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Scientists identify key mechanism in estrogen's role in preventing bone loss

n deficiency, they removed the ovaries from mice, then studied the effects of estrogen on immune cells and on bone marrow in culture. They measured the level of TGFb in bone marrow macrophages (BMM) and discovered that the level of TGFb in the BMM of mice lacking ovaries was about half that of mice with ovaries. When they treated the mice with estrogen, levels of TGFb in the bone marrow increased about three-fold in mice with ovaries and about eight-fold in mice without ovaries.

In order to test the effects of TGFb on bone-marrow density, the scientists used a transgenic mouse model in which TBFb signaling in T cells is blocked. Although these mice had the same level of bone density as control mice at birth, they gradually lost bone density over time, suggesting that when T cells are insensitive to TGFb signaling, they stimulate the loss of bone.

"Our research shows that mice with T-cell specific blockade of TGFb signaling are completely insensitive to the bone-sparing effects of estrogen," says Dr. Pacifici. "This results from a failure of estrogen to repress the production of IFN-g, which in turn leads to increased T cell activation and TNF production. We also found in mice that a lack of estrogen production blunts the levels of TGFb in the bone marrow and that overexpression of TGFb in vivo prevents bone loss caused by removal of the ovaries. This critical mechanism in the estrogen-bone loss pathway, should it be confirmed in humans, could lead us to inhibition of T-cell activation or simulation of TGFB signaling as new therapeutic approaches for preventing bone loss."

Other authors included Wei-Ping Qian, Kimberly Dark, Gianluca Toraldo, and M. Neale Weitzmann from Emory School of Medicine; Angela S.P. Lin and Robert E. Guldberg from the Georgia Institute of Technology; and Richard A. Flavell from Yale University School of Medicine. The research was supported by grants from the National Institutes of Health.


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Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University Health Sciences Center
28-Oct-2004


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