Pathogenesis of Enthesopathy

项目摘要 超过一半的运动损伤涉及肌腱和肌腱，即肌腱或韧带与骨骼的附着点。 一种常见的末端畸形，占肌腱疾病的四分之一，导致长期的 干扰负荷转移，是疼痛和残疾的主要原因。黄褐斑的确切发病机制 终末病在很大程度上是未知的，也没有有效的疾病修正治疗方法来治疗这种疾病。这个 拟议的项目旨在阐明末端病的致病机制并开发潜力 预防/治疗这种疾病的治疗方案。我们的初步研究表明，转化生长因子β在骨骼中的激活 末端组织对末端损伤后异常机械负荷的反应是早期的改变。 终末病的进展。在末端病小鼠模型中，我们观察到转化生长因子β活性在 骨-纤维软骨结合较早，套叠后进行性降解较晚。此外， 在骨骼中有活性转化生长因子β过度表达的转基因小鼠概括了终末病变的表型，而 用转化生长因子β中和抗体治疗的末端病小鼠减慢了末端退化。至 实现骨靶向递送和在骨组织中的缓释，我们产生了一种新的药物，它结合了 转化生长因子β抑制剂通过代谢性可水解性连接物合成阿伦磷酸钠。该结合物有效地抑制了 转化生长因子β转基因小鼠骨组织中转化生长因子β活性的研究这项研究的中心假设是这种反常 转化生长因子β在骨-纤维软骨交界处的激活通过招募干细胞/祖细胞来启动终末病 纤维软骨区血管侵犯和骨化。为了检验这一假设，我们将检验 使用不同的小鼠模型研究活性转化生长因子β升高在终末病进展中的作用(目标1)。我们还将 用两种基因确定转化生长因子β招募的干/祖细胞在终末病进展中的作用 血统追踪小鼠和可诱导的组织特异性转化生长因子β受体消融小鼠(目标2)。最后，我们会 检查转化生长因子β抑制剂-阿仑膦酸盐结合物在终端病中的治疗潜力(目标3)。结果 将为该结合物作为终末病治疗方法的临床应用提供证据。

Project Summary Over half of sports injuries involve tendons and entheses, the insertion sites of tendons or ligaments to bones. A common enthesis disorder enthesophathy, representing one fourth of tendon diseases, results in a long-term disturbance of the load transfer and is a major cause of pain and disability. The exact pathogenesis of enthesopathy is largely unknown, and there is no effective disease modifying treatment for this disorder. The proposed project aims to elucidate the pathogenic mechanisms of enthesopathy and develop potential therapeutic solutions to prevent/treat this disease. Our preliminary studies suggest that TGFβ activation in bone tissue of the enthesis, in response to aberrant mechanical loading after enthesis injury, is an early change in the progression of enthesopathy. In a mouse model of enthesopathy, we observed upregulated TGFβ activity at the bone-fibrocartilage junction earlier, and entheses progressive degradation later after entheses injury. Moreover, transgenic mice with active TGFβ overexpression in bone recapitulated the enthesopathy phenotype, whereas the enthesopathy mice treated with a TGFβ neutralizing antibody had decelerated enthesis degeneration. To achieve bone-targeting delivery and slow release in bone tissue, we generated a new drug that conjugates a TGFβ inhibitor to Alendronate through a metabolically hydrolysable linker. The conjugate effectively inhibited TGFβ activity in bone in the active TGFβ transgenic mice. The central hypothesis of this study is that aberrant TGFβ activation at the bone-fibrocartilage junction initiates enthesopathy by recruiting stem/progenitor cells for blood vessel invasion and ossification in the fibrocartilage zone. To test this hypothesis, we will examine the role of elevated active TGFβ in the progression of enthesopathy using different mouse models (Aim 1). We will also determine the role of TGFβ-recruited stem/progenitor cells in the progression of enthesopathy using two genetic lineage tracing mice and an inducible tissue-specific TGFβ receptor-ablation mice (Aim 2). Finally, we will examine the therapeutic potential of the TGFβ inhibitor–Alendronate conjugate in enthesopathy (Aim 3). Results will provide evidence for clinical application of this conjugate as a therapy for enthesopathy.