Chronic alcohol (EtOH) consumption causes the generation of excess reactive oxygen species (ROS) in bone resulting in osteopenia due to increased bone resorption and decreased bone formation. This mechanism has been shown to involve ROS produced by NADPH Oxidases (NOX). EtOH-induced ROS within bone has been shown to drive RANKL induced osteoclastogenesis while simultaneously inhibiting translocation of ?-catenin to the nucleus of pre-osteoblasts preventing osteoblastogenesis. Three specific aims were developed to test the hypothesis that excess NOX-derived and other ROS generated by chronic ethanol consumption is responsible for alcohol induced osteopenia and that ROS signaling is critical for controlling normal bone turnover. In Aim1 it was hypothesized that feeding different dietary antioxidants could counteract the effects of alcohol on bone. Mice fed alcohol and either N-acetyl cysteine (NAC) or α-tocopherol (Vit.E) were protected against reduced trabecular bone volume associated with EtOH and did not exhibit increases in marrow adiposity due to EtOH. NAC blocked ROS in vivo, determined by nitrotyrosine staining. Aim2 hypothesized that mice over-expressing human catalase (TgCAT) would be protected against EtOH effects on bone. EtOH-fed TgCAT mice did not differ in bone volume from pair-fed controls, but the apparent genotype effect obscured a conclusion of protection. Observing bone phenotypes of TgCAT mice at 6 and 14 weeks of age demonstrated that hydrogen peroxide plays different roles during bone development as 6-week old TgCAT mice had a high bone mass while 14-week old TgCAT mice had low bone mass compared to wildtype mice. Finally, Aim3 hypothesized that NOX4 knockout mice would be protected against both EtOH inhibition of bone formation and stimulation of resorption. NOX4 knockout mice did not display elevated bone mass compared to wild-type as previously reported, were highly susceptible to EtOH-induced decreased bone volume, and exhibited compensatory upregulation of NOX2. These studies demonstrate that excess NOX-derived and other ROS due to EtOH greatly contribute to osteopenia along with other effects of EtOH and that different types of ROS impact bone turnover and development in unique ways.
|Advisor:||Ronis, Martin J., Suva, Larry J.|
|Commitee:||Light, Kim, MacMillan-Crow, Lee Ann, Morello, Roy, Shankar, Kartik|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology|
|Keywords:||Alcohol, Bone, Nadph oxidases, Reactive oxygen species|
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