The Flavonoid Kaempferol Mitigates Periprosthetic Osteolysis by Regulating the <scp>NLRP3</scp> Inflammasome and Balancing Bone Metabolism

Total joint arthroplasty (TJA) is an effective intervention for end-stage arthritis; however, its long-term success is often compromised by wear particle-induced osteolysis, leading to aseptic loosening and implant failure. This study investigates the potential of kaempferol (Ka), a natural flavonoid with anti-inflammatory properties, to alleviate osteolysis by modulating NLRP3 inflammasome activation. In a murine calvarial osteolysis model, Ka administration significantly attenuated bone loss induced by CoCrMo alloy particles. Mechanistically, Ka dose-dependently inhibited NLRP3 inflammasome activation in macrophages, as evidenced by reduced IL-1β secretion, decreased ASC oligomerisation and suppressed GSDMD cleavage, ultimately leading to decreased pyroptosis. These effects were found to be partially mediated via GPR109a. Furthermore, Ka markedly suppressed osteoclast differentiation and activity both in vivo and in vitro while promoting osteoblast differentiation, thereby contributing to the restoration of bone remodelling balance. Taken together, our findings suggest that Ka exerts a protective effect against wear particle-induced osteolysis by targeting the NLRP3 inflammasome and modulating osteoimmune responses, which may offer a novel therapeutic strategy to manage periprosthetic osteolysis and prolong implant longevity.