TGFbeta2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression.
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 beta (TGFbeta) in a common signaling cascade to regulate hypertrophic differentiation in embryonic mouse metatarsal organ cultures. As members of the TGFbeta superfamily have been shown to mediate the effects of Hedgehog in several developmental systems, we proposed a model where TGFbeta 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 TGFbeta 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 TGFbeta 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 TGFbeta2, as cultures from Tgfb3-null embryos respond to Shh but cultures from Tgfb2-null embryos do not. Taken together, these data suggest that TGFbeta2 acts as a signal relay between Ihh and PTHrP in the regulation of cartilage hypertrophic differentiation.
Alvarez
Jesus
J
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0576, USA.
Sohn
Philip
P
Zeng
Xin
X
Doetschman
Thomas
T
Robbins
David J
DJ
Serra
Rosa
R
D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000254:growth & development; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics; D015870:Gene Expression; D053823:Hedgehog Proteins; D006984:Hypertrophy; D008682:Metatarsal Bones / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009924:Organ Culture Techniques; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000235:genetics*; D011509:Proteoglycans / Q000235:genetics; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism* / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
D024121:Collagen Type X; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; C071736:betaglycan