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Submitted on August 4, 2004
Accepted on October 27, 2004
Department of Cellular Pathology, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
* To whom correspondence should be addressed. E-mail: tchamber{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, while depletion of glutathione by buthionine sulfoximine administration provoked substantial bone loss. To analyze further the mechanism by which antioxidant defenses modulate bone loss, we have now compared expression of the known antioxidant enzymes in osteoclasts. We found that glutathione peroxidase 1 (Gpx), the enzyme primarily responsible for the intracellular degradation of hydrogen peroxide, is overwhelmingly the predominant antioxidant enzyme expressed by osteoclasts, and that its expression was increased in bone marrow macrophages by RANKL and in osteoclasts by 17-
estradiol. We therefore tested the effect of overexpression of Gpx in osteoclasts, by stable transfection of RAW 264.7 (RAW) cells, which are capable of osteoclastic differentiation in response to RANKL, with a Gpx-expression construct. Osteoclast formation was abolished. The Gpx expression construct also suppressed RANKL-induced NF
B activation, and increased resistance to oxidation of DCF by exogenous hydrogen peroxide.
We therefore tested the role of hydrogen peroxide in the loss of bone caused by estrogen deficiency, by administering pegylated catalase (CAT) to mice. We found that CAT prevented ovariectomy-induced bone loss. These results suggest that hydrogen peroxide is the reactive oxygen species (ROS) responsible for signaling the bone loss of estrogen-deficiency.
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