Zoledronic acid inhibits osteoclast differentiation and function through the regulation of NF-κB and JNK signalling pathways

Abstract

It is well known that extensive osteoclast formation plays a key role in osteoporosis in post-menopausal women and the elderly. The suppression of extensive osteoclastogenesis and bone resorption may be an effective preventive strategy for osteoporosis. Zoledronic acid (ZOL) has been indicated to play an essential role in regulating bone mineral density and has already been used in large clinical trials. However, the effects of ZOL on osteoclastogenesis remain to be fully elucidated. Therefore, the present study aimed to determine the effects of ZOL on osteoclastogenesis, and to explore the corresponding signalling pathways. By using a cell viability assay, as well as in vitro osteoclastogenesis, immunofluorescence and resorption pit assays, we demonstrated that ZOL (0.1-5 µ M) suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and bone resorptive activity. Furthermore, western blot analysis and reverse transcription-quantitative PCR indicated that ZOL inhibited the RANKL-induced activation of NF-κB and the phosphorylation of JNK in RAW264.7 cells, and subsequently decreased the expression of osteoclastogenesis-associated genes, including calcitonin receptor, tartrate-resistant acid phosphatase and dendritic cell-specific transmembrane protein. ZOL inhibited osteoclast formation and resorption in vitro by specifically suppressing NF-κB and JNK signalling. On the whole, the findings of this study indicate that ZOL may serve as a potential agent for the treatment of osteoclast-associated diseases, including osteoporosis.

Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats

“…50–52 The counteraction of ZOL on OVX-caused bone mass loss may be mechanistically attributed, in part, to its inhibition of the OVX-caused activation of the RANKL-NF-κB signalling pathway that leads to enhanced differentiation of osteoclasts. 24,28,34 It cannot be excluded that the increase in the number of apoptotic osteoblasts in the OVX group and the decrease in the number of apoptotic osteoblasts in the ZOL group also involve the same molecular mechanism. However, this hypothetical thinking remains to be further determined, as osteoblasts are much smaller in size and it is difficult to quantify their IHC staining intensity.…”

“…These effects are associated, in a dose- and time-dependent manner, with an inhibition of expression of the NF-κB, JNK, and some genes regulating osteoclast formation, including the calcitonin receptor (calcitonin receptor, CTR), RANK, and activated T nuclear factor (nuclear factor of activated T cells, NFATC1). 34 In the present study, we further determined whether these cellular and molecular effects of ZOL observed in vitro would also occur in animals that receive a single low dose of ZOL.…”

Effect of Zoledronic Acid Combined With Metformin on Bone of Db/db Mice

“…The mechanism of anti-osteoporosis using zoledronic acid is to inhibit osteoclasts activity and reduce bone loss [11]. Lin et al demonstrated that zoledronic acid inhibited NF-κB and JNK signaling pathways by cell activity assay, osteoclast generation, immuno uorescence and bone resorptive lacunae test for inhibiting the generation and absorption of osteoclasts [40]. Other studies also demonstrated that zoledronic acid inhibits osteoclast migration, differentiation and bone resorption through the AMPK pathway [15].…”

The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw

“…As a transcription factor of the nuclear factor in the activated T cell (NFAT) family ( 105 ), NFATc1 is a vital downstream target of RANK. When RANKL binds to RANK, TNF receptor-associated factor 6 (Traf6) is recruited and activated, thereby causing signal pathway activation of NF-κB, MAPK, and c-Fos ( 106 ). These signal pathways trigger the activation of NFATc1 as well as the process of osteoclast differentiation.…”