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Development 129, 1913-1924 (2002)
© 2002 The Company of Biologists Limited

TGFß2 mediates the effects of Hedgehog on hypertrophic differentiation and PTHrP expression

Jesus Alvarez1, Philip Sohn1, Xin Zeng2, Thomas Doetschman2, David J. Robbins2 and Rosa Serra1,*

1 Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA
2 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, USA

*Author for correspondence (e-mail: serrar{at}email.uc.edu)

Accepted 23 January 2002

The development of endochondral bones requires the coordination of signals from several cell types within the cartilage rudiment. A signaling cascade involving Indian hedgehog (Ihh) and parathyroid hormone related peptide (PTHrP) has been described in which hypertrophic differentiation is limited by a signal secreted from chondrocytes as they become committed to hypertrophy. In this negative-feedback loop, Ihh inhibits hypertrophic differentiation by regulating the expression of Pthrp, which in turn acts directly on chondrocytes in the growth plate that express the PTH/PTHrP receptor. Previously, we have shown that PTHrP also acts downstream of transforming growth factor ß (TGFß) in a common signaling cascade to regulate hypertrophic differentiation in embryonic mouse metatarsal organ cultures. As members of the TGFß superfamily have been shown to mediate the effects of Hedgehog in several developmental systems, we proposed a model where TGFß acts downstream of Ihh and upstream of PTHrP in a cascade of signals that regulate hypertrophic differentiation in the growth plate. This report tests the hypothesis that TGFß signaling is required for the effects of Hedgehog on hypertrophic differentiation and expression of Pthrp. We show that Sonic hedgehog (Shh), a functional substitute for Ihh, stimulates expression of Tgfb2 and Tgfb3 mRNA in the perichondrium of embryonic mouse metatarsal bones grown in organ cultures and that TGFß signaling in the perichondrium is required for inhibition of differentiation and regulation of Pthrp expression by Shh. The effects of Shh are specifically dependent on TGFß2, as cultures from Tgfb3-null embryos respond to Shh but cultures from Tgfb2-null embryos do not. Taken together, these data suggest that TGFß2 acts as a signal relay between Ihh and PTHrP in the regulation of cartilage hypertrophic differentiation.

Key words: Endochondral bone, Cartilage, Perichondrium, TGFß, Hedgehog, PTHrP, Mouse




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© The Company of Biologists Ltd 2002