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J. Biol. Chem., Vol. 280, Issue 9, 8343-8350, March 4, 2005

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Smad3 Induces Chondrogenesis through the Activation of SOX9 via CREB-binding Protein/p300 Recruitment^*

Takayuki Furumatsu, Masanao Tsuda, Noboru Taniguchi, Yoshitaka Tajima, and Hiroshi Asahara¶||**

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, the Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan, the ^¶National Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan, and ^||PRESTO.SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan

The transcriptional activation by SRY-type high mobility group box 9 (SOX9) and the transforming growth factor (TGF-) signals are necessary for chondrogenic differentiation. We have previously shown that CREB-binding protein (CBP/p300) act as an important SOX9 co-activator during chondrogenesis. In the present study, we investigated the relationship between TGF--dependent Smad2/3 signaling pathways and the SOX9-CBP/p300 transcriptional complex at the early stage of chondrogenesis. Overexpressed Smad3 strongly induced the primary chondrogenesis of human mesenchymal stem cells. In addition, Smad3 enhanced the transcriptional activity of SOX9 and the expression of 1(II) collagen gene (COL2A1), and small interference RNA against Smad3 (si-Smad3) inhibited them. We observed that Smad2/3 associated with Sox9 in a TGF--dependent manner and formed the transcriptional complexes with SOX9 on the enhancer region of COL2A1. Interestingly, the association between Sox9 and CBP/p300 was increased by Smad3 overexpression and was suppressed by si-Smad3. Our findings indicate that Smad3 has a stronger potential to stimulate the SOX9-dependent transcriptional activity by modulating the interaction between SOX9 and CBP/p300, rather than Smad2. This study suggests that the Smad3 pathway presents a key role for the SOX9-dependent transcriptional activation in primary chondrogenesis.

Received for publication, December 10, 2004

^* This work was supported in part by NIAMS, National Institutes of Health Grant AR50631-01, by the Arthritis Foundation (Arthritis Investigator Award), by the Japan Science and Technology Agency (JST PRESTO.SORST), and by a fellowship conferred from Uehara Memorial Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1-S3.

^** To whom correspondence should be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Rd., MEM161, La Jolla, CA 92037. Tel.: 858-784-9026; Fax: 858-784-2695; E-mail: asahara{at}scripps.edu.

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