Inhibition of ERK5 activity ameliorates osteoarthritis by suppressing NLRP3 inflammasome-mediated chondrocyte pyroptosis

Osteoarthritis (OA) is a widespread degenerative joint disorder manifesting as chronic pain, functional impairment, and progressive disability, imposing a substantial burden on global public health. Despite extensive research, the precise molecular pathways underlying OA pathogenesis remain incompletely elucidated. Our data indicated that human OA cartilage and cartilaginous tissues from aged mice exhibited markedly elevated levels of extracellular signal-related kinase 5 (ERK5) enzyme activity. Using Col2a1-CreER T2 / Erk5 flox/flox mice, we found that Erk5 deletion in cartilage inhibited the progression of post-traumatic and aging OA mouse while constitutive activation of ERK5 significantly accelerated OA development via intra-articular injection of adeno-associated virus model. Mechanistically, ERK5 interacted with the PYD domain of NLRP3 and mediated NLRP3 phosphorylation at serine 198, which facilitated mature inflammasome assembly, triggered pyroptosis and subsequently exacerbated OA progression. Furthermore, we identified a small compound, Oroxylin A, which attenuated ERK5 activation and effectively ameliorated the development of post-traumatic and aging-induced OA in mice. Taken together, our studies demonstrate that ERK5 is a key regulator effecting chondrocytes inflammation and pyroptosis through activating NLRP3 inflammasome and ERK5 is a potential therapeutic target for OA treatment.