Etiology and Treatment of Parathyroid Bone Disease

描述(申请人提供)：拟议研究的目标是了解调节慢性甲状旁腺功能亢进(HPT)对骨骼的有害影响的细胞和分子机制，以便确定干预的治疗靶点。目前的提案重点是一种严重的甲状旁腺骨病，纤维性骨炎。这种疾病的组织学表现通常包括大量的骨转换增加，以及骨髓纤维化。骨髓纤维化优先分布于骨表面附近，提示慢性HPT导致局部衍生生长因子过度产生，这些生长因子对成纤维细胞具有趋化作用，刺激成纤维细胞增殖，诱导病理性骨吸收。这项建议将重点放在血小板衍生生长因子-A(PDGF-A)作为致病因子的作用上，因为初步研究表明，这种生长因子在持续性而不是搏动性的PTH中过度表达，并对成纤维细胞产生影响，可能导致纤维性骨炎。基于大量的初步证据，推测PDGF-A在HPT过程中的过度表达在严重甲状旁腺骨病的病因中起重要作用。拟议的研究将使用高度逼真地复制人类疾病的大鼠模型来验证这一假设，方法是实现以下4个特定目标：(1)确定PDGF信号转导抑制剂曲匹地尔在预防甲状旁腺骨病中的剂量-反应效应；(2)确定PDGF-A信号对于成纤维细胞的趋化反应、增殖反应或两者都是必不可少的；(3)确定曲匹地尔是否有效治疗已建立的甲状旁腺骨病纤维性骨炎；以及(4)确定曲匹地尔在预防甲状旁腺骨病中的长期有效性。如果中心假说是正确的，那么阻断PDGF-A信号将是预防和治疗PTH骨病的一种新的治疗方法。由于PDGF拮抗剂如曲匹地尔可供人类使用，积极的结果可能很快扩展到临床实践。

DESCRIPTION (provided by applicant): 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.