Paroxetine attenuates osteoarthritis progression by regulating chondrocyte pyroptosis and inhibiting osteoclast formation

Abstract Background Osteoarthritis (OA), a common chronic joint disease, is characterized by cartilage degeneration and subchondral bone reconstruction. Nuclear factor kappa-B (NF-κB) signaling pathway-activated inflammation and NLR family pyrin domain containing 3 (NLRP3)-induced pyroptosis play essential roles in the development of OA. In this study, we examine whether paroxetine, a well-known selective reuptake inhibitor of 5-hydroxytryptamine, can inhibit pyroptosis and reduce osteoclast formation, thereby delaying the destruction of knee joints. Methods We assayed the cytotoxic effects of paroxetine by the CCK8 assay. High-density cultures, in conjunction with quantitative polymerase chain reactions and western blots, were used to observe the effects of paroxetine on extracellular matrix synthesis and catabolism. NF-κB and pyroptosis-related signaling pathway proteins were examined by western blots and immunofluorescence assays. Furthermore, the effects of paroxetine on receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced osteoclast formation were also investigated. To investigate the protective effects of paroxetine on articular chondrocytes, a mouse model of OA in which the medial meniscus was destabilized, was established. Results Paroxetine delayed the catabolism of extracellular matrix components and promoted the anabolism of extracellular matrix components by chondrocytes. Paroxetine inhibited the interleukin 1 beta-induced activation of NF-κB and pyroptosis. In addition, it decreased the expression of osteoclast marker genes and reduced the formation of osteoclasts. Compared to control animals, mice treated with paroxetine showed slower disease progression. Conclusion Paroxetine can inhibit pyroptosis and reduce osteoclast formation, suggesting that it may have therapeutic effects in patients with OA.