Nepetin inhibits osteoclastogenesis by inhibiting RANKL-induced activation of NF-κB and MAPK signalling pathway, and autophagy.

Aseptic prosthetic loosening due to wear particle-induced inflammatory osteolysis is the main cause of failure for artificial joint replacement. The inflammatory response and the production of pro-osteoclastic factors lead to elevation of osteoclast formation and excessive activity results in extensive bone destruction around the bone-implant interface. Here we showed that Nepetin, a natural bioactive flavonoid with proven anti-inflammatory and anti-proliferative properties, potently inhibited RANKL-induced osteoclast differentiation, formation and bone resorption in vitro, and protected mice against the deleterious effects of titanium particle-induced calvarial osteolysis in vivo. Mechanistically, Nepetin attenuated RANKL-induced activation of NF-κB and MAPK signalling pathways and TRAF6-dependent ubiquitination of Beclin 1 which is necessary for the induction of autophagy. In brief, our study demonstrates the potential therapeutic application of Nepetin against osteoclast-mediated osteolytic diseases.