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.