Alteration of macrophage viability, differentiation, and function by bisphosphonates

Area of Science:

• Immunology
• Pharmacology
• Cell Biology

Background:

• Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse effect of long-term bisphosphonate (BP) use.
• Suppression of immune cells is a potential mechanism underlying BRONJ.
• Monocytes/macrophages are key immune cells residing in bone and blood, making them susceptible to BP exposure.

Purpose of the Study:

• To investigate the in vitro effects of bisphosphonates (BPs) on macrophage viability, differentiation, and function.
• To analyze the impact of specific BPs, alendronate (ALN) and zoledronic acid (ZA), on macrophage behavior.

Main Methods:

• Utilized the human monocytic cell line THP-1 as a model system.
• Assessed macrophage viability, morphology, differentiation, and function using MTT assays, morphological analysis, flow cytometry, qPCR, and gelatin zymography.
• Examined the effects of varying concentrations of ALN and ZA.

Main Results:

• BPs significantly impaired macrophage viability across tested concentrations (1-100 μM).
• High BP concentrations (100 μM) altered cell morphology and reduced differentiation.
• Low doses (1-10 μM) of ALN and ZA increased matrix metalloproteinase (MMP) mRNA expression and activity, while high doses affected differentiation.

Conclusions:

• Bisphosphonates exert direct cytotoxic and functional effects on macrophages.
• BPs reduce macrophage survival, induce morphological changes, and impair monocyte-to-macrophage differentiation.
• Macrophage function, at both mRNA and activity levels, is significantly affected by BP treatment, potentially contributing to BRONJ.