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J. Biol. Chem., Vol. 283, Issue 14, 9239-9247, April 4, 2008

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Focal Adhesion Kinase/Src Suppresses Early Chondrogenesis

CENTRAL ROLE OF CCN2^*

Daphne Pala¹, Mohit Kapoor², Anita Woods³, Laura Kennedy⁴, Shangxi Liu, Shioqiong Chen, Laura Bursell⁵, Karen M. Lyons^¶, David E. Carter^||, Frank Beier⁶, and Andrew Leask, An Arthritis Society (Scleroderma Society of Ontario) New Investigator, member of the CIHR Canadian Scleroderma Research Group New Emerging Team, and recipient of an Early Investigator Award⁷

From the Department of Physiology and Pharmacology and Division of Oral Biology, Canadian Institute of Health Research Group in Skeletal Development and Remodeling, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5C1, Canada, ^¶Departments of Biological Chemistry and Orthopedic Surgery, David Geffen School of Medicine, University of California, Los Angeles, California 90095, and ^||London Regional Genomics Centre, Robarts Building, London, Ontario N6A 5C1, Canada

Adhesive signaling plays a key role in cellular differentiation, including in chondrogenesis. Herein, we probe the contribution to early chondrogenesis of two key modulators of adhesion, namely focal adhesion kinase (FAK)/Src and CCN2 (connective tissue growth factor, CTGF). We use the micromass model of chondrogenesis to show that FAK/Src signaling, which mediates cell/matrix attachment, suppresses early chondrogenesis, including the induction of Ccn2, Agc, and Sox6. The FAK/Src inhibitor PP2 elevates Ccn2, Agc, and Sox6 expression in wild-type mesenchymal cells in micromass culture, but not in cells lacking CCN2. Our results suggest a reduction in FAK/Src signaling is a critical feature permitting chondrogenic differentiation and that CCN2 operates downstream of this loss to promote chondrogenesis.

Received for publication, June 25, 2007 , and in revised form, January 22, 2008.

^* This work was supported in part by the Canadian Foundation for Innovation, the Arthritis Society, the Canadian Institute of Health Research (CIHR), and the Scleroderma Society. 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 Recipient of an OGSST graduate fellowship. A NORTH summer undergraduate dental student.

² Recipient of Canadian Arthritis Network and Ontario Ministry of Innovation postdoctoral fellowships.

³ Recipient of a Canada graduate scholarship from CIHR and a Canadian Arthritis Network graduate scholarship.

⁴ Recipient of an NSERC graduate fellowship.

⁵ Recipient of a Canadian Arthritis Network graduate scholarship.

⁶ A Canada Research Chair.

⁷ To whom correspondence should be addressed. E-mail: Andrew.Leask{at}schulich.uwo.ca.

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