Epidemiological and in vitro data suggest an association between atherosclerosis and osteoporosis. A possible mechanism for this association emerged from studies that have shown serum lipid levels negatively correlate with bone mineral content (BMC) and bone mineral density (BMD). Furthermore, high plasma-low-density lipoprotein (LDL) concentration is a known risk factor for osteopenia in postmenopausal women. In vitro experiments have shown that lipids and lipoprotein oxidation have both an inhibitory effect on the differentiation of bone-forming osteoblasts, and an enhancing effect on the differentiation of bone-resorbing osteoclasts in culture.

Interestingly, lipids also play a key role in the immune system, where, for example, lipid oxidation products mediate an inflammatory response by T lymphocytes. Moreover, it is becoming increasingly evident that the immune system also plays a significant role in bone regulation, particularly via activation-induced T lymphocyte production of receptor activator of NFκB ligand (RANKL). Well-documented as a mediator of T lymphocyte/dendritic cell interactions, RANKL also stimulates the maturation and activation osteoclasts. The work described in this dissertation focuses on the effects of oxidized lipids on the production of osteoclastogenic factors by T lympocytes in vitro, and the role of T lymphocytes in diet-induced bone loss in vivo.

We first examined the effects of oxidized lipids on RANKL production by T lymphocytes. Our data indicate that acute, short-term exposure of both unstimulated and activated human T lymphocytes to minimally oxidized low density lipoprotein (MM-LDL) promotes the expression of the lectin-like LDL receptor-1 (LOX-1), a receptor specific for oxidized lipids that had previously only been documented on endothelial cells, and significantly enhances RANKL production. We next examined the effects of chronic exposure to oxidized lipids on the biology of T lymphocytes. Our preliminary data show that chronic exposure to oxidized lipids inhibited T lymphocyte proliferation and accelerated the process of replicative senescence. In addition, oxidized lipids also enhanced RANKL and IFN-γ expression, and decreased OPG production. Finally, utilizing a high-fat diet atherogenic mouse model, we evaluated the contributory role of T lymphocytes to the bone loss observed in these mice. We found that splenic T lymphocytes isolated from the high-fat group had increased expression of transcripts for LOX-1, as well as for inflammatory and osteoclastogenic cytokines, including RANKL, IL-6, TNF-α, IL-1β and IFN-γ. Collectively, the studies described herein help elucidate a possible T lymphocyte-mediated contribution to the frequently observed clinical associations between cardiovascular disease and decreased bone mass.