The cessation of estrogen (E) production induced by natural menopause or ovariectomy (ovx) is followed by a period of rapid bone loss which is instrumental for the development of postmenopausal osteoporosis. Ovx induced bone loss is caused by a stimulation of osteoclast (OC) number and activity insufficiently compensated by an increase in bone formation. The mechanisms by which ovx alters bone resorption and formation are not completely understood. We have reported that enhanced production of TNF by an expanded bone marrow (BM) pool of activated T cells plays a key role in ovx induced bone loss. Our data show that BM T cells are primarily localized near osteoclasts (OC) and that ovx increases the number of T cells in close proximity to remodeling endosteal surfaces. We thus hypothesize that ovx causes bone loss by inducing T cell production of TNF in niches near endosteal bone surfaces. Therefore, in Aim 1 we will investigate weather the ovx induced increased colocalization of OC and T cells is a cause or a consequence of stimulated bone resorption. This will be achieved by transferring T cells from E replete and ovx mice into E replete and ovx mice and in WT mice pretreated with PTH or Alendronate to increase or decrease bone resorption, respectively. We will also investigate the interactions between T cells and OCs in vitro. Preliminary data demonstrate that T cells stimulate proliferation and survival of stromal cells (SCs), increase the capacity of SCs to support OC formation, increase SC production of osteoclastogenic cytokines, and promote SC differentiation into OBs through stimulation of CD40 signaling in SCs by T cell expressed CD40L. Thus, in Aim 2 we will determine the contribution of the CD40L/CD40 mediated T cell-SC crosstalk to the increase in SC osteoclastogenic activity, bone resorption and bone loss.
In Aim 3 we will investigate the role of the CD40L/CD40 mediated T cell-SC crosstalk in the compensatory stimulation of osteoblastogenesis and bone formation induced by ovx. To accomplish these goals we will utilize two experimental models, WT ovx mice treated with the anti CD40L antibody MR-1, and WT ovx mice first depleted of T cells by anti CD4/8 antibodies, and then reconstituted with T cells from CD40L null mice. This project is relevant for public health as may lead to a better characterization of the mechanism of action of estrogen in bone, demonstrate a link between T lymphocytes and bone cells, and identify novel therapeutic targets for osteoporosis. ? ? ?
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