Chondrocyte‐intrinsic Smad3 represses Runx2‐inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis

Abstract

Objective To identify mechanisms by which Smad3 maintains articular cartilage and prevents 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. Results 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. Conclusion 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.

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…Smurf2 is highly expressed in human OA cartilage but is not present in normal cartilage. TGF-β signaling is decreased, and expression of chondrocyte hypertrophic markers (ColX and MMP13) is increased in transgenic mice (24), leading to progressive articular cartilage degradation, including reduced cartilage area and fibrillation, as well as subchondral sclerosis and osteophyte formation (25). These findings suggest that loss of TGF-β signaling represents one of the possible mechanisms underlying OA development.…”

Role of Smad3 and S1P Signaling in Mandibular Condylar Cartilage Homeostasis

“…When chondrocyte-specific deletion of Smad3 was achieved in mice, OA in the knee joint was induced [54]. Correspondingly, in humans, mutations in Smad3 have been found in the MH2 domain of Smad3 protein, a region that is extremely well conserved among other species and among other Smad proteins that are associated with early onset of OA [55].…”

The molecular mechanism of treating osteoarthritis with dipsacus saponins by inhibiting chondrocyte apoptosis

“…Chondrocytes help maintain joint function and serve an important role in the development of OA (17). The pathological changes that occur in OA primarily manifest as cartilage lesions, which lead to degenerative changes occurring in the cartilage cells and matrix (18).…”