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J. Biol. Chem., Vol. 282, Issue 37, 27285-27297, September 14, 2007

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Skeletal Involution by Age-associated Oxidative Stress and Its Acceleration by Loss of Sex Steroids^*

Maria Almeida, Li Han, Marta Martin-Millan, Lilian I. Plotkin, Scott A. Stewart, Paula K. Roberson, Stavroula Kousteni¹, Charles A. O'Brien, Teresita Bellido, A. Michael Parfitt, Robert S. Weinstein, Robert L. Jilka, and Stavros C. Manolagas²

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

Both aging and loss of sex steroids have adverse effects on skeletal homeostasis, but whether and how they may influence each others negative impact on bone remains unknown. We report herein that both female and male C57BL/6 mice progressively lost strength (as determined by load-to-failure measurements) and bone mineral density in the spine and femur between the ages of 4 and 31 months. These changes were temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate; as well as increased osteoblast and osteocyte apoptosis, increased reactive oxygen species levels, and decreased glutathione reductase activity and a corresponding increase in the phosphorylation of p53 and p66^shc, two key components of a signaling cascade that are activated by reactive oxygen species and influences apoptosis and lifespan. Exactly the same changes in oxidative stress were acutely reproduced by gonadectomy in 5-month-old females or males and reversed by estrogens or androgens in vivo as well as in vitro.We conclude that the oxidative stress that underlies physiologic organismal aging in mice may be a pivotal pathogenetic mechanism of the age-related bone loss and strength. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against 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 P01 AG13918, R01 AR51187, R01 AR49794, and R01 AR46191, Department of Veterans Affairs merit review grants (to R. S. W., R. L. J., and S. C. M.) and a research enhancement award program; and tobacco settlement funds provided by the University of Arkansas for Medical Sciences. 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 Present address: Dept. of Medicine, Division of Endocrinology, Columbia University, New York, NY 10032.

² 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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