Targeting Cellular Mechanosensing to Alleviate Joint Stiffness in Synovial Fibrosis

点击翻译按钮获取中文摘要

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.