PROJECT SUMMARY Fibroblast-like synoviocytes populate the synovial surfaces of the joints. They have critical roles in the maintenance of joint health and in the pathology of arthritic diseases. Our data suggest that the SOXC group of transcription factors are key players in implementing the pathological properties of fibroblast- like synoviocytes. SOXC proteins were previously shown to be critical for the survival of mesenchymal and neural progenitor cells that give rise in the embryo to multiple body structures, including the skeleton, heart, and nervous system. They were also shown to promote the proliferation, migration and invasive properties of many types of cancer cells. Our preliminary results suggest that SoxC genes contribute to the aggressive cancer cell-like behavior of fibroblast-like synoviocytes in arthritic diseases. The overarching hypothesis of this project is that the biological activities of SOXC proteins in the fibroblast-like synoviocytes significantly contribute to the inflammation-mediated degeneration of articular cartilage and bones in arthritis and related joint diseases. Our primary goal is to determine whether the SoxC genes are involved in regulation of gene expression and cellular behavior of fibroblast-like synoviocytes that are under the stress of inflammation. We will then investigate the upstream molecular mechanisms that regulate the activities of SOXC proteins in fibroblast-like synoviocytes. Next, we will test whether blocking SOXC protein functions in fibroblast-like synoviocytes reduces joint degeneration in arthritic diseases. We anticipate that our new findings will lead to a more profound understanding of the molecular regulation of fibroblast-like synoviocytes in joint pathologies. These new findings will likely impact the design of new, successful strategies for synovial fibroblast- based joint repair and regeneration therapies for patients suffering from osteoarthritis and rheumatoid arthritis.