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J. Biol. Chem., Vol. 282, Issue 42, 30938-30948, October 19, 2007

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Noncanonical Wnt-4 Signaling Enhances Bone Regeneration of Mesenchymal Stem Cells in Craniofacial Defects through Activation of p38 MAPK^*

Jia Chang, Wataru Sonoyama^¶, Zhuo Wang, Qiming Jin^||, Chengfei Zhang^**, Paul H. Krebsbach, William Giannobile^||, Songtao Shi^¶, and Cun-Yu Wang¹

From the Department of Biologic and Materials Sciences, ^||Department of Periodontics and Oral Medicine, School of Dentistry, and Department of Biomedical Engineering, College of Engineering, University of Michigan, Ann Arbor, Michigan 48109, the ^**School and Hospital of Stomatology, Peking University Health Science Center, Beijing 100081, China, the ^¶Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, Los Angeles, California 90033, and the Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095

Mesenchymal stem cells (MSCs) are multipotent cells that can be differentiated into osteoblasts and provide an excellent cell source for bone regeneration and repair. Recently, the canonical Wnt/-catenin signaling pathway has been found to play a critical role in skeletal development and osteogenesis, implying that Wnts can be utilized to improve de novo bone formation mediated by MSCs. However, it is unknown whether noncanonical Wnt signaling regulates osteogenic differentiation. Here, we find that Wnt-4 enhanced in vitro osteogenic differentiation of MSCs isolated from human adult craniofacial tissues and promoted bone formation in vivo. Whereas Wnt-4 did not stabilize -catenin, it activated p38 MAPK in a novel noncanonical signaling pathway. The activation of p38 was dependent on Axin and was required for the enhancement of MSC differentiation by Wnt-4. Moreover, using two different models of craniofacial bone injury, we found that MSCs genetically engineered to express Wnt-4 enhanced osteogenesis and improved the repair of craniofacial defects in vivo. Taken together, our results reveal that noncanonical Wnt signaling could also play a role in osteogenic differentiation. Wnt-4 may have a potential use in improving bone regeneration and repair of craniofacial defects.

Received for publication, March 20, 2007 , and in revised form, August 23, 2007.

^* This work was supported by NIDCR, National Institutes of Health, Grants DE16513 (to C. Y. W.) and DE13397 (to W. V. G.) and by the Department of Defense (to C. Y. W. and P. K.). 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 Figs. 1-4.

¹ To whom correspondence should be addressed: Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-825-4415; Fax: 310-794-7109; E-mail: cwang{at}dentistry.ucla.edu.

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