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Tumor Necrosis Factor- Mediates Osteopenia Caused by Depletion of Antioxidants

Department of Cellular Pathology, St. George’s Hospital Medical School, London SW17 0RE, United Kingdom

Address all correspondence and requests for reprints to: Professor T. J. Chambers, Department of Cellular Pathology, St. George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, United Kingdom. E-mail: t.chambers{at}sghms.ac.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, whereas depletion of glutathione by buthionine sulfoximine (BSO) administration provoked substantial bone loss. It has been shown that the estrogen-deficiency bone loss is dependent on TNF 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 signaling. We found that the loss of bone caused by either BSO administration or ovariectomy was inhibited by administration of soluble TNF receptors and abrogated in mice deleted for TNF gene expression. In both circumstances, lack of TNF 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 signaling. Furthermore, in ovariectomized mice treated with soluble TNF 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 reactive oxygen species levels, which in turn induce expression of TNF, which causes loss of bone.

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