Figure 5.

Pyroptotic pathways related to OA

The canonical pyroptotic pathway involves the activation of caspase-1 activity leading to the cleavage of GSDMD through the activation of nod-like receptor (NLR) proteins. GSDMD translocases to the plasma membrane and form pores that converge in cellular membrane rupturing. Caspase-8 is activated by TNF-α derived from macrophages and activates GSDMD and GSDMC, resulting in pyroptosis. In the non-canonical pyroptotic pathway, caspase-3/6 activation triggers pyroptosis by cleaving GSDMC. Moreover, p-Stat3 drives PD-L1 translocation, promoting the expression of GSDMC. Caspase-3 cleaves GSDME. Pyroptosis in the non-canonical pathway is induced by caspases-4/5/11 that activate GSDMD and is mediated by Pannexin-1 causing the release of cellular ATP and inducing pyroptotic cell death by the ion channel P2X7 receptor. Finally, the potential therapeutic agents for targeting pyroptosis in OA animal models are shown within the green boxes. Abbreviations: P2X7R, P2X purinoceptor 7; ATP, Adenosine triphosphate; GSDMD, Gasdermin D; GSDME, Gasdermin E; GSDMC, Gasdermin C.