CADPE Suppresses RANKL-induced Osteoclastogenesis And Prevents Ovariectomy-induced Bone Loss And The Molecular Mechanism

RANKL stimulation leads to activation of MAPKs/AP-1signaling pathway and initiation of Ca2+-NFATc1axis. Targeting these pathways involved in osteoclastogenesis has been an encouraging strategy for bone related diseases, such as post-menopausal osteoporosis. In this study, we examined the effects of caffeic acid3,4-dihydroxy-phenethyl ester (CADPE) on osteoclastogenesis. In mouse BMMs and RAW264.7cells, CADPE suppresses RANKL-induced osteoclast differentiation and function in a dose-dependent manner within non-growth inhibitory concentrations at the early stage, but has no effect on M-CSF induced proliferation and differentiation in BMMs. At the molecular level, CADPE inhibits RANKL-induced phosphorylation of MAPKs, including ERK1/2, p38and JNK without significantly affecting the degradation of IκBα; and phosphorylation of p65in the NF-κB signaling pathway. Moreover, CADPE abrogates RANKL-induced AP-1/c-Fos nuclear translocation and activity, and overexpression of c-Fos prevents the inhibition of CADPE on osteoclast differentiation. Furthermore, CADPE inhibits RANKL-induced Ca2+oscillation and decreases osteoclastogenesis-related marker gene expression, including NFATcl, TRAP, cathepsin K, and c-Src. To test the effects of CADPE on osteoclast activity in vivo, we showed that CADPE prevented ovariectomy-induced bone loss in mouse models by inhibiting osteoclast activity. Together, our data demonstrate that CADPE suppresses osteoclastogenesis and bone loss through inhibiting RANKL-induced MAPKs and Ca2+-NFATc1signaling pathways and that CADPE is a novel agent in the treatment of osteoclast-related diseases, such as osteoporosis.