Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation

The proteins of the hedgehog (Hh) family regulate various aspects of develo pment. Recently, members of this family have been shown to regulate skeleta l formation in vertebrates and to control both chondrocyte and osteoblast d ifferentiation. In the present study, we analyzed the effect of Sonic hedge hog (Shh) on the osteoblastic and adipocytic commitment/differentiation. Re combinant N-terminal Shh (N-Shh) significantly increased the percentage of both the pluripotent mesenchymal cell lines C3H10T112 and ST2 and calvaria cells responding to bone morphogenetic protein 2 (BMP-2), in terms of osteo blast commitment as assessed by measuring alkaline phosphatase (ALP) activi ty. This synergistic effect was mediated, at least partly, through the posi tive modulation of the transcriptional output of BMPs via Smad signaling, F urthermore, N-Shh was found to abolish adipocytic differentiation of C3H10T 1/2 cells both in the presence or absence of BMP-2, A short treatment with N-Shh was sufficient to dramatically reduce the levels of the adipocytic-re lated transcription factors C/EBP alpha and PPAR gamma in both C3H10T1/2 an d calvaria cell cultures. Given the inverse relationship between marrow adi pocytes and osteoblasts with aging, agonists of the Hh signaling pathway mi ght constitute potential drugs for preventing and/or treating osteopenic di sorders.