Fig. 3: Pyroptosis in OA pathogenesis.
From: The regulatory role and therapeutic application of pyroptosis in musculoskeletal diseases

The basic pathological processes of OA include cartilage degeneration, synovial fibrosis, and chronic inflammation. On the one hand, excessive ROS can activate NLRP3 inflammasome and downstream caspase-1. On the other hand, it promotes the processing and release of HMGB1, IL-1β/-18, and GSDMD. The activation of caspase-4/-5/-11 and P2X7R in the non-canonical pathway is also involved in this process. NF-kB signal has crosstalk with both canonical and non-canonical pathways, which jointly promote pyroptosis of chondrocytes, imbalance of matrix synthesis and degradation, and release of proinflammatory cytoplasmic components, leading to cartilage degeneration. Synovial fibrosis is mainly mediated by FLSs pyroptosis, in which NLRP1 and NLRP3 participate in the classical pathway and enhance the release of IL-1β/-18, resulting in tissue inflammation. Macrophage pyroptosis also enhances the process of synovial fibrosis. Abnormal angiogenesis is related to cartilage degeneration and synovial inflammation, which is mainly mediated by VEGF. Together with activated immune cells and cytokines, angiogenesis constitutes a chronic inflammatory environment and participates in the occurrence of OA.