Phenobarbital inhibits osteoclast differentiation and function through NF-κB and MAPKs signaling pathway.

The purpose of this study was to determine the direct effects of phenobarbital (PB) on receptor activator of nuclear factor kappa-B ligand (RANKL) induced osteoclast differentiation and function in vitro and in vivo. Here, PB significantly inhibited osteoclast formation and bone resorption ability induced by RANKL in vitro. Meanwhile, intracellular signaling transduction analysis revealed PB specifically decreasing the phosphorylation level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK), respectively. Besides, oral administration of PB at the dose of 60 mg/kg/day for 6 weeks led to improve the bone loss and to decrease the activity on both osteoblast and osteoclast. This suppression effect is more obvious in osteoblast-induced bone formation than that on osteoclast-induced bone resorption. Taken together, our findings demonstrated that PB down-regulate osteoclast differentiation and activity through modulation of NF-κB and MAPKs signaling pathway. The direct suppression effect on osteoclast can induce bone loss after long term oral administration. This bone loss is due to reducing bone turnover rate on both sides of bone formation and bone resorption.