Deficiency of the m⁶A reader IGF2BP2 mediates cellular senescence of chondrocytes and triggers cartilage degeneration

Accumulating evidence has identified N⁶-methyladenosine (m⁶A) regulation in the progression of age-related diseases. However, whether the m⁶A reader protein IGF2BP2 affects the occurrence of cartilage degeneration is still unknown. Western blotting revealed dose-dependent IGF2BP2 attenuation with increasing IL-1β concentrations in C28/I2 chondrocytes. Downregulation of IGF2BP2 caused impaired glycolysis and abnormal mitochondrial function, which ultimately resulted in senescence and disturbance of extracellular matrix homeostasis. Overexpressing HIF-1α at the cellular level in chondrocytes partially rescued mitochondrial dysfunction and senescence triggered by IGF2BP2 deficiency and thus alleviated the progression of cartilage degeneration. In vivo, chondrocyte-specific Igf2bp2-knockout mice (Col2a1-CreERT; Igf2bp2flox/flox) developed cartilage degeneration. Our study, for the first time, reveals the essential role of the m⁶A reader IGF2BP2 in the pathogenesis of cartilage degeneration through downregulation of HIF-1α and extends the potential role of the PINK1/Parkin pathway, downregulation of which leads to the onset of mitochondrial dysfunction and senescence in the progression of articular cartilage loss.