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J. Biol. Chem., Vol. 280, Issue 21, 20509-20515, May 27, 2005

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Fibroblast Growth Factor (FGF) 18 Signals through FGF Receptor 3 to Promote Chondrogenesis^*

David Davidson, Antoine Blanc¶, Dominic Filion¶, Huifen Wang, Paul Plut, Gerald Pfeffer||, Michael D. Buschmann¶, and Janet E. Henderson**

From the Department of Medicine, Centre for Bone and Periodontal Research, McGill University, Montreal H3A 1A4, Canada and ^¶Department of Chemical Engineering, Ecole Polytechnique, Montreal, Quebec H3C 3A7, Canada

Signaling by fibroblast growth factor (FGF) 18 and FGF receptor 3 (FGFR3) have been shown to regulate proliferation, differentiation, and matrix production of articular and growth plate chondrocytes in vivo and in vitro. Notably, the congenital absence of either FGF18 or FGFR3 resulted in similar expansion of the growth plates of fetal mice and the addition of FGF18 to human articular chondrocytes in culture enhanced proliferation and matrix production. Based on these and other experiments it has been proposed that FGF18 signals through FGFR3 to promote cartilage production by chondrocytes. Its role in chondrogenesis remains to be defined. In the current work we used the limb buds of FGFR3^+/+ and FGFR3^–/– embryonic mice as a source of mesenchymal cells to determine how FGF18 signaling affects chondrogenesis. Confocal laser-scanning microscopy demonstrated impaired cartilage nodule formation in the FGFR3^–/– cultures. Potential contributing factors to the phenotype were identified as impaired mitogenic response to FGF18, decreased production of type II collagen and proteoglycan in response to FGF18 stimulation, impaired interactions with the extracellular matrix resulting from altered integrin receptor expression, and altered expression of FGFR1 and FGFR2. The data identified FGF18 as a selective ligand for FGFR3 in limb bud mesenchymal cells, which suppressed proliferation and promoted their differentiation and production of cartilage matrix. This work, thus, identifies FGF18 and FGFR3 as potential molecular targets for intervention in tissue engineering aimed at cartilage repair and regeneration of damaged cartilage.

Received for publication, September 3, 2004 , and in revised form, February 22, 2005.

^* This work was supported in part by grants from the Canadian Institutes of Health Research, the Arthritis Society of Canada (TAS), and the Canadian Arthritis Network Centres of Excellence (CAN) (to J. E. H.) and from the Canadian Institutes of Health Research and The Natural Sciences and Engineering Research Council (to M. B.). 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 and S2.

Supported by doctoral awards from Canadian Institutes of Health Research and Fonds de la Recherche en Santé du Québec.

^|| Supported by a Challenge Summer Studentship from Human Resources Development Canada.

^** A Chercheur Boursier Senior of the Fonds de la Recherche en Santé du Québec. To whom correspondence should be addressed: Centre for Bone and Periodontal Research, 740 Avenue Dr., Penfield, Rm. 2203, Montreal H3A 1A4, Canada. Tel: 514-398-5112; Fax: 514-398-4020; E-mail: janet.henderson{at}mcgill.ca.

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