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Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation.


ABSTRACT: 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.

SUBMITTER: Grassi F 

PROVIDER: S-EPMC1986617 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation.

Grassi Francesco F   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  

Proceedings of the National Academy of Sciences of the United States of America 20070911 38


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  ...[more]

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