The CREB family of activators is required for endochondral bone development

We have evaluated the importance of the CREB family of transcriptional acti vators for endochondral bone formation by expressing a potent dominant nega tive CREB inhibitor (A-CREB) in growth plate chondrocytes of transgenic mic e. A-CREB transgenic mice exhibited short-limbed dwarfism and died minutes after birth, apparently due to respiratory failure from a diminished rib ca ge circumference. Consistent with the robust Ser133 phosphorylation and, he nce, activation of CREB in chondrocytes within the proliferative zone of wi ld-type cartilage during development, chondrocytes in A-CREB mutant cartila ge exhibited a profound decrease in proliferative index and a delay in hype rtrophy, Correspondingly, the expression of certain signaling molecules in cartilage, most notably the Indian hedgehog (Ihh) receptor patched (Ptch), was lower in A-CREB expressing versus wild-type chondrocytes, CREB appears to promote Ptch expression in proliferating chondrocytes via an Ihh-indepen dent pathway; phospho-CREB levels were comparable in cartilage from Ihh(-/- ) and wild-type mice. These results demonstrate the presence of a distinct signaling pathway in developing bone that potentiates Ihh signaling and reg ulates chondrocyte proliferation, at least in part, via the CREB family of activators.