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FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression.
FASEB J. 2008 Nov; 22(11):3813-22.FJ

Abstract

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 beta-catenin, a key player involved in bone formation induced by Wnt signaling. FHL2-beta-catenin interaction potentiates beta-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/beta-catenin signaling- dependent Runx2 expression.

Authors+Show Affiliations

INSERM U606, Hopital Lariboisiere, 2 rue Ambroise Pare, 75475 Paris cedex 10, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18653765

Citation

Hamidouche, Zahia, et al. "FHL2 Mediates Dexamethasone-induced Mesenchymal Cell Differentiation Into Osteoblasts By Activating Wnt/beta-catenin Signaling-dependent Runx2 Expression." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 22, no. 11, 2008, pp. 3813-22.
Hamidouche Z, Haÿ E, Vaudin P, et al. FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression. FASEB J. 2008;22(11):3813-22.
Hamidouche, Z., Haÿ, E., Vaudin, P., Charbord, P., Schüle, R., Marie, P. J., & Fromigué, O. (2008). FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 22(11), 3813-22. https://doi.org/10.1096/fj.08-106302
Hamidouche Z, et al. FHL2 Mediates Dexamethasone-induced Mesenchymal Cell Differentiation Into Osteoblasts By Activating Wnt/beta-catenin Signaling-dependent Runx2 Expression. FASEB J. 2008;22(11):3813-22. PubMed PMID: 18653765.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression. AU - Hamidouche,Zahia, AU - Haÿ,Eric, AU - Vaudin,Pascal, AU - Charbord,Pierre, AU - Schüle,Roland, AU - Marie,Pierre J, AU - Fromigué,Olivia, Y1 - 2008/07/24/ PY - 2008/7/26/pubmed PY - 2008/11/19/medline PY - 2008/7/26/entrez SP - 3813 EP - 22 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 22 IS - 11 N2 - 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 beta-catenin, a key player involved in bone formation induced by Wnt signaling. FHL2-beta-catenin interaction potentiates beta-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/beta-catenin signaling- dependent Runx2 expression. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/18653765/FHL2_mediates_dexamethasone_induced_mesenchymal_cell_differentiation_into_osteoblasts_by_activating_Wnt/beta_catenin_signaling_dependent_Runx2_expression_ L2 - https://doi.org/10.1096/fj.08-106302 DB - PRIME DP - Unbound Medicine ER -