MICA: Synovial fibroblast pain pathotypes: A roadmap to understanding and targeting the complexity of patient-reported joint pain in osteoarthritis

点击翻译按钮获取中文摘要

BackgroundOsteoarthritis (OA) is highly painful joint disorder and a leading cause of disability. Current pain-relief medications are only minimally effective and are associated with side effects over the long term. One of the challenges in developing a more effective pain-relieving OA drug is understanding of the complex underlying mechanisms of OA joint pain. Importantly, inflammation of the synovial joint lining tissue (termed synovitis) is associated with increased pain severity in knee OA patients, and we have shown that the cells which reside within the synovial tissue (known as synovial fibroblasts) regulate the inflammatory environment of the joint by secreting factors that promote inflammation. To investigate the cellular and molecular basis for the relationship between synovitis and OA joint pain, we involved knee OA patients in a study where we mapped the anatomical location of synovitis by MRI and of patient-reported pain by asking patients to mark on a diagram of the knee joint, where they felt most pain and where they felt least pain. We then collected synovial tissue samples from both sites of patient-reported pain and sites of no pain. Significantly, the degree of synovitis was closely associated with the pattern of patient-reported pain, and furthermore that synovial joint lining tissue at the site of patient-reported pain contained distinct populations of synovial fibroblast cells, that promoted inflammation and secreted factors that promoted the growth and survival of nerve cells. Since the synovial joint lining tissue contains numerous nerve endings we believe that the activity of these pain-associated synovial fibroblast cells is a major contributor to OA joint pain. We hypothesise that therapeutics that reduce the activity of these synovial fibroblasts will alleviate joint pain in patients with knee OA. AimThe overarching aim of the proposal is to map the relationship between the presence and location of pain-associated synovial fibroblasts with patient-reported pain and synovitis in a larger patient cohort, and then to determine whether modulating the activity of these cells using a novel gene silencing therapeutic reduces sensory nerve function and alleviates pain.Experimental PlanTo address these aims we will expand our current knee OA patient pain study to 82 patients (41 with early OA disease and 41 with end-stage disease). The anatomical location and degree of synovitis in the joint will be measured by MRI and patient-reported pain severity and pain location captured by questionnaires and completion of the anatomical pain map. Blood and joint fluid will be collected, and synovial joint lining tissue collected from sites of patient-reported pain and no pain. The expression and spatial location of pain-associated synovial fibroblast gene signatures will be measured, and their relationship mapped to synovitis, blood and joint fluid biomarkers of inflammation and patient-reported pain determined. Gene expression data of synovial tissue and fibroblast cells from sites of pain and no-pain will be analysed using computational modelling to build networks of the gene pathways that connect the activity of synovial fibroblasts with nerve cells in order to identify new candidate pain gene mediators. We will then design gene silencing therapeutics to target candidate pain genes, and examine the effect of these therapeutics on modulating nerve cell activity and in a mouse model of OA, determine the uptake of the therapeutic to the joint tissues and its effect on reducing joint inflammation and pain. These experiments will provide the first evidence of whether targeting specific pain-associated synovial fibroblast cells in the joint can alleviate joint inflammation and pain. In summary, this project will advance our understanding of the role of synovial fibroblasts in inflammatory pain and lay the groundwork for the clinical development of a new pain-relieving therapeutic for OA patients.