ROS/TGF-β signal mediated accumulation of SOX4 in OA-FLS promotes cell senescence

Osteoarthritis (OA) is an age-related disease, which is mainly treated with oral, topical, and/or intra-articular options to relieve symptoms and lack of specific treatment measures. Fibroblasts (FLS) are crucial cells in joint inflammation and destruction. Cellular senescence plays an important role during OA pathogenesis and senescent cells exhibit cell-cycle arrest and senescence-associated secretory phenotype (SASP). SRY-related HMG-box 4 (SOX4) is a contributing factor during many developmental processes and is elevated in inflamed synovium than in noninflamed synovium from arthritis patients. This study was designed to investigate whether SOX4 participate in the pathogenesis of OA by affecting FLS senescence and explore the internal mechanism. Firstly, we found that FLS cells exhibited more cellular senescence in OA compared with control group. We also verified the role of reactive oxygen species (ROS)/TGF-β signal in the induction of OA-FLS senescence. During the exploration of SOX4 in cell senescence, the results indicated that SOX4 activation promotes cell senescence and SASP of OA-FLS. Apart from that, we also confirmed that SOX4, regulated by ROS/TGF-β signal, was critical transcription factor associated with OA-FLS senescence. Therefore, SOX4 is likely to be a novel therapeutic target and early diagnostic marker during OA pathogenesis.