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Currently,dendritic cell-specific transmembrane protein (DC-STAMP),a multipass transmembrane protein,is considered as the master regulator of cell-cell fusion,which underlies the formation of functional multinucleated osteoclasts.Thus,DC-STAMP has become a promising target for osteoclast-associated osteolytic diseases.In this study,we investigated the effects of oridonin (ORI),a natural tetracyclic diterpenoid compound isolated from the traditional Chinese herb Rabdosia rubescens,on osteoclastogenesis in vivo and ex vivo.ICR mice were injected with LPS (5 mg/kg,ip,on day 0 and day 4) to induce inflammatory bone destruction.Administration of ORI (2,10 mg.kg-1·-1,ig,for 8 days) dose dependently ameliorated inflammatory bone destruction and dramatically decreased DC-STAMP protein expression in BMMs isolated from LPS-treated mice.Treatment of preosteoclast RAW264.7 cells with ORI (0.78-3.125 μM) dose dependently inhibited both mRNA and protein levels of DC-STAMP,and suppressed the following activation of NFATc1 during osteoclastogenesis.Knockdown of DC-STAMP in RAW264.7 cells abolished the inhibitory effects of ORI on RANKL-induced NFATc1 activity and osteoclast formation.In conclusion,we show for the first time that ORI effectively attenuates inflammation-induced bone loss by suppressing DC-STAMP expression,suggesting that ORI is a potential agent against inflammatory bone diseases.