Zoledronic acid promotes TLR-4–mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw
2019
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a detrimental side effect of the long-term administration of bisphosphonates. Although macrophages were reported to be an important mediator of BRONJ, the detailed potential mechanism of BRONJ remains unclear. Here, we reported an elevated TLR-4 expression in macrophages under action of zoledronic acid (ZA), resulting in enhanced M1 macrophage polarization and decreased M2 macrophage polarization both in vitro and in vivo. After inhibiting the TLR-4 signaling pathway, the activation of the TLR-4/NF-κB signaling pathway and the induction of NF-κB nuclear translocation and production of proinflammatory cytokines by ZA were suppressed in macrophages, thereby inhibiting M1 macrophage polarization. By utilizing the TLR-4−/− mice, development of BRONJ was markedly ameliorated, and M1 macrophages were significantly attenuated in the extraction socket tissues in the TLR-4−/− mice. Importantly, the systemic administration of the TLR-4 inhibitor TAK-242 imp...
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