Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw

Abstract

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. FASEB J. 33, 5208–5219 (2019). http://www.fasebj.org

Bisphosphonates and atrial fibrillation: revisiting the controversy

“…96 Macrophages also appear to play a role in this process, since inhibition of macrophage TLR4 signaling pathways appear to ameliorate zoledronic acid-induced inflammation in rat models of osteonecrosis of the jaw. 97 Thus, BP administration may exert a proarrhythmic effect on myocardium by facilitating arrhythmic triggers and substrates through local and systemic inflammatory processes centered around an acute phase response.…”

AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations

“…The details of western blot were described elsewhere [31]. Brie y, cells were lysed by RIPA buffer (Beyotime, China), and the lysate was loaded onto 10% or 12% SDS-PAGE and then transferred to PVDF membranes (Millipore, USA).…”

“…Immunohistochemical staining was performed using continuous para n sections of venous malformations. Details of immunohistochemical staining are described elsewhere [31]. Brie y, the serial tissue sections were immersed in 3% H 2 O 2 for 30 minutes.…”

AKT/FOXO1 axis links cross-talking of endothelial cell and pericyte in TIE2-mutated venous malformations

“…The details of western blot were described elsewhere [30]. Briefly, cells were lysed by RIPA buffer (Beyotime, China), and the lysate was loaded onto 10% or 12% SDS-PAGE and then transferred to PVDF membranes (Millipore, USA).…”

“…Immunohistochemical staining was performed using continuous paraffin sections of venous malformations. Details of immunohistochemical staining are described elsewhere [30]. PDFGB (Abclonal, #A1195) and α-SMA (Proteintech, #23081-1-AP) primary antibody were used to detect relative molecular expression.…”