Ovariectomy Induced T Cell Inflammatory Cytokines/Bone Loss in Young & Old Mice

描述（由申请人提供）：绝经后骨质疏松症（PMO）是由更年期卵巢功能停止引起的老年妇女的常见病。对卵巢切除（ovx）小鼠（一种已建立的PMO模型）的研究表明，激活T细胞池的扩大增加了TNF的产生，在ovx诱导的骨质流失机制中起关键作用。然而，目前尚不清楚ovx是否仅通过刺激BM中T细胞TNF的产生（而不是增强所有淋巴器官中T细胞TNF的产生）而导致骨质流失。因此，在目的1中，我们将确定：a) ovx是否改变了归巢到骨的T细胞的表型和数量，b)抑制归巢到骨髓的T细胞（通过抗LFA-1a和抗整合素a4亚基治疗）是否可以防止ovx诱导的骨质流失，以及c) ovx是否会导致缺乏次级淋巴器官的小鼠骨质流失。

DESCRIPTION (provided by applicant): Postmenopausal osteoporosis (PMO) is a frequent disease of aging women stemming from the cessation of ovarian function at menopause. Studies in ovariectomized (ovx) mice, an established model of PMO, have disclosed that enhanced production of TNF by an expanded pool of activated T cells plays a key role in the mechanism of ovx induced bone loss. However, it is presently unknown if ovx causes bone loss by stimulating T cell TNF production exclusively in the BM (as opposed to enhancing T cell TNF production in all lymphoid organs). Thus, in aim 1 we will determine: a) if ovx alters the phenotype and the number of T cells which home to bone, b) whether the suppression of T cell homing to the BM (via treatment with anti- LFA-1a and anti-integrin a4 subunit) prevents ovx induced bone loss, and c) if ovx causes bone loss in mice lacking the secondary lymphoid organs. Our data show that estrogen (E) deficiency causes a rebound in thymic T cell output that contributes to the T cell pool expansion and the bone loss induced by ovx in young adult mice. The resurgence of thymic activity induced by E deficiency is attenuated in older mice and we hypothesize that such diminished rebound in thymic T cell export mitigates the capacity of ovx to induce bone loss in older mice. Thus, in Aim 2 we will utilize thymectomized/ovx mice to determine the contribution of thymic T cell output to ovx-induced bone loss in aging mice. Both aging and castration decrease immune tolerance. Accordingly, our data show that ovx increases MHC expression and antigen presentation, suggesting that ovx induces higher MHC mediated presentation of self peptides. We hypothesize that this enhanced T cell response to self-peptide/MHC is essential for ovx-induced bone loss. We will test this hypothesis by: a) determining the contribution of MHC expression to ovx induced bone loss, b) testing if the response of T cells to self-peptide/MHC changes after ovx, c) determining if there is a change in the T cell repertoire after ovx due to an oligoclonal expansion of self-reactive T cells, and d) investigating if ovx breaks tolerance to a defined antigen. The project fulfills the objective of this RFA, that is to solicits applications designed to determine either the causes of the changes in inflammatory mediators induced by aging (including studies on the source of the altered cytokine production), or the consequences of such changes in conditions and diseases characteristic of senescence. This project is also relevant for public health as may lead to a better characterization of the mechanism of action of E in bone at different ages, demonstrate a link between the immune system and bone, and identify novel therapeutic targets for osteoporosis.