Fisetin inhibits osteoclastogenesis through prevention of RANKLInduced ROS production by Nrf2-mediated Up-regulation of Phase II antioxidant enzymes

Osteoclasts (ocls) are multinucleated bone-resorbing cells that are differentiated by stimulation with receptor activator of nuclear factor kappa-b ligand (rankl) and macrophage colony-stimulating factor. we recently demonstrated that regulation of heme-oxygenase 1 (ho-1),a stress-induced cytoprotective enzyme,also functions in ocl differentiation. in this study,we investigated effects of fisetin,a natural bioactive flavonoid that has been reported to induce ho-1 expression,on the differentiation of macrophages into ocls. fisetin inhibited the formation of ocls in a dose-dependent manner and suppressed the bone-resorbing activity of ocls. moreover,fisetin-treated ocls showed markedly decreased phosphorylation of extracellular signal-regulated kinase,akt,and jun n-terminal kinase,but fisetin did not inhibit p38 phosphorylation. fisetin up-regulated mrna expression of phase ii antioxidant enzymes including ho-1 and interfered with rankl-mediated reactive oxygen species (ros) production. studies with rna interference showed that suppression of nf-e2-related factor 2 (nrf2),a key transcription factor for phase ii antioxidant enzymes,rescued fisetin-mediated inhibition of ocl differentiation. furthermore,fisetin significantly decreased rankl-induced nuclear translocation of cfos and nuclear factor of activated t cells cytoplasmic-1 (nfatc1),which is a transcription factor critical for osteoclastogenic gene regulation. therefore,fisetin inhibits ocl differentiation through blocking ranklmediated ros production by nrf2-mediated up-regulation of phase ii antioxidant enzymes. © the japanese pharmacological society.