Project 464582

Osteoarthritis (OA) is a progressive, degenerative disease of the joints, with the knee most commonly affected. Patients with OA experience significant pain, stiffness and loss of quality of life. Available and approved drugs only mask pain, with joint replacement surgery as a last option. There are no approved therapies to stop OA disease progression. The knee is made of a number of tissues including cartilage, involved in cushioning the joint during motion, and the synovium, which covers the joint and produces a lubricating fluid allowing for smooth joint movement. During OA, cartilage is lost, and the synovium becomes inflamed and scarred. Research to date has mostly focused on cartilage loss; however, the synovium has recently gained attention for its contributions to OA progression. Using advanced sequencing techniques that can determine genes at the level of a cell, combined with sophisticated informatics tools, we have identified a number of different cell types within the synovium. In addition, we found that some of the cell types can be further separated into "subsets" by the individual genes they express, and by the disease stage of the patient from which tissues were obtained. In this proposal, we aim to determine the roles of specific cell types and their subsets to OA disease initiation and progression. Using synovium from patients (females and males) with early or late stages of knee OA disease from our established tissue bank and knee joints from animal model of OA, we will use a combination of advanced sequencing, molecular and mechanistic techniques to: (i) identify cells (and their subsets) found in early vs late stages of knee OA, (ii) determine the differences in gene expression of cell subsets in the synovium and (iii) evaluate the role of these cells in OA disease initiation and progression. From this study, we anticipate uncovering specific cell subsets that contribute to OA disease process, providing a novel target(s) for future therapy.