TNF-{alpha} MEDIATES OSTEOPENIA CAUSED BY DEPLETION OF ANTIOXIDANTS.
Jagger CJ, Lean JM, Davies JT, Chambers TJ.
Department of Cellular Pathology, St George's Hospital Medical School, London, UK.
We recently found that estrogen deficiency leads to a lowering of thiol antioxidant defenses in rodent bone. Moreover, administration of agents that increase the concentration in bone of glutathione, the main intracellular antioxidant, prevented estrogen-deficiency bone loss, while depletion of glutathione by buthionine sulfoximine (BSO) administration provoked substantial bone loss. It has been shown that the estrogen-deficiency bone loss is dependent upon TNF-alpha signaling. Therefore, a model in which estrogen-deficiency causes bone loss by lowering antioxidant defenses predicts that the osteopenia caused by lowering antioxidant defenses should similarly depend on TNF-alpha signaling. We found that the loss of bone caused by either BSO administration or ovariectomy was inhibited by administration of soluble TNF-alpha receptors, and abrogated in mice deleted for TNF-alpha gene expression. In both circumstances, lack of TNF-alpha signaling prevented the increase in bone resorption and the deficit in bone formation that otherwise occurred. Thus, depletion of thiol antioxidants by BSO, like ovariectomy, causes bone loss through TNF-alpha signaling. Furthermore, in ovariectomized mice treated with soluble TNF-alpha receptors, thiol antioxidant defenses in bone remained low, despite inhibition of bone loss. This suggests that the low levels of antioxidants in bone seen after ovariectomy are the cause, rather than the effect, of the increased resorption. These experiments are consistent with a model for estrogen-deficiency bone loss in which estrogen deficiency lowers thiol antioxidant defenses in bone cells, thereby increasing ROS levels, which in turn induce expression of TNF-alpha, which causes loss of bone. (Okt. 2004) 

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