Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation

被引:280
作者
Lean, JM [1 ]
Jagger, CJ [1 ]
Kirstein, B [1 ]
Fuller, K [1 ]
Chambers, TJ [1 ]
机构
[1] St George Hosp, Sch Med, Dept Cellular Pathol, London SW17 0RE, England
关键词
D O I
10.1210/en.2004-1021
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-kappaB ligand (RANKL) and in osteoclasts by 17beta-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-kappaB 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.
引用
收藏
页码:728 / 735
页数:8
相关论文
共 32 条
[1]   NF-kappa B: Ten years after [J].
Baeuerle, PA ;
Baltimore, D .
CELL, 1996, 87 (01) :13-20
[2]   STIMULATION OF OSTEOCLASTIC BONE-RESORPTION BY HYDROGEN-PEROXIDE [J].
BAX, BE ;
ALAM, ASMT ;
BANERJI, B ;
BAX, CMR ;
BEVIS, PJR ;
STEVENS, CR ;
MOONGA, BS ;
BLAKE, DR ;
ZAIDI, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 183 (03) :1153-1158
[3]   Osteoclast differentiation and activation [J].
Boyle, WJ ;
Simonet, WS ;
Lacey, DL .
NATURE, 2003, 423 (6937) :337-342
[4]   The inactivation mechanism of low molecular weight phosphotyrosine-protein phosphatase by H2O2 [J].
Caselli, A ;
Marzocchini, R ;
Camici, G ;
Manao, G ;
Moneti, G ;
Pieraccini, G ;
Ramponi, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (49) :32554-32560
[5]  
Chambers TJ, 2000, J PATHOL, V192, P4
[6]   ESTROGEN MAINTAINS TRABECULAR BONE VOLUME IN RATS NOT ONLY BY SUPPRESSION OF BONE-RESORPTION BUT ALSO BY STIMULATION OF BONE-FORMATION [J].
CHOW, J ;
TOBIAS, JH ;
COLSTON, KW ;
CHAMBERS, TJ .
JOURNAL OF CLINICAL INVESTIGATION, 1992, 89 (01) :74-78
[7]   Premature aging in mice deficient in DNA repair and transcription [J].
de Boer, J ;
Andressoo, JO ;
de Wit, J ;
Huijmans, J ;
Beems, RB ;
van Steeg, H ;
Weeda, G ;
van der Horst, GTJ ;
van Leeuwen, W ;
Themmen, APN ;
Meradji, M ;
Hoeijmakers, JHJ .
SCIENCE, 2002, 296 (5571) :1276-1279
[8]   Free radicals in the physiological control of cell function [J].
Dröge, W .
PHYSIOLOGICAL REVIEWS, 2002, 82 (01) :47-95
[9]   Requirement for NF-κB in osteoclast and B-cell development [J].
Franzoso, G ;
Carlson, L ;
Xing, LP ;
Poljak, L ;
Shores, EW ;
Brown, KD ;
Leonardi, A ;
Tran, T ;
Boyce, BF ;
Siebenlist, U .
GENES & DEVELOPMENT, 1997, 11 (24) :3482-3496
[10]   TNFa potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL [J].
Fuller, K ;
Murphy, C ;
Kirstein, B ;
Fox, SW ;
Chambers, TJ .
ENDOCRINOLOGY, 2002, 143 (03) :1108-1118