Etiology and Treatment of Parathyroid Bone Disease

描述（由申请人提供）：拟议研究的目标是了解介导慢性甲状旁腺功能亢进（HPT）对骨骼有害影响的细胞和分子机制，以确定干预的治疗靶点。目前的建议集中在甲状旁腺骨病的严重形式，纤维性骨炎。这种疾病的组织学表现通常包括骨转换大大升高以及骨髓纤维化。骨髓纤维化优先位于骨表面附近，这表明慢性HPT导致局部来源的生长因子过量产生，这些生长因子对成纤维细胞具有趋化性，刺激成纤维细胞增殖，并诱导病理性骨吸收。该提案将重点关注血小板衍生生长因子-A（PDGF-A）作为致病因子的作用，因为初步研究表明，这种生长因子通过连续而非脉动的PTH过度表达，并对可能导致纤维性骨炎的成纤维细胞产生影响。基于广泛的初步证据，假设HPT期间PDGF-A的过度表达在严重甲状旁腺骨病的病因学中起重要作用。拟进行的研究将使用高度逼真地复制人类疾病的大鼠模型通过实现以下4个特定目的来检验这一假设：（1）确定曲匹地尔（一种PDGF信号传导抑制剂）在预防甲状旁腺骨病中的剂量-反应效应;（2）确定PDGF-A信号传导是否对成纤维细胞的趋化反应、增殖反应或两者都是必需的;（3）确定曲匹地尔是否有效治疗已建立的纤维性骨炎甲状旁腺骨病;和（4）确定曲匹地尔预防甲状旁腺骨病的长期有效性。如果中心假设是正确的，那么PDGF-A信号传导的中断将是一种有效的预防和治疗PTH骨病的新疗法。由于PDGF拮抗剂如曲匹地尔可用于人类使用，因此阳性结果可以迅速扩展到临床实践。

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.