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First published online 18 February 2009
doi: 10.1242/dev.029926

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BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation

¹ Orthopaedic Hospital/UCLA Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
² Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
³ Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.

^* Author for correspondence (e-mail: klyons{at}mednet.ucla.edu)

Accepted 2 February 2009

Bone morphogenetic protein (BMP) signaling is required for endochondral bone formation. However, whether or not the effects of BMPs are mediated via canonical Smad pathways or through noncanonical pathways is unknown. In this study we have determined the role of receptor Smads 1, 5 and 8 in chondrogenesis. Deletion of individual Smads results in viable and fertile mice. Combined loss of Smads 1, 5 and 8, however, results in severe chondrodysplasia. Smad1/5^CKO (cartilage-specific knockout) mutant mice are nearly identical to Smad1/5^CKO;Smad8^-/- mutants, indicating that Smads 1 and 5 have overlapping functions and are more important than Smad8 in cartilage. The Smad1/5^CKO phenotype is more severe than that of Smad4^CKO mice, challenging the dogma, at least in chondrocytes, that Smad4 is required to mediate Smad signaling through BMP pathways. The chondrodysplasia in Smad1/5^CKO mice is accompanied by imbalances in cross-talk between the BMP, FGF and Ihh/PTHrP pathways. We show that Ihh is a direct target of BMP pathways in chondrocytes, and that FGF exerts antagonistic effects on Ihh expression. Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo.

Key words: BMP, Smad, Growth plate, Chondrogenesis, Mouse

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