Parathyroid hormone (PTH) is a promising anabolic agent in bone yet the mechanisms of its action are still unclear. Progress in this area has been hindered by the lack of effective model systems to test hypotheses. In vitro model systems of PTH actions on osteoblasts have provided valuable information regarding signaling mechanisms and downstream mediators of PTH action; however, PTH is generally not anabolic in vitro and hence there is a critical need to effectively utilize in vivo and in vitro strategies to understand PTH action. A combination of in vivo and in vitro model systems have provided preliminary data that support the overall hypothesis that anabolic actions of PTH are dependent on differentiation stage dependent regulation of apoptosis and osteoblast-mediated expression of AP-1 transcription family members. The dependence of PTH on c-fos for its anabolic actions are apparent from the lack of an anabolic effect of PTH in mice with c-fos gene ablation. The studies proposed will determine the role of the osteoblast and bone formation in the anabolic actions of PTH. Additionally, results of differential PTH effects on apoptosis during osteoblast differentiation in vitro suggest that PTH has both anti- and pro-apoptotic effects in bone. These effects on apoptosis likely contribute to the overall impact of PTH to evoke increased bone formation. This will be confirmed using in vivo models and the downstream mediators for these actions identified. The first Specific Aim will determine if anabolic actions of PTH are dependent on bone formation activity by comparing PTH effects in models with high and low bone formation rates.
Aim 2 will identify osteoblast differentiation dependence for PTH-mediated apoptotic events in bone. Finally, Aim 3 will elucidate the key downstream mediators of PTH effects on apoptosis in bone with a focus on members of the AP-1 family of transcriptional mediators. These studies will optimize the use of novel model systems such as an ectopic ossicle model, gene-targeted and strain-specific murine models to determine mechanisms of PTH action in bone. The outcome will be a reconciliation of existing knowledge and validation of new paradigms of PTH action in bone. These studies are timely since PTH is under consideration for use in humans and hence there is a critical need for an understanding of its mechanisms of action in order to optimize its therapeutic regime and minimize adverse effects. ? ?
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