Alteration of macrophage viability, differentiation, and function by bisphosphonates.

Abstract

A serious adverse effect of long-term bisphosphonate (BP) administration is bisphosphonate-related osteonecrosis of the jaw (BRONJ). Among different proposed pathogenesis, suppression of immune cells is gaining interest. Because monocytes/macrophages could get access to BP since residing in the blood and bone microenvironment, the aim of this study was to analyze the behaviors of macrophages after BP treatments in vitro. THP-1 cell, an established human monocytic cell model, was used in this study. The effects of BPs, alendronate (ALN) and zoledronic acid (ZA), on macrophage viability, differentiation, and function were investigated. MTT, morphological analysis, flow cytometry, quantitative PCR, and gelatin zymography assay were performed. BPs impaired macrophage viability at almost all concentration tested (1-100μM). Cell morphology was altered in the presence of 100μM BPs. Furthermore, differentiating macrophage viability was also affected by both ALN and ZA at 100 and 10-100μM, respectively. At high concentration (100μM), ZA caused a reduction in cell differentiation. On the contrary, ALN and ZA increased matrix metalloproteinase mRNA expressions and activities at low doses (1-10μM). BPs directly acted on macrophage by reducing macrophage survival, inducing morphological alterations, impairing differentiation from monocytes to macrophages, and affecting macrophage function at both mRNA and activity levels.