Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast‐Like Synoviocytes in Arthritic Disease

OBJECTIVE: Fibroblast‐like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer‐like and aggressively contribute to joint degeneration in inflammatory arthritis. The aim of this study was to determine whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions. METHODS: We inactivated the SOXC genes in FLS from adult mice and studied the effect on joint homeostasis and tumor necrosis factor (TNF)–induced arthritis. We used primary cells and synovial biopsy specimens from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins. RESULTS: Postnatal inactivation of the SOXC genes had no major effect on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNF. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNF on FLS by increasing their survival and migration. SOXC RNA levels were not changed by TNF and other proinflammatory cytokines, but SOXC proteins were strongly stabilized and able to potentiate the TNF‐induced up‐regulation of genes involved in FLS transformation. Substantiating the relevance of these findings in human disease, SOXC protein levels, but not RNA levels, were significantly higher in inflamed synovium than in noninflamed synovium from arthritis patients. CONCLUSION: SOXC proteins are targets and pivotal mediators of proinflammatory cytokines during FLS transformation in arthritic diseases. Targeting of these proteins could thus improve current strategies to treat arthritic diseases and possibly other inflammatory diseases.