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J. Biol. Chem., Vol. 282, Issue 1, 526-533, January 5, 2007

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-Catenin Signaling Pathway Is Crucial for Bone Morphogenetic Protein 2 to Induce New Bone Formation^*

Yan Chen¹, Heather C. Whetstone, Andrew Youn, Puviindran Nadesan, Edwin C. Y. Chow, Alvin C. Lin, and Benjamin A. Alman, Supported by the Canadian Research Chair's Program²

From the Program in Developmental Biology, Research Institute, the Hospital for Sick Children, University of Toronto, Toronto, Ontario M5G 1X8, Canada

Endochondral ossification is recapitulated during bone morphogenetic protein (BMP)-induced ectopic bone formation. Although BMP and -catenin have been investigated in bone development and in mesenchymal cells, how they interact in this process is not clear. We implanted recombinant BMP-2 into the muscle of mice to investigate the effect of -catenin signaling on BMP-induced in vivo endochondral bone formation. BMP-2 induced expression of several Wnt ligands and their receptors and also activated -catenin-mediated T cell factor-dependent transcriptional activity. An adenovirus expressing Dickkopf-1 (Dkk-1, an inhibitor of canonical Wnt pathway) inhibited -catenin signaling and endochondral bone formation. Interestingly, Dkk-1 inhibited both chondrogenesis and osteogenesis. Likewise, mice expressing conditional -catenin null alleles also displayed an inhibition of BMP-induced chondrogenesis and osteogenesis. This is in contrast to studies of embryonic skeletogenesis, which demonstrate that -catenin is required for osteogenesis but is dispensable for chondrogenesis. These findings suggest that embryonic development pathways are not always recapitulated during post-natal regenerative processes, and the biochemical pathways utilized to regulate cell differentiation may be different. During in vivo ectopic bone formation, BMP-2 induces -catenin-mediated signaling through Wnt ligands, and -catenin is required for both chondrogenesis and osteogenesis.

Received for publication, March 22, 2006 , and in revised form, August 23, 2006.

^* This work was supported by grants from the Canadian Institutes of Health Research. 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 Supported by the Premier's Research Excellence Program of Ontario.

² To whom correspondence should be addressed: Program in Developmental Biology, the Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, Ontario M5G1X8, Canada. Tel.: 416-813-7980; Fax: 416-813-6414; E-mail: benjamin.alman{at}sickkids.ca.

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