Molecular Mechanism Of Xanthohumol Suppressing Osteoclastogenesis And Function

Osteoclast formation and activation are regulated by receptor activator of nuclear factor κB ligand (RANKL). The interaction of RANKL to its cognate receptor (RANK) drives the activation of downstream signaling pathways; which ultimately induce the formation and activation of osteoclasts.When the function of osteoclast cells is excessive and the bone environment is imbalanced, a lot of bone diseases will generate, such as osteoporosis. RANKL-induced NF-κB signaling and Ca2+oscillation are the main pathways during osteoclastogenesis. Targeting NF-κB and Ca2+signaling to modulate osteoclast activity has been a promising strategy for osteoclast-related diseases. In this study, we show that a natural compound, xanthohumol, inhibits osteoclast formation at the early stage. Furthermore, xanthohumol could attenuate RANKL-induced bone resorption in vitro. Xanthohumol suppresses RANKL-induced osteoclast formation, and diminishes the expression of osteoclastogenesis marker genes, including TRAP, NFATc1, Cathepsin K and CTR. Molecular studies reveal that xanthohumol inhibits RANKL-induced IκBα degradation, concomitant with the phosphorylation and nuclear translocation of p65, and downregulates NF-κB activity. In addition, xanthohumol also exhibits an inhibitory effect on RANKL-induced Ca2+oscillation, and overexpression of Ca2+-NFAT2rescues the inhibition of xanthohumol on osteoclast differentiation. Collectively, our results demonstrate that xanthohumol could inhibits osteoclastogenesis by blocking RANKL-induced NF-κB pathway and Ca2+oscillation, showing the potential application of Xanthohumol for the treatment and prevention of bone diseases involving excessive osteoclast differentiation.