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J. Biol. Chem., Vol. 283, Issue 14, 9136-9145, April 4, 2008

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The Effects of Myostatin on Adipogenic Differentiation of Human Bone Marrow-derived Mesenchymal Stem Cells Are Mediated through Cross-communication between Smad3 and Wnt/β-Catenin Signaling Pathways^*

Wen Guo¹, John Flanagan, Ravi Jasuja, James Kirkland, Lan Jiang, and Shalender Bhasin

From the Sections of Endocrinology, Diabetes, and Nutrition and Geriatrics, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts 02118 and the Karolinska Institute, Stockholm SE-171 77, Sweden

The effects of myostatin on adipogenic differentiation are poorly understood, and the underlying mechanisms are unknown. We determined the effects of human recombinant myostatin protein on adipogenesis of bone marrow-derived human mesenchymal stem cells (hMSCs) and adipose tissue-derived preadipocytes. For both progenitor cell types, differentiation in the presence of myostatin caused a dose-dependent reduction of lipid accumulation and diminished incorporation of exogenous fatty acid into cellular lipids. Myostatin significantly down-regulated the expression of adipocyte markers PPAR, C/EBP, leptin, and aP2, but not C/EBPβ. Overexpression of PPAR, but not C/EBPβ, blocked the inhibitory effects of myostatin on adipogenesis. Myostatin induced phosphorylation of Smad3 in hMSCs; knockdown of Smad3 by RNAi or inhibition of its upstream kinase by an Alk5 inhibitor blocked the inhibitory effect of myostatin on adipogenesis in hMSCs, implying an important role of Smad3 activation in this event. Furthermore, myostatin enhanced nuclear translocation of β-catenin and formation of the Smad3-β-catenin-TCF4 complex, together with the altered expression of a number of Wnt/β-catenin pathway genes in hMSCs. The inhibitory effects of myostatin on adipogenesis were blocked by RNAi silencing of β-catenin and diminished by overexpression of dominant-negative TCF4. The conclusion is that myostatin inhibited adipogenesis in human bone marrow-derived mesenchymal stem cells and preadipocytes. These effects were mediated, in part, by activation of Smad3 and cross-communication of the TGFβ/Smad signal to Wnt/β-catenin/TCF4 pathway, leading to down-regulation of PPAR.

Received for publication, October 31, 2007 , and in revised form, January 18, 2008.

^* This work was supported by National Institutes of Health Grants R01DK59261 (to W. G.) and R01DK70431 and R01DK49296 (to S. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: 670 Albany St., Boston, MA 02118. E-mail: wguo{at}bu.edu.

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