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了大量的活动性关节炎患者。 现役军人和退伍军人的发病率高于普通大众。尽管疾病流行， 目前还没有具有显著改善疾病能力的非手术治疗方法， 终末期疾病在全膝关节成形术中达到顶点。本提案的研究目标是开发和 测试非手术干预，以减轻关节僵硬和保护关节的软骨表面。滑膜 纤维化，成纤维细胞向肌成纤维细胞分化通过细胞介导的细胞外基质导致关节硬化 沉积和重组。此外，滑膜成纤维细胞的这种纤维化分化导致减少的 润滑剂分泌到滑液中。机械感应，或细胞对机械感应的解释， 微环境是纤维化发展的关键方面，并且可能构成治疗靶点。在这 根据这项提议，我们将针对滑膜细胞的收缩性，或细胞对其局部环境的拉动程度， 一种既能减轻纤维化细胞分化又能恢复关节中润滑剂表达的疗法。我们将测试 我们的假设是，调节细胞机械感应可以使用两个目的抑制滑膜纤维化。上 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， 从全膝关节置换术患者收集的成纤维细胞。在第二个目标中，我们将使用 通过关节损伤和制动诱导的滑膜纤维化的兔模型。该目标将测试两种治疗方法 在受伤后的疾病潜伏期和受伤后的治疗策略， 在再动员时纤维化发作。总的来说，这项工作有可能引入一种新的治疗方法。 对于经历关节疼痛和僵硬的退伍军人来说，这是一种选择，可以推迟手术干预的需要。