Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation.
Increased production of tumor necrosis factor alpha (TNF) in the bone marrow (BM) in response to both oxidative stress and T cell activation contributes to the bone loss induced by estrogen deficiency, but it is presently unknown whether oxidative stress causes bone loss through T cells. Here we show that ovariectomy causes an accumulation in the BM of reactive oxygen species, which leads to increased production of TNF by activated T cells through up-regulation of the costimulatory molecule CD80 on dendritic cells. Accordingly, bone loss is prevented by treatment of ovariectomized mice with either antioxidants or CTLA4-Ig, an inhibitor of the CD80/CD28 pathway. In summary, reactive oxygen species accumulation in the BM is an upstream consequence of ovariectomy that leads to bone loss by activating T cells through enhanced activity of BM dendritic cells, and these findings suggest that the CD80/CD28 pathway may represent a therapeutic target for postmenopausal bone loss.
Grassi
Francesco
F
Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University, Atlanta, GA 30322, USA.
Tell
Gianluca
G
Robbie-Ryan
Michaela
M
Gao
Yuhao
Y
Terauchi
Masakazu
M
Yang
Xiaoying
X
Romanello
Milena
M
Jones
Dean P
DP
Weitzmann
M Neale
MN
Pacifici
Roberto
R
D000069594:Abatacept; D000818:Animals; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology*; D001862:Bone Resorption / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D005434:Flow Cytometry; D018796:Immunoconjugates / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010052:Ovariectomy; D018384:Oxidative Stress; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018122:B7-1 Antigen; D018106:CD28 Antigens; D004967:Estrogens; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept