Snail Is a Critical Mediator of Invadosome Formation and Joint Degradation in Arthritis

Progressive cartilage destruction, mediated by invasive fibroblast-like synoviocytes, is a central feature in the pathogenesis of rheumatoid arthritis (RA). Members of the Snail family of transcription factors are required for cell migration and invasion, but their role in joint destruction remains unknown. Herein, we demonstrate that Snail is essential for the formation of extracellular matrix degrading invadosomal structures by synovial cells from collagen-induced arthritis (CIA) rats and RA patients. Mechanistically, Snail induces extracellular matrix degradation in synovial cells by repressing PTEN, resulting in increased phosphorylation of platelet-derived growth factor receptor and activation of the phosphatidylinositol 3-kinase/AKT pathway. Of significance, Snail is overexpressed in synovial cells and tissues of CIA rats and RA patients, whereas knockdown of Snail in CIA joints prevents cartilage invasion and joint damage. Furthermore, Snail expression is associated with an epithelial-mesenchymal transition gene signature characteristic of transglutaminase 2/transforming growth factor-beta activation. Transforming growth factor-beta and transglutaminase 2 stimulate Snail-dependent invadosome formation in rat and human synoviocytes. Our results identify the Snail-PTEN platelet-derived growth factor receptor/phosphatidylinositol 3-kinase axis as a novel regulator of the prodestructive invadosome-forming phenotype of synovial cells. New therapies for RA target inflammation, and are only partly effective in preventing joint damage. Blocking Snail and/or its associated gene expression program may provide an additional tool to improve the efficacy of treatments to prevent joint destruction.