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

10/28/04

Scientists have uncovered a significant new link in the chain of immune system events through which estrogen prevents bone loss and that contribute to bone loss when estrogen is deficient. Through research in mice, the scientists discovered that an immune signaling molecule called type b transforming growth factor (TGFb) is responsible for a cascade of events that leads estrogen to prevent bone loss. When TGFb signaling in T cells is blocked, the bone-sparing effects of estrogen are lost. The findings could lead to new therapeutic approaches for preventing bone loss. Results of the research were published online in the Proceedings of the National Academy of Sciences the week of October 25.

The study's senior author was Roberto Pacifici, MD, Herndon professor of medicine and director of the Division of Endocrinology at Emory University School of Medicine. Lead author was Emory research associate Yuhao Gao, PhD.

Previous research has shown that bone loss due to estrogen deficiency is caused by the overexpansion of immune T cells. T cells are known to produce a protein called tumor necrosis factor (TNF), which increases the formation of osteoclasts in rodents and humans. Osteoclasts are cells that help cause the absorption and removal of bone.

In research published in PNAS in August 2003, Dr. Pacifici and his colleagues demonstrated that estrogen deficiency leads to the expression of the immune regulatory protein interferon gamma (IFN-g), which in turn stimulates a protein called class II transactivator (CIITA). They found that increased expression of CIITA leads to expanded antigen presentation by macrophages (immune cells that alert T cells to the presence of invading organisms) and in turn to enhanced T cell activation in the bone marrow and extended T-cell lifespan.

The investigators' new research traces another step in the "upstream" pathway leading to estrogen's effect on bone. In order to model postmenopausal estrogen 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.

Source: Eurekalert & others

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