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J. Biol. Chem., Vol. 281, Issue 3, 1381-1388, January 20, 2006

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The Wnt-inducible Transcription Factor Twist1 Inhibits Chondrogenesis^*

Martina I. Reinhold, Ravi M. Kapadia, Zhixiang Liao, and Michael C. Naski1

From the Departments of Pathology and Biochemistry, University of Texas Health Science Center, San Antonio, Texas 78229

Wnt signaling is essential for many developmental processes, including skeletogenesis. To investigate the effects of Wnt signaling during skeletogenesis we studied the effects of Wnt on cultured chondrocytic cells and differentiating limb-bud mesenchyme. We showed that Wnt3a strongly repressed chondrogenesis and chondrocyte gene expression. Canonical Wnt signaling was responsible for the repression of differentiation, as evidenced by results showing that inhibition of glycogen synthase kinase 3 or expression of -catenin caused similar repression of differentiation. Significantly, we showed that the transcription repressor Twist1 is induced by canonical Wnt signaling. Expression of Twist1 strongly inhibited chondrocyte gene expression and short hairpin RNA knockdown of Twist1 transcript levels caused increased expression of the chondrocyte-specific genes aggrecan and type II collagen. Interestingly, Twist1 interfered with BMP2-induced expression of aggrecan and type II collagen expression and knockdown of Twist1 augmented BMP2-induced aggrecan and type II collagen expression. These data support the conclusions that Twist1 contributes to the repression of chondrogenesis and chondrocyte gene expression resulting from canonical Wnt signaling and that Twist1 interferes with BMP-dependent signaling.

Received for publication, May 3, 2005 , and in revised form, November 8, 2005.

^* This work was supported by National Institutes of Health Grants AR47070 and AR050024 and the Paul Beeson Physician Faculty Scholars in Aging Research Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-4126; Fax: 210-567-4819; E-mail: naski{at}uthscsa.edu.

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