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J. Biol. Chem., Vol. 280, Issue 12, 11626-11634, March 25, 2005

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RhoA/ROCK Signaling Regulates Sox9 Expression and Actin Organization during Chondrogenesis^*

Anita Woods, Guoyan Wang, and Frank Beier, Supported by grants from the Canadian Institutes of Health Research, the Arthritis Society, the Canadian Arthritis Network, the Canada Research Chair Foundation, the National Science and Engineering Research Council, and the Hospital for Sick Children Foundation¶

From the Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada

Endochondral ossification is initiated by the differentiation of mesenchymal precursor cells to chondrocytes (chondrogenesis). This process is characterized by a strong interdependence of cell shape, cytoskeletal organization, and the onset of chondrogenic gene expression, but the molecular mechanisms mediating these interactions are not known. Here we investigated the role of the RhoA/ROCK pathway, a well characterized regulator of cytoskeletal organization, in chondrogenesis. We show that pharmacological inhibition of ROCK signaling by Y27632 resulted in increased glycosaminoglycan synthesis and elevated expression of the chondrogenic transcription factor Sox9, whereas overexpression of RhoA in the chondrogenic cell line ATDC5 had the opposite effects. Suppression of Sox9 expression by ROCK signaling was achieved through repression of Sox9 promoter activity. These molecular changes were accompanied by reorganization of the actin cytoskeleton, where RhoA/ROCK signaling suppressed cortical actin organization, a hallmark of differentiated chondrocytes. This led us to analyze the regulation of Sox9 expression by drugs affecting cytoskeletal dynamics. Both inhibition of actin polymerization by cytochalasin D and stabilization of existing actin filaments by jasplakinolide resulted in increased Sox9 mRNA levels, whereas inhibition of microtubule polymerization by colchicine completely blocked Sox9 expression. In conclusion, our data suggest that RhoA/ROCK signaling suppresses chondrogenesis through the control of Sox9 expression and actin organization.

Received for publication, August 10, 2004 , and in revised form, January 5, 2005.

^* 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.

Recipient of a scholarship from the Canadian Arthritis Network.

Supported by the Kunming Medical College and the Science Foundation of Yunnan Education Committee of China.

^¶ To whom correspondence should be addressed: CIHR Group in Skeletal Development and Remodeling, Dept. of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada. Tel.: 519-661-2111 (ext. 85344); Fax: 519-661-3827; E-mail: fbeier{at}uwo.ca.

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