The Role of T-cells in Women Undergoing Surgical Menopause

Estrogen (E) deficiency is a major cause of post-menopausal osteoporosis. The mechanisms by which E deficiency causes osteoporosis has been recently linked to regulation of two key osteoclastic cytokines: RANKL and TNFα (TNF) , , produced by the T-cell in the bone micro-environment. TNF is a cytokine that has long been associated with bone destruction during E deficiency in both animal and human models. However, the cellular sources of TNF and its exact mechanism of action are poorly understood. Previous studies in animal models has demonstrated that in marked contrast to responses in wild type (WT) mice, ovariectomy (ovx) failed to induce bone loss and did not stimulate osteoclast (OC) formation in T-cell deficient mice. This phenomenon is reversed by T cell reconstitution with WT T cells but not with T cells from TNF -/- mice2,4. These findings established T-cells and T-cell produced TNF as essential mediators of the bone-wasting effects of E deficiency in vivo. TNF further enhances OC formation by up regulating the stromal cell production of RANKL and M-CSF and by augmenting the responsiveness of OC precursors to RANKL4. The mechanisms by which E deficiency leads to enhanced levels of T-cell derived TNF involve a realignment of the adaptive immune response that ultimately leads to an expansion in the pool of TNF secreting T-cells. Dr. Pacifici's group showed that these pathways in mouse models involve the up-regulation of antigen presentation by macrophages and dendritic cells, leading to T cell activation and peripheral expansion of TNF producing T cells. They also showed that E deficiency causes a rebound in thymic T cell output that contributes to both the T cell expansion and the bone loss induced by ovx in young adult mice .

The objective of this study is to translate these critical findings in the mouse for the first time to E deficient women following ovx. If this work defines an important role for T-cells in E deficiency-induced bone loss, this could stimulate the development of novel therapies designed to block T-cell expansion or their contribution to cytokine production and thus prevent or attenuate bone loss in this common clinical setting. The hypothesis of the research plan is that T-cells derived from women, rendered E deficient after undergoing ovx, exhibit: 1) increased T-cell activation, and proliferation; 2) enhanced production of pro-osteoclastogenic cytokines RANKL and TNF; and 3) demonstrate increased T-cell output from the thymus that together cause bone loss.