Methyltransferase‐Like 3‐Mediated m6A Modification of Heat Shock Protein Family A Member 4‐Like Facilitates Interleukin‐1β‐Induced Chondrocyte Injury to Promote Osteoarthritis Progression

Heat shock protein family A member 4‐like (HSPA4L) has been shown to be overexpressed in osteoarthritis (OA) patients, but its role in OA process still unknown. Chondrocytes were stimulated with interleukin‐1β (IL‐1β) to mimic OA cell model in vitro, and rat was injected with monosodium iodoacetate (MIA) to construct OA rat model in vivo. The expression of HSPA4L, methyltransferase‐like 3 (METTL3) and extracellular matrix (ECM)‐related markers was examined by qRT‐PCR or western blot. Cell proliferation and apoptosis were determined by CCK8 assay, EdU assay, TUNEL staining and flow cytometry. The levels of TNF‐α and ROS were determined to assess cell inflammation and oxidative stress. The interaction between HSPA4L and METTL3 was confirmed by MeRIP assay and dual‐luciferase reporter assay. Saffron‐O and fast green staining was performed to evaluate cartilage degeneration in rats. HSPA4L expression was higher in OA patients and IL‐1β‐induced chondrocytes. Silencing of HSPA4L enhanced proliferation, while suppressed IL‐1β‐induced chondrocyte apoptosis, ECM degradation, inflammation and oxidative stress. METTL3 was upregulated in OA patients and IL‐1β‐induced chondrocytes, and it could increase HSPA4L expression by m6A modification. METTL3 knockdown inhibited IL‐1β‐induced chondrocyte injury, as well as alleviated cartilage degeneration in OA rat models, while these effects were reversed by HSPA4L overexpression. METTL3‐mediated HSPA4L accelerated OA progression through m6A modification, providing a novel insight for OA treatment.