TGF-β/Smad3 Signals Repress Chondrocyte Hypertrophic Differentiation and Are Required for Maintaining Articular Cartilage

By Xiao Yang, Lin Chen, Xiaoling Xu, Cuiling Li, Cui-fen Huang, C. Deng. Journal of Cell Biology, 2001

676 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/5faaa4ceb46430e53a866d7da7104767747ce7b0

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Citations in the corpus

Smad3 as a mediator of the fibrotic response (2004, background): “Smad3 KO mice also show diminished T-cell responsiveness to TGF-b and skeletal abnormalities due to defects in differentiation of hypertrophic chondrocytes, resulting in a progressive degenerative cartilage disease (Yang et al. 2001).”
Reaching a genetic and molecular understanding of skeletal development. (2002, background): “…forms of TRAFs caused inhibition ofthrough which osteoblastic/stromal cells stimulate osRANK-mediated NF- B activation (Wong et al., 1998).teoclast formation and resorption, as RANKL (Lacey et Therefore, TRAFs are required for NF- B activation inal., 1998; Wong et al., 1999; Yasuda et al., 1998).”
Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis (2011, background): “However, in Smad3 knockdown mice, progressive loss of articular cartilage, formation of osteophytes and intervertebral disc degeneration have been observe”
Making sense of latent TGFβ activation (2003, background): “…(Dabovic et al., 2002), which also occur in mice that have defective TGFβ signaling pathways resulting from either mutations in Smad3 (osteoarthritis) (Yang et al., 2001) or the expression of a dominant negative type II TGFβ receptor in osteoblasts (osteopetrosis) (Filvaroff et al., 1999).”