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J. Biol. Chem., Vol. 279, Issue 13, 13205-13214, March 26, 2004

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RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation^*

Guoyan Wang, Anita Woods, Shalev Sabari, Luca Pagnotta, Lee-Anne Stanton, and Frank Beier¶||

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

Coordinated proliferation and differentiation of growth plate chondrocytes is required for normal growth and development of the endochondral skeleton, but little is known about the intracellular signal transduction pathways regulating these processes. We have investigated the roles of the GTPase RhoA and its effector kinases ROCK1/2 in hypertrophic chondrocyte differentiation. RhoA, ROCK1, and ROCK2 are expressed throughout chondrogenic differentiation. RhoA overexpression in chondrogenic ATDC5 cells results in increased proliferation and a marked delay of hypertrophic differentiation, as shown by decreased induction of alkaline phosphatase activity, mineralization, and expression of the hypertrophic markers collagen X, bone sialoprotein, and matrix metalloproteinase 13. These effects are accompanied by activation of cyclin D1 transcription and repression of the collagen X promoter by RhoA. In contrast, inhibition of Rho/ROCK signaling by the pharmacological inhibitor Y27632 inhibits chondrocyte proliferation and accelerates hypertrophic differentiation. Dominant-negative RhoA also inhibits induction of the cyclin D1 promoter by parathyroid hormone-related peptide. Finally, Y27632 treatment partially rescues the effects of RhoA overexpression. In summary, we identify the RhoA/ROCK signaling pathway as a novel and important regulator of chondrocyte proliferation and differentiation.

Received for publication, October 17, 2003 , and in revised form, January 7, 2004.

^* 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.

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

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

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