Activation of Hedgehog Signaling Inhibits Osteoblast Differentiation of Human Mesenchymal Stem Cells§

Authors

  • Magali Plaisant,

    1. Institute of Signaling, Biology, Development and Cancer, Université de Nice Sophia-Antipolis, CNRS UMR6543, France
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  • Coralie Fontaine,

    1. Institute of Signaling, Biology, Development and Cancer, Université de Nice Sophia-Antipolis, CNRS UMR6543, France
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  • Wendy Cousin,

    1. Institute of Signaling, Biology, Development and Cancer, Université de Nice Sophia-Antipolis, CNRS UMR6543, France
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  • Nathalie Rochet,

    1. GEPITOS, Université de Nice Sophia-Antipolis, CNRS, UFR de Médecine, France
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  • Christian Dani,

    1. Institute of Signaling, Biology, Development and Cancer, Université de Nice Sophia-Antipolis, CNRS UMR6543, France
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  • Pascal Peraldi

    Corresponding author
    1. Institute of Signaling, Biology, Development and Cancer, Université de Nice Sophia-Antipolis, CNRS UMR6543, France
    • Centre de Biochimie (UMR 6,543 CNRS), Université de Nice-Sophia Antipolis, Faculte des Sciences, 28 Avenue Valrose, 06108 Nice Cedex 2, France
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    • Telephone: 33-493377704; Fax: 33-4-92076404


  • Disclosure of potential conflicts of interest is found at the end of this article.

  • Author contributions: M.P.: collection and assembly of data, data analysis and interpretation, manuscript writing; C.F.: collection of data, data analysis and interpretation; W.C.: collection of data; N.R.: data analysis and interpretation, provision of study material; C.D.: conception and design, data analysis and interpretation, financial support; P.P.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing.

  • §

    First published online in STEM CELLSExpress December 18, 2008.

Abstract

Mesenchymal stem cells within the bone are responsible for the generation of osteoblasts, chondrocytes, and adipocytes. In rodents, Indian hedgehog has been shown to play a role in osteoblast differentiation. However, evidence for a direct function of hedgehog (Hh) in human osteoblastic differentiation is missing. Using different models of human mesenchymal stem cells we show that Hh signaling decreases during osteoblast differentiation. This is associated with a decrease in Smoothened expression, a key partner that triggers Hh signaling, and in the number of cells displaying a primary cilium, an organelle necessary for Hh signaling. Remarkably, treatment of human mesenchymal stem cells with sonic hedgehog or two molecules able to activate Hh signaling inhibits osteoblast differentiation. This inhibition is visualized through a decrease in mineralization and in the expression of osteoblastic genes. In particular, activation of Hh signaling induces a decrease in Runx2 expression, a key transcriptional factor controlling the early stage of osteoblast differentiation. Consistently, the activation of Hh signaling during the first days of differentiation is sufficient to inhibit osteoblast differentiation, whereas differentiated osteoblasts are not affected by Hh signaling. In summary, we show here, using various inducers of Hh signaling and mesenchymal stem cells of two different origins, that Hh signaling inhibits human osteoblast differentiation, in sharp contrast to what has been described in rodent cells. This species difference should be taken into account for screening for pro-osteogenic molecules. STEM CELLS2009;27:703–713

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