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J. Biol. Chem., Vol. 282, Issue 19, 14515-14524, May 11, 2007

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Wnt Signaling Stimulates Osteoblastogenesis of Mesenchymal Precursors by Suppressing CCAAT/Enhancer-binding Protein and Peroxisome Proliferator-activated Receptor ^*

Sona Kang¹, Christina N. Bennett², Isabelle Gerin, Lauren A. Rapp, Kurt D. Hankenson, and Ormond A. MacDougald^¶3

From the Departments of Molecular and Integrative Physiology, Orthopedic Surgery, and ^¶Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0622

Mesenchymal precursor cells have the potential to differentiate into several cell types, including adipocytes and osteoblasts. Activation of Wnt/-catenin signaling shifts mesenchymal cell fate toward osteoblastogenesis at the expense of adipogenesis; however, molecular mechanisms by which Wnt signaling alters mesenchymal cell fate have not been fully investigated. Our prior work indicates that multipotent precursors express adipogenic and osteoblastogenic transcription factors at physiological levels and that ectopic expression of Wnt10b in bipotential ST2 cells suppresses expression of CCAAT/enhancer-binding protein (C/EBP) and peroxisome proliferator-activated receptor (PPAR) and increases expression of Runx2, Dlx5, and osterix. Here, we demonstrate that transient activation of Wnt/-catenin signaling rapidly suppresses C/EBP and PPAR, followed by activation of osteoblastogenic transcription factors. Enforced expression of C/EBP or PPAR partially rescues lipid accumulation and decreases mineralization in ST2 cells expressing Wnt10b, suggesting that suppression of C/EBP and PPAR is required for Wnt/-catenin to alter cell fate. Furthermore, knocking down expression of C/EBP, PPAR, or both greatly reduces adipogenic potential and causes spontaneous osteoblastogenesis in ST2 cells and mouse embryonic fibroblasts, suggesting that Wnt signaling alters the fate of mesenchymal precursor cells primarily by suppressing C/EBP and PPAR.

Received for publication, January 2, 2007 , and in revised form, March 8, 2007.

^* This work was supported by National Institutes of Health Grant DK62876 (to O. A. M.). Additional support was provided by the Michigan Metabolomics and Obesity Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Jack Lapides and Rackham Graduate Fellowships.

² Supported by the American Physiological Society Porter Fellowship and the Tissue Engineering and Regeneration Training Grant.

³ To whom correspondence should be addressed: Dept. of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine Rd., Ann Arbor, MI 48109-0622. Tel.: 734-647-4880; Fax: 734-936-8813; E-mail: macdouga{at}umich.edu.

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