The goal of the proposed research is to understand the cellular and molecular mechanisms mediating the detrimental skeletal effects of chronic hyperparathyroidism (HPT) in order to identify therapeutic targets for intervention. The current proposal focuses on a severe form of parathyroid bone disease, osteitis fibrosa. The histological presentation of this disease often includes greatly elevated bone turnover, as well as bone marrow fibrosis. The marrow fibrosis is preferentially localized adjacent to bone surfaces, suggesting that chronic HPT results in overproduction of locally-derived growth factors that are chemotactic to fibroblasts, stimulate fibroblast proliferation, and induce pathological bone resorption. This proposal will focus on the role of Platelet Derived Growth Factor-A (PDGF-A) as a causative agent because preliminary studies have shown that this growth factor is over-expressed by continuous, but not pulsatile PTH, and has effects on fibroblasts that could lead to osteitis fibrosa. Based on the extensive preliminary evidence, it is hypothesized that over-expression of PDGF-A during HPT plays an essential role in the etiology of severe parathyroid bone disease. The proposed studies will test this hypothesis using a rat model that replicates the human disease with a high degree of fidelity by accomplishing the following 4 Specific Aims: (1) determine the dose-response effects of trapidil, an inhibitor of PDGF signaling, in preventing parathyroid bone disease; (2) determine whether PDGF-A signaling is essential for the chemotactic response of fibroblasts, the proliferative response, or both; (3) determine whether trapidil is effective in curing established osteitis fibrosa parathyroid bone disease; and (4) determine the long-term effectiveness of trapidil in preventing parathyroid bone disease. If the central hypothesis is correct, then interruption of PDGF-A signaling will be effective as a novel therapy for preventing and treating PTH bone disease. Since PDGF antagonists such as trapidil are available for human use, positive results could be quickly extended to clinical practice.
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