Targeting Cellular Mechanosensing to Alleviate Joint Stiffness in Synovial Fibrosis

靶向细胞机械传感减轻滑膜纤维化引起的关节僵硬

• 批准号: 10657546
• 负责人: Carla Rose Scanzello
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657546
• 关键词: Address; Affect; Area; Arthralgia; Attenuated; Behavior; Biochemical; Biophysics; Cartilage; Cell Differentiation process; Cell Nucleus; Cells; Contracture; Cues; Cytoskeleton; Data; Degenerative polyarthritis; Deposition; Development; Disease; Drug Delivery Systems; Drug Targeting; Elements; Environment; Epigenetic Process; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; General Population; Goals; Homeostasis; Human; Immobilization; In Vitro; Incidence; Incubated; Injury; Intervention; Joints; Kidney; Knowledge; Liver; Lubricants; Lung; Mechanics; Mediating; Mediator; Memory; Microspheres; Military Personnel; Modeling; Movement; Myofibroblast; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Proteins; Regulation; Research; Role; Science; Signal Transduction; Source; Surface; Synovial Cell; Synovial Fluid; Synovial Membrane; Testing; Time; Tissues; Transcriptional Coactivator with PDZ-Binding Motif; Transforming Growth Factor beta; United States; Veterans; Work; active duty; articular cartilage; body system; cell behavior; cellular targeting; chondroprotection; cytokine; disability; druggable target; end stage disease; experience; fasudil; functional restoration; innovation; joint destruction; joint function; joint injury; joint stiffness; knee replacement arthroplasty; lubricin; mechanotransduction; microsphere delivery; military veteran; patient population; small molecule; small molecule therapeutics; therapeutic target; transcription factor; treatment strategy

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.

与骨关节炎和滑膜纤维化相关的关节疼痛和僵硬影响大量活跃人群 尽管疾病流行，但执勤军人和退伍军人的发病率仍高于普通公众。 目前还没有具有显着改善疾病能力的非手术治疗方法，因此 终末期疾病最终导致全膝关节置换术。本提案的研究目标是开发和实施全膝关节置换术。 测试非手术干预措施以减轻关节僵硬并保护滑液中的关节软骨表面。 纤维化，成纤维细胞向肌成纤维细胞的分化通过细胞介导的细胞外基质导致关节僵硬 此外，滑膜成纤维细胞的纤维化分化导致减少。 润滑剂分泌到滑液中的机械传感，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，并可能成为这一领域的治疗靶点。 提案中，我们将针对滑膜细胞收缩力，或者细胞对其局部环境的拉力，来介绍 我们将测试一种既能减轻纤维化细胞分化又能恢复关节润滑剂表达的疗法。 我们的假设是，调节细胞机械传感可以通过两个目标抑制滑膜纤维化。 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纤维化行为 从全膝关节置换术患者身上收集的成纤维细胞在第二个目标中，我们将使用这种治疗方法进行评估。 通过关节损伤和固定诱导的兔滑膜纤维化模型该目的将测试两种治疗方法。 策略是在受伤后疾病潜伏期以及受伤后引入治疗 总的来说，这项工作有可能引入一种新的治疗方法。 为经历关节疼痛和僵硬的退伍军人提供的选择，这些疼痛和僵硬可以延迟手术干预的需要。