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CELLULAR AND MOLECULAR

Estradiol Protects against Ethanol-Induced Bone Loss by Inhibiting Up-Regulation of Receptor Activator of Nuclear Factor-B Ligand in Osteoblasts

Departments of Pharmacology and Toxicology (J.-R.C., M.H., K.S., X.L., M.J.J.R.), Pediatrics (C.K.L., P.M.S.), and Physiology and Biophysics (T.M.B.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Arkansas Children's Nutrition Center, Little Rock, Arkansas (J.-R.C., R.L.H., M.H., K.S., X.L., T.M.B., M.J.J.R.)

To investigate the effects of sex hormones on ethanol (EtOH)-induced bone loss, female Sprague-Dawley rats were fed control or EtOH-containing diets (12 g/kg/day) by intragastric infusion. After 3 weeks, rats receiving EtOH had significant decreases in tibial trabecular and total bone mineral density, induction of receptor activator of nuclear factor-B ligand (RANKL) mRNA expression, and enhanced bone resorption, all of which were prevented by treatment with 17-estradiol (E₂). The addition of progesterone did not enhance the beneficial effect of E₂ alone. Consistent with our in vivo findings, EtOH stimulated RANKL mRNA expression in cultured primary osteoblasts, and this expression was blocked by 4-methylpyrazole. Acetaldehyde also induced RANKL expression. Class 1 alcohol dehydrogenase was found to be expressed and EtOH-inducible in cultured osteoblasts, whereas CYP2E1 was undetectable. We found that EtOH induced phosphorylation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription 3 (STAT3). E₂ and the mitogenactivated protein kinase kinase inhibitor 2'-amino-3'-methoxyflavone (PD98059) blocked ERK and STAT3 phosphorylation and blocked RANKL induction. Moreover, E₂ completely blocked EtOH-induced osteoclastogenesis in a primary osteoblast and osteoclast precursor coculture system. The E₂ effects were estrogen receptor-mediated. Therefore, E₂ prevents EtOH-induced bone loss by opposing the induction of RANKL mRNA in osteoblasts and ethanol-induced osteoclastogenesis, through opposing effects on sustained ERK signaling.

Address correspondence to: Dr. Martin J. J. Ronis, Arkansas Children's Nutrition Center, Slot 512-20B, 1120 Marshall St., Little Rock, AR 72202. E-mail: ronismartinj{at}uams.edu.

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