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RESEARCH PAPER
-catenin control chondrocyte differentiation
1 Department of Molecular Genetics, 2 Department of Biochemistry and Molecular Biology, and 3 Graduate Program in Genes & Development, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA; 4 Department of Pharmacology and 5 Department of Orthopaedic Surgery, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
Chondrogenesis is a multistep process that is essential for endochondral bone formation. Previous results have indicated a role for 
-catenin and Wnt signaling in this pathway. Here we show the existence of physical and functional interactions between -catenin and Sox9, a transcription factor that is required in successive steps of chondrogenesis. In vivo, either overexpression of Sox9 or inactivation of -catenin in chondrocytes of mouse embryos produces a similar phenotype of dwarfism with decreased chondrocyte proliferation, delayed hypertrophic chondrocyte differentiation, and endochondral bone formation. Furthermore, either inactivation of Sox9 or stabilization of -catenin in chondrocytes also produces a similar phenotype of severe chondrodysplasia. Sox9 markedly inhibits activation of -catenin-dependent promoters and stimulates degradation of -catenin by the ubiquitination/proteasome pathway. Likewise, Sox9 inhibits -catenin-mediated secondary axis induction in Xenopus embryos. -Catenin physically interacts through its Armadillo repeats with the C-terminal transactivation domain of Sox9. We hypothesize that the inhibitory activity of Sox9 is caused by its ability to compete with Tcf/Lef for binding to -catenin, followed by degradation of -catenin. Our results strongly suggest that chondrogenesis is controlled by interactions between Sox9 and the Wnt/-catenin signaling pathway.
[Keywords: Chondrocyte differentiation; Sox9; -catenin]
Received November 21, 2003; revised version accepted March 22, 2004.
6 E-MAIL hakiyama{at}mdacc.tmc.edu; FAX (713) 794-4295.
7 E-MAIL bdecromb{at}mail.mdanderson.org; FAX (713) 794-4295.
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