Pyroptosis Plays a Role in Osteoarthritis

Abstract

Recent studies have revealed novel forms of cell death beyond the canonical types of cellular apoptosis and necrosis, and these novel forms of cell death are induced by extreme microenvironmental factors. Pyroptosis, a type of regulated cell death, occurs when pattern recognition receptors (PRRs) induce the activation of cysteine-aspartic protease 1 (caspase-1) or caspase-11, which can trigger the release of the pyrogenic cytokines interleukin-1β (IL-1β) and IL-18. Osteoarthritis (OA), the most common joint disease worldwide, is characterized by low-grade inflammation and increased levels of cytokines, including IL-1β and IL-18. Additionally, some damaged chondrocytes associated with OA exhibit morphological changes consistent with pyroptosis, suggesting that this form of regulated cell death may contribute significantly to the pathology of OA. This review summarizes the molecular mechanisms of pyroptosis and shows the critical role of NLRP3 (NLR family, pyrin domain containing 3; NLR refers to "nucleotide-binding domain, leucine-rich repeat") inflammasomes. We also provide evidence describing potential role of pyroptosis in OA, including the relationship with OA risk factors and the contribution to cartilage degradation, synovitis and OA pain.

Keywords: caspase; inflammation; osteoarthritis; pyroptosis.

Figure 1.

Pyroptosis in knee osteoarthritis progression. In macrophages or other cells in the synovium or synovial fluid of the knee joint, DAMPs can stimulate and combine with PRRs (e.g., TLRs) on the membrane, forming inflammasomes (ASC, pro-caspase-1 and NLRP3), which are activated by two steps: priming and activation. Inflammasomes can convert pro-caspase-1 into active caspase-1, which cleaves GSDMD and form GSDMD-N. GSDMD-N generates membrane pores and leads to cell swelling and eventual lysis. Moreover, caspase-1 induces the release of more mature proinflammatory cytokines, including IL-1β and IL-18, which can in turn lead to further inflammatory cytokine release and promote pyroptosis. This is the canonical pathway of pyroptosis. LPS can directly activate caspase-4/5 (human) or caspase-11 (mouse), which can also activate GSDMD, and this is a noncanonical pyroptosis pathway. Compared with the inflammatory activity in normal knee joints, the increased inflammatory activities caused by pyroptosis in the joint promote osteoarthritis progression, with exacerbated synovitis, cartilage degradation and increased sensory input to the central nervous system, which can generate more pain.