Bone remodeling involves a delicate balance between osteoblasts, bone matrix-forming cells, and osteoclasts, bone-matrix resorbing cells. Memory CD8+ T cells with hallmarks of replicative senescence (loss of CD28 expression, shortened telomeres, non-proliferative) predominate in many elderly persons. Although it was been established that the immune system is closely involved with both bone formation and resorption, the main thrust of the current """"""""osteoimmunology"""""""" research is in the area of arthritis. Thus, a critical issue that has not been addressed in previous research is how these immune cells affect bone remodeling. My proposed research will investigate the interactions between T cells and bone at the cellular level to identify the intrinsic and extrinsic factors that contribute to altered osteoblast and osteoclast activity during aging.
The specific aims of the research are: I. To investigate the role of chronically activated CD8 T cells on osteoclasts; Ii. To examine the effect of CD8 replicative senescence on osteoblasts; and II!. To test the hypothesis that genetic manipulations that prevent replicative senescence in CD8 T cells will reverse the deleterious effects on bone homeostasis.
|Graham, Lucia S; Tintut, Yin; Parhami, Farhad et al. (2010) Bone density and hyperlipidemia: the T-lymphocyte connection. J Bone Miner Res 25:2460-9|
|Tseng, Wendy; Graham, Lucia S; Geng, Yifan et al. (2010) PKA-induced receptor activator of NF-kappaB ligand (RANKL) expression in vascular cells mediates osteoclastogenesis but not matrix calcification. J Biol Chem 285:29925-31|
|Graham, Lucia S; Parhami, Farhad; Tintut, Yin et al. (2009) Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss. Clin Immunol 133:265-75|