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J. Biol. Chem., Vol. 282, Issue 35, 25501-25508, August 31, 2007

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A Novel Ligand-independent Function of the Estrogen Receptor Is Essential for Osteocyte and Osteoblast Mechanotransduction^*

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

Bone senses and adapts to meet mechanical needs by means of an extensive mechanotransduction network comprising osteocytes (former osteoblasts entrapped in mineral) and their cytoplasmic projections through which osteocytes communicate with osteoblasts and osteoclasts on the bone surface. Mechanical stimulation promotes osteocyte (and osteoblast) survival by activating the extracellular signal-regulated kinases, ERKs. Estrogens have similar effects and, intriguingly, the adaptive response of bone to mechanical forces is defective in mice lacking estrogen receptor (ER) or ER. We report that ERKs are not activated by stretching in osteocytic and osteoblastic cells in which both ER and ER have been knocked out or knocked down and this is reversed partially by transfection of either one of the two human ERs and fully by transfection of both receptors. ERK activation in response to stretching is also recovered by transfecting the ligand-binding domain (E) of either receptor or an ER mutant that does not bind estrogens. Furthermore, mechano-responsiveness is restored by transfecting the E targeted to the plasma membrane, but not to the nucleus, whereas ER mutants with impaired plasma membrane localization or binding to caveolin-1 fail to confer ERK activation in response to stretching. Lastly, the ER antagonist ICI 182,780 abrogates ERK activation and the anti-apoptotic effect of mechanical stimulation. We conclude that in addition to their role as ligand-dependent mediators of the effects of estrogens, the ERs participate in the transduction of mechanical forces into pro-survival signaling in bone cells, albeit in a ligand-independent manner.

Received for publication, March 14, 2007 , and in revised form, July 3, 2007.

^* This work was supported by National Institutes of Health Grants KO2-AR02127 and P01-AG13918) and the U. S. Department of Veterans Affairs. 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 Physiological Sciences, College of Veterinary Medicine, University of Florida, P. O. Box 100144, Gainesville, FL 32610.

² Present address: Research Unit, La Paz University Hospital, Madrid, Spain.

³ To whom correspondence should be addressed. Tel.: 501-686-8971; Fax: 501-686-8148; E-mail: tmbellido{at}uams.edu.

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