Targeting Cellular Mechanosensing to Alleviate Joint Stiffness in Synovial Fibrosis

与骨关节炎和滑膜纤维化相关的关节疼痛和僵硬影响着大量的活跃人群 现役军人和退伍军人的发病率高于普通民众。尽管疾病盛行， 目前还没有具有显著改变疾病能力的非手术治疗方法，因此 终末期疾病在全膝关节置换术中达到顶峰。这项建议的研究目标是开发和 测试一种非手术干预措施，以减轻关节僵硬并保护关节的软骨表面。在滑膜中 纤维化，成纤维细胞向肌成纤维细胞分化通过细胞外基质导致关节僵硬 沉积和重组。此外，滑膜成纤维细胞的这种纤维性分化导致减少 润滑剂分泌到滑液中。机械传感，或细胞对机械的解释 微环境，是纤维化发展的一个关键方面，并可能成为治疗的靶点。在这 建议，我们将以滑膜细胞的收缩为目标，即细胞对其局部环境的拉力，以引入 一种既能缓解纤维细胞分化又能恢复关节润滑剂表达的疗法。我们将测试 我们的假设是，调节细胞机械感觉可以抑制滑膜纤维化，目的有两个。在第一个 目的：我们将评估微球递送的小分子法舒地尔如何抑制滑膜的纤维化行为。 成纤维细胞采集自全膝关节置换术患者。在第二个目标中，我们将使用 关节损伤制动致兔滑膜纤维化模型的建立。这一目标将测试两种治疗方法 通过介绍创伤后疾病潜伏期和创伤后疾病潜伏期的治疗 再动员时出现纤维化。总体而言，这项工作有可能引入一种新的治疗方法 退伍军人关节疼痛和僵硬的选择，可以推迟手术干预的需要。

Joint pain and stiffness associated with osteoarthritis and synovial fibrosis affects a large population of active duty military and veterans with an incidence higher than the general public. Despite the prevalence of disease, there are currently no non-surgical treatments with significant disease-modifying capabilities, and consequently end stage disease culminates in total knee arthroplasty. The research goal of this proposal is to develop and test a non-surgical intervention to alleviate joint stiffness and protect the joint’s cartilage surfaces. In synovial fibrosis, fibroblast to myofibroblast differentiation leads to joint stiffening via cell-mediated extracellular matrix deposition and reorganization. Additionally, this fibrotic differentiation of synovial fibroblasts leads to reduced lubricant secretion into the synovial fluid. Mechanosensing, or a cell’s interpretation of the mechanical microenvironment, is a crucial facet of fibrosis development and may potentially pose a therapeutic target. In this proposal, we will target synovial cell contractility, or how much a cell pulls on its local environment, to introduce a therapy that can both mitigate fibrotic cell differentiation and restore lubricant expression in joints. We will test our hypothesis that modulating cellular mechanosensing can inhibit synovial fibrosis using two Aims. In the first Aim, we will assess how a microsphere-delivered small molecule, fasudil, can inhibit fibrotic behaviors of synovial fibroblasts collected from total knee arthroplasty patients. In the second Aim, we will assess this treatment using a rabbit model of synovial fibrosis induced via joint injury and immobilization. This Aim will test two treatment strategies by introducing the treatment in the incubation periods of disease following injury and also after the onset of fibrosis at the time of remobilization. Overall, this work has the potential to introduce a new treatment option for veterans experiencing joint pain and stiffness that can delay the need for surgical intervention.