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J. Biol. Chem., Vol. 282, Issue 37, 27298-27305, September 14, 2007

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Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting -Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription^*

From the Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 72205

We have elucidated that oxidative stress is a pivotal pathogenetic factor of age-related bone loss and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation. To gain insight into the molecular mechanism by which oxidative stress exerts such adverse effects, we have tested the hypothesis that induction of the Forkhead box O (FoxO) transcription factors by reactive oxygen species may antagonize Wnt signaling, an essential stimulus for osteoblastogenesis. In support of this hypothesis, we report herein that the expression of FoxO target genes increases, whereas the expression of Wnt target genes decreases, with increasing age in C57BL/6 mice. Moreover, we show that in osteoblastic cell models, oxidative stress (exemplified by H₂O₂) promotes the association of FoxOs with -catenin, -catenin is required for the stimulation of FoxO target genes by H₂O₂, and H₂O₂ promotes FoxO-mediated transcription at the expense of Wnt-/T-cell factor-mediated transcription and osteoblast differentiation. Furthermore, -catenin overexpression is sufficient to prevent FoxO-mediated suppression of T-cell factor transcription. These results demonstrate that diversion of the limited pool of -catenin from T-cell factor- to FoxO-mediated transcription in osteoblastic cells may account, at least in part, for the attenuation of osteoblastogenesis and bone formation by the age-dependent increase in oxidative stress.

Received for publication, April 3, 2007 , and in revised form, July 6, 2007.

^* This work was supported by National Institutes of Health Grants P01AG13918 and R01AR51187, a Department of Veterans Affairs Merit Review grant and a Research Enhancement Award Program, and Tobacco Settlement funds provided by the University of Arkansas for Medical Sciences College of Medicine. 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. S1 and S2.

¹ To whom correspondence should be addressed: 4301 West Markham, 587, Little Rock, AR 72205-7199. Tel.: 501-686-5130; Fax: 501-686-8148; E-mail: manolagasstavros{at}uams.edu.

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