Zoledronic acid inhibits osteoclastogenesis and bone resorptive function by suppressing RANKL‑mediated NF‑κB and JNK and their downstream signalling pathways.

Abstract

Targeting excessive osteoclast differentiation and activity is considered a valid therapeutic approach for osteoporosis. Zoledronic acid (ZOL) plays a pivotal role in regulating bone mineral density. However, the exact molecular mechanisms responsible for the inhibitory effects of ZOL on receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation are not entirely clear. The present study aimed to investigate the role of ZOL in osteoclast differentiation and function, and to determine whether NF-κB and mitogen-activated protein kinase, and their downstream signalling pathways, are involved in this process. RAW264.7 cells were cultured with RANKL for differentiation into osteoclasts, in either the presence or absence of ZOL. Osteoclast formation was observed by tartrate-resistant acid phosphatase staining and bone resorption pit assays using dentine slices. The expression of osteoclast-specific molecules was analysed using reverse transcription-quantitative polymerase chain reaction and western blotting assays to deduce the molecular mechanisms underlying the role of ZOL in osteoclastogenesis. The results showed that ZOL significantly attenuated osteoclastogenesis and bone resorptive capacity in vitro. ZOL also suppressed the activation of NF-κB and the phosphorylation of c-Jun N-terminal kinase. Furthermore, it inhibited the expression of the downstream factors c-Jun, c-Fos and nuclear factor of activated T cells c1, thereby decreasing the expression of dendritic cell-specific transmembrane protein and other osteoclast-specific markers. In conclusion, ZOL may have therapeutic potential for osteoporosis.