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

doi:10.1083/jcb.153.1.35

Published online 26 March 2001. doi:10.1083/jcb.153.1.35

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© The Rockefeller University Press, 0021-9525/2001/4/35/ $5.00
The Journal of Cell Biology, Volume 153, Number 1, April 2, 2001 35-46

Original Article

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

Xiao Yang^a,b, Lin Chen^a, Xiaoling Xu^a, Cuiling Li^a, Cuifen Huang^b, and Chu-Xia Deng^a
^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

Correspondence to: Chu-Xia Deng, National Institutes of Health/NIDDK, 10/9N105, 10 Center Dr., Bethesda, MD 20892. Tel:(301) 402-7225 Fax:(301) 480-1135 E-mail:chuxiad{at}bdg10.niddk.nih.gov.

Endochondral ossification begins from the condensation and differentiationof mesenchymal cells into cartilage. The cartilage then goesthrough a program of cell proliferation, hypertrophic differentiation,calcification, apoptosis, and eventually is replaced by bone.Unlike most cartilage, articular cartilage is arrested beforeterminal hypertrophic differentiation. In this study, we showedthat TGF-ß/Smad3 signals inhibit terminal hypertrophicdifferentiation of chondrocyte and are essential for maintainingarticular cartilage. Mutant mice homozygous for a targeted disruptionof Smad3 exon 8 (Smad3^ex8/ex8) developed degenerative jointdisease resembling human osteoarthritis, as characterized byprogressive loss of articular cartilage, formation of largeosteophytes, decreased production of proteoglycans, and abnormallyincreased number of type X collagen–expressing chondrocytesin synovial joints. Enhanced terminal differentiation of epiphysealgrowth plate chondrocytes was also observed in mutant mice shortlyafter weaning. In an in vitro embryonic metatarsal rudimentculture system, we found that TGF-ß1 significantlyinhibits chondrocyte differentiation of wild-type metatarsalrudiments. However, this inhibition is diminished in metatarsalbones isolated from Smad3^ex8/ex8 mice. These data suggest thatTGF-ß/Smad3 signals are essential for repressing articularchondrocyte differentiation. Without these inhibition signals,chondrocytes break quiescent state and undergo abnormal terminaldifferentiation, ultimately leading to osteoarthritis.

Key Words: TGF-ß/Smad3, mouse model, osteoarthritis, synovium,growth plate

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