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CELLULAR AND MOLECULAR

Protective Effects of Estradiol on Ethanol-Induced Bone Loss Involve Inhibition of Reactive Oxygen Species Generation in Osteoblasts and Downstream Activation of the Extracellular Signal-Regulated Kinase/Signal Transducer and Activator of Transcription 3/Receptor Activator of Nuclear Factor-B Ligand Signaling Cascade

Departments of Pharmacology and Toxicology (J.-R.C., K.S., M.J.J.R.), Physiology and Biophysics (T.M.B.), and Microbiology and Immunology (S.N.), University of Arkansas for Medical Sciences and Arkansas Children's Nutrition Center (T.M.B., J.-R.C., K.S., S.N., M.J.J.R.), Little Rock, Arkansas

Bone loss occurs following chronic ethanol (EtOH) consumption in males and cycling females in part as a result of increased bone resorption. We have demonstrated in vivo that estradiol treatment can reverse this effect. Using osteoclast precursors from bone marrow and osteoblast/preosteoclast coculture, we found that EtOH-induced receptor activator of nuclear factor-B ligand (RANKL) expression in osteoblasts was able to promote osteoclastogenesis. These effects were blocked by pretreatment of cells with either 17β-estradiol (E₂) or the anti-oxidant N-acetyl cysteine (NAC). EtOH treatment of stromal osteoblasts increased the intracellular level of reactive oxygen species (ROS). This was associated with induction of NADPH oxidase (NOX) and a downstream signaling cascade involving sustained activation of extracellular signal-regulated kinase (ERK) and activation of signal transducer and activator of transcription 3, resulting in increased gene expression of RANKL. In the presence of EtOH, sustained nuclear ERK translocation >24 h was observed in calvarial osteoblasts and UMR-106 cells transfected with green fluorescent protein-ERK2 plasmid. This was abolished by pretreatment with either E₂ or NAC. NOX subtypes 1, 2, and 4, but not 3, were expressed in stromal osteoblasts. Chemical inhibition of NOX by diphenylene iodonium also reversed the ability of EtOH to phosphorylate ERK and induce RANKL mRNA expression. Down-regulation of EtOH-induced ROS generation in osteoblasts was also observed after treatment with E₂ or NAC. These data suggest that the molecular mechanisms whereby E₂ prevents EtOH-induced bone loss involve interference with ROS generation and cytoplasmic kinase activation.

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