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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M1))
Program Officer
Williams, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Alvarez, Jessica A; Ziegler, Thomas R; Millson, Erin C et al. (2016) Body composition and lung function in cystic fibrosis and their association with adiposity and normal-weight obesity. Nutrition 32:447-52
Li, Jau-Yi; Tawfeek, Hesham; Bedi, Brahmchetna et al. (2011) Ovariectomy disregulates osteoblast and osteoclast formation through the T-cell receptor CD40 ligand. Proc Natl Acad Sci U S A 108:768-73
Pacifici, Roberto (2010) The immune system and bone. Arch Biochem Biophys 503:41-53
Pacifici, Roberto (2010) T cells: critical bone regulators in health and disease. Bone 47:461-71
Terauchi, Masakazu; Li, Jau-Yi; Bedi, Brahmchetna et al. (2009) T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab 10:229-40
Gao, Yuhao; Wu, Xiaojun; Terauchi, Masakazu et al. (2008) T cells potentiate PTH-induced cortical bone loss through CD40L signaling. Cell Metab 8:132-45
Pacifici, Roberto (2008) Estrogen deficiency, T cells and bone loss. Cell Immunol 252:68-80
Grassi, Francesco; Tell, Gianluca; Robbie-Ryan, Michaela et al. (2007) Oxidative stress causes bone loss in estrogen-deficient mice through enhanced bone marrow dendritic cell activation. Proc Natl Acad Sci U S A 104:15087-92
Gao, Yuhao; Grassi, Francesco; Ryan, Michaela Robbie et al. (2007) IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest 117:122-32