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© The Rockefeller University Press, 0021-9525/2001//35 $5.00
The Journal of Cell Biology, Volume 153, Number 1, , 2001 35-46

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

^a Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892
^b Institute of Biotechnology, Bejing 100071, China
National Institutes of Health/NIDDK, 10/9N105, 10 Center Dr., Bethesda, MD 20892.(301) 480-1135(301) 402-7225

chuxiad{at}bdg10.niddk.nih.gov

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.

Key Words: TGF-β/Smad3 • mouse model • osteoarthritis • synovium • growth plate

© 2001 The Rockefeller University Press

Abbreviations used in this paper: BMP, bone morphogenetic protein; FGFR, FGF receptor; HL, hypertrophic length; Ihh, Indian hedgehog; P, postnatal day; TL, total length.

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