runx2–inducible MMP–13 expression.
- However, in the absence of Smad3, TGF–(beta) signals through p38 and Runx2 to induce MMP–13 expression.
