This Article Full Text Full Text (PDF) All Versions of this Article: 146/2/728    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lean, J. M. Articles by Chambers, T. J. Search for Related Content PubMed PubMed Citation Articles by Lean, J. M. Articles by Chambers, T. J.

Hydrogen Peroxide Is Essential for Estrogen-Deficiency Bone Loss and Osteoclast Formation

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: 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, whereas 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 receptor activator of nuclear factor-B ligand (RANKL) and in osteoclasts by 17ß-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 nuclear factor-B activation and increased resistance to oxidation of dihydrodichlorofluorescein 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 to mice. We found that catalase prevented ovariectomy-induced bone loss. These results suggest that hydrogen peroxide is the reactive oxygen species responsible for signaling the bone loss of estrogen deficiency.

This article has been cited by other articles:

				C. Pridans, M. L. Holmes, M. Polli, J. M. Wettenhall, A. Dakic, L. M. Corcoran, G. K. Smyth, and S. L. Nutt Identification of Pax5 Target Genes in Early B Cell Differentiation J. Immunol., February 1, 2008; 180(3): 1719 - 1728. [Abstract] [Full Text] [PDF]

				S. R. Hammes and E. R. Levin Extranuclear Steroid Receptors: Nature and Actions Endocr. Rev., December 1, 2007; 28(7): 726 - 741. [Abstract] [Full Text] [PDF]

				F. Grassi, G. Tell, M. Robbie-Ryan, Y. Gao, M. Terauchi, X. Yang, M. Romanello, D. P. Jones, M. N. Weitzmann, and R. Pacifici Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation PNAS, September 18, 2007; 104(38): 15087 - 15092. [Abstract] [Full Text] [PDF]

				M. Almeida, L. Han, M. Martin-Millan, L. I. Plotkin, S. A. Stewart, P. K. Roberson, S. Kousteni, C. A. O'Brien, T. Bellido, A. M. Parfitt, et al. Skeletal Involution by Age-associated Oxidative Stress and Its Acceleration by Loss of Sex Steroids J. Biol. Chem., September 14, 2007; 282(37): 27285 - 27297. [Abstract] [Full Text] [PDF]

				R. H. Straub The Complex Role of Estrogens in Inflammation Endocr. Rev., August 1, 2007; 28(5): 521 - 574. [Abstract] [Full Text] [PDF]

				B. Oh, S.-Y. Kim, D. J. Kim, J. Y. Lee, J.-K. Lee, K. Kimm, B. L. Park, H. D. Shin, T.-H. Kim, E. K. Park, et al. Associations of catalase gene polymorphisms with bone mineral density and bone turnover markers in postmenopausal women J. Med. Genet., January 1, 2007; 44(1): e62 - e62. [Abstract] [Full Text] [PDF]

				E. Hinoi, T. Takarada, Y. Tsuchihashi, S. Fujimori, N. Moriguchi, L. Wang, K. Uno, and Y. Yoneda A Molecular Mechanism of Pyruvate Protection against Cytotoxicity of Reactive Oxygen Species in Osteoblasts Mol. Pharmacol., September 1, 2006; 70(3): 925 - 935. [Abstract] [Full Text] [PDF]

				E. Hinoi, S. Fujimori, L. Wang, H. Hojo, K. Uno, and Y. Yoneda Nrf2 Negatively Regulates Osteoblast Differentiation via Interfering with Runx2-dependent Transcriptional Activation J. Biol. Chem., June 30, 2006; 281(26): 18015 - 18024. [Abstract] [Full Text] [PDF]

				M. S. Kim, C. J. Day, C. I. Selinger, C. L. Magno, S. R. J. Stephens, and N. A. Morrison MCP-1-induced Human Osteoclast-like Cells Are Tartrate-resistant Acid Phosphatase, NFATc1, and Calcitonin Receptor-positive but Require Receptor Activator of NF{kappa}B Ligand for Bone Resorption J. Biol. Chem., January 13, 2006; 281(2): 1274 - 1285. [Abstract] [Full Text] [PDF]