Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China; and.
FASEB J. 2019 Apr;33(4):5208-5219. doi: 10.1096/fj.201801791RR. Epub 2019 Jan 9.
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 improved the wound healing of the extraction socket and decreased the incidence rate of BRONJ. Taken together, our findings suggest that TLR-4-mediated macrophage polarization participates in the pathogenesis of BRONJ in mice, and TLR-4 may be a potential target for the prevention and therapeutic treatment of BRONJ.-Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR-4-mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw.
唑来膦酸相关颌骨骨坏死（BRONJ）是长期使用双膦酸盐的一种有害副作用。虽然有报道称巨噬细胞是 BRONJ 的重要介质，但 BRONJ 的详细潜在机制仍不清楚。在这里，我们报道了唑来膦酸（ZA）作用下巨噬细胞中 TLR-4 表达升高，导致体外和体内 M1 巨噬细胞极化增强和 M2 巨噬细胞极化减少。抑制 TLR-4 信号通路后，ZA 诱导的 TLR-4/NF-κB 信号通路激活和 NF-κB 核易位及促炎细胞因子产生被抑制，从而抑制 M1 巨噬细胞极化。利用 TLR-4 小鼠，BRONJ 的发展明显改善，TLR-4 小鼠拔牙窝组织中的 M1 巨噬细胞明显减少。重要的是，TLR-4 抑制剂 TAK-242 的全身给药改善了拔牙窝的愈合，并降低了 BRONJ 的发生率。总之，我们的研究结果表明，TLR-4 介导的巨噬细胞极化参与了 BRONJ 的发病机制，TLR-4 可能是预防和治疗 BRONJ 的潜在靶点。-Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR-4-mediated M1 macrophage polarization in bisphosphonate-related osteonecrosis of the jaw.
