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

Sylviane Spinella-Jaegle^1,*, Georges Rawadi^1,*, Shinji Kawai¹, Sylvie Gallea¹, Chi Faucheu¹, Patrick Mollat¹, Brigitte Courtois¹, Brigitte Bergaud¹, Valérie Ramez¹, Anne Marie Blanchet¹, Guillaume Adelmant², Roland Baron³ and Sergio Roman-Roman^1,

¹ Bone Diseases Group, Department of Biotechnology, Hoechst-Marion-Roussel, 111 route de Noisy, 93230 Romainville, France
² Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115, USA
³ Departments of Cell Biology and Orthopaedics, Yale University School of Medicine, New Haven, CT 06510, USA
^* Both authors equally contributed to this work

Author for correspondence (e-mail: sergio.romanroman{at}aventis.com)

Accepted March 7, 2001

The proteins of the hedgehog (Hh) family regulate various aspects of development. Recently, members of this family have been shown to regulate skeletal formation in vertebrates and to control both chondrocyte and osteoblast differentiation. In the present study, we analyzed the effect of Sonic hedgehog (Shh) on the osteoblastic and adipocytic commitment/differentiation. Recombinant N-terminal Shh (N-Shh) significantly increased the percentage of both the pluripotent mesenchymal cell lines C3H10T1/2 and ST2 and calvaria cells responding to bone morphogenetic protein 2 (BMP-2), in terms of osteoblast commitment as assessed by measuring alkaline phosphatase (ALP) activity. This synergistic effect was mediated, at least partly, through the positive modulation of the transcriptional output of BMPs via Smad signaling. Furthermore, N-Shh was found to abolish adipocytic differentiation of C3H10T1/2 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-related transcription factors C/EBP and PPAR in both C3H10T1/2 and calvaria cell cultures. Given the inverse relationship between marrow adipocytes and osteoblasts with aging, agonists of the Hh signaling pathway might constitute potential drugs for preventing and/or treating osteopenic disorders.

Key words: Sonic hedgehog, Bone morphogenetic protein 2, Osteoblast, Adipocyte, Differentiation

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