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FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/β-catenin signaling-dependent Runx2 expression

Zahia Hamidouche^*, Eric Haÿ^*, Pascal Vaudin, Pierre Charbord, Roland Schüle, Pierre J. Marie^*,1 and Olivia Fromigué^*

^* INSERM U606 and University Paris VII, Paris, France;

Université François Rabelais, Tours, France;

INSERM-ESPRI, Tours, France; and

Zentrum für Klinische Forschung and Universitäts-Frauenklinik, Freiburg, Germany

¹Correspondence: INSERM U606, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris cedex 10, France. E-mail: pierre.marie{at}inserm.fr

The differentiation of bone marrow mesenchymal stem cells (MSCs) into osteoblasts is a crucial step in bone formation. However, the mechanisms involved in the early stages of osteogenic differentiation are not well understood. In this study, we identified FHL2, a member of the LIM-only subclass of the LIM protein superfamily, that is up-regulated during early osteoblast differentiation induced by dexamethasone in murine and human MSCs. Gain-of-function studies showed that FHL2 promotes the expression of the osteoblast transcription factor Runx2, alkaline phosphatase, type I collagen, as well as in vitro extracellular matrix mineralization in murine and human mesenchymal cells. Knocking down FHL2 using sh-RNA reduces basal and dexamethasone-induced osteoblast marker gene expression in MSCs. We demonstrate that FHL2 interacts with β-catenin, a key player involved in bone formation induced by Wnt signaling. FHL2-β-catenin interaction potentiates β-catenin nuclear translocation and TCF/LEF transcription, resulting in increased Runx2 and alkaline phosphatase expression, which was inhibited by the Wnt inhibitor DKK1. Reduction of Runx2 transcriptional activity using a mutant Runx2 results in inhibition of FHL2-induced alkaline phosphatase expression in MSCs. These findings reveal that FHL2 acts as an endogenous activator of mesenchymal cell differentiation into osteoblasts and mediates osteogenic differentiation induced by dexamethasone in MSCs through activation of Wnt/β-catenin signaling- dependent Runx2 expression.—Hamidouche, Z., Haÿ, E., Vaudin, P., Charbord, P., Schüle, R., Marie, P. J., and Fromigué, O. FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/β-catenin signaling-dependent Runx2 expression.

Key Words: osteogenesis • signaling • cell therapy

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