Osteoclast-induced bone disordering diseases, such as osteoporosis, are quite prevalent in modem society.However, the current marked drugs for these diseases are far from ideal, and many alternative drugs are under investigated in pursuit of better effect.The glycosides and derivative of oleanolic acid (OA) have been report ed to prevent bone loss in ovariectomized mice by inhi biting the osteoclastogenesis.However, the roles of OA in receptor activator of nuclear factor kappa-B ligan d (RANKL)-mediated osteoclastogenesis is still not el ucidated.In this study, we carried out series in vitro an d in vivo assays to fully investigate the role of OA in osteoclast biology.Here we show that OA dose-depend ently inhibit RANKL-mediated osteoclastogenesis and the formation of functional osteoclast in bone marrow macrophages (BMMs) at the optimal level of RANK L.Moreover, OA significantly increase the bone marr ow density (BMD) in ovariectomized mice partly by inhibiting osteoclast activity.We found that OA exert inhibitory effects on osteoclastogenesis not by impairin g the viability and osteoclastic potential of BMMs.Me chanistically, we found that OA inhibiting osteoclasto genesis not by affecting on RANKL-induced activatio n of the NF-κB, JNK, and p38 and ERK pathways in BMMs, but inhibit osteoclastogenesis by suppressing RANKL-induced expression of nuclear factor of activated T-cells cl (NFATc 1) and c-Fos in BMMs, which are two key transcriptional regulators of osteoclastogen esis.Moreover, OA significantly suppress the expressi on of RANKL-induced osteoclast genes encoding mat rix metalloproteinase 9 (MMP9), cathepsin K (Ctsk), tartrate-resistant acid phosphatase (TRAP) and carboni c anhydrase Ⅱ (Car2) in BMMs.Interestingly, the inhibitory of OA on osteoclastogenesis and the expression of RANKL-induced NFATc 1 and osteoclast genes are not affected even if BMMs were pretreated by RAN KL.Taken together, these findings have not only ident ify the precise role of OA in osteoclastogenesis, but also revealed the molecular mechanism by which OA regulated osteoclastogenesis.