Estrogen prevents bone loss through transforming growth factor β signaling in T cells

Y Gao, WP Qian, K Dark, G Toraldo… - Proceedings of the …, 2004 - National Acad Sciences
Y Gao, WP Qian, K Dark, G Toraldo, ASP Lin, RE Guldberg, RA Flavell, MN Weitzmann…
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-
producing T cells through an IFN-γ-dependent pathway that results in increased levels of the
osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-γ production is
instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism
is unknown. We now show that mice with T cell-specific blockade of type β transforming
growth factor (TGFβ) signaling are completely insensitive to the bone-sparing effect of E …
Estrogen (E) deficiency leads to an expansion of the pool of tumor necrosis factor (TNF)-producing T cells through an IFN-γ-dependent pathway that results in increased levels of the osteoclastogenic cytokine TNF in the bone marrow. Disregulated IFN-γ production is instrumental for the bone loss induced by ovariectomy (ovx), but the responsible mechanism is unknown. We now show that mice with T cell-specific blockade of type β transforming growth factor (TGFβ) signaling are completely insensitive to the bone-sparing effect of E. This phenotype results from a failure of E to repress IFN-γ production, which, in turn, leads to increased T cell activation and T cell TNF production. Furthermore, ovx blunts TGFβ levels in the bone marrow, and overexpression of TGFβ in vivo prevents ovx-induced bone loss. These findings demonstrate that E prevents bone loss through a TGFβ-dependent mechanism, and that TGFβ signaling in T cells preserves bone homeostasis by blunting T cell activation. Thus, stimulation of TGFβ production in the bone marrow is a critical “upstream” mechanism by which E prevents bone loss, and enhancement of TGFβ levels in vivo may constitute a previously undescribed therapeutic approach for preventing bone loss.
National Acad Sciences