Abstract
BackgroundZoledronic acid (Zol), one of the bisphosphonates, is frequently utilized for the treatment of osteoporosis and bone metastasis. However, the onset of medication-related osteonecrosis of the jaw (MRONJ) following dental treatments has become a serious issue. We reported previously that osteonecrosis can be induced by Zol and lipopolysaccharide (LPS) in vivo, suggesting the involvement of Zol in inflammation. Macrophages are divided into M1/M2 macrophages. M1 macrophages are involved in the induction and exacerbation of inflammation and express proinflammatory mediators including interleukin (IL)-1. On the other hand, M2 macrophages are associated with anti-inflammatory reactions through the expression of anti-inflammatory cytokines, such as IL-10. In the present study, we clarified the effects of Zol on M1/M2 macrophage polarization in vitro.MethodsHuman monocytic THP-1 cells were polarized to macrophage-like cells by phorbol 12-myristate 13-acetate (PMA), and, after culturing for an additional 24 h with or without Zol, then polarized to M1 macrophages by LPS or to M2 macrophages by IL-4. Cell viability was examined by the WST-8 assay. Gene expression was confirmed by the real-time polymerase chain reaction. Protein expression was detected by western blotting and enzyme-linked immunosorbent assays.ResultsZol treatment upregulated the expression of IL-1β mRNA and protein through NLRP3 inflammasome activation in LPS-treated THP-1 cells. Zol treatment did not affect the expression of IL-10, IL-1ra, or CD206 in IL-4-treated THP-1 cells.ConclusionsZol enhanced LPS-induced M1, but not M2, macrophage polarization through the NLRP3 inflammasome-dependent pathway, resulting in the production of inflammatory cytokines in THP-1 cells.
Highlights
Zoledronic acid (Zol), one of the bisphosphonates, is frequently utilized for the treatment of osteoporosis and bone metastasis
We reported that the combined use of Zol and lipopolysaccharide (LPS) in vivo induced ONJ and osteonecrosis of the femur in rats, suggesting that Zol is involved in the inflammatory response during the progression of medication-related osteonecrosis of the jaw (MRONJ) [5,6,7]
Zol enhanced IL-1β expression and the secretion of mature IL-1β during M1 macrophage differentiation THP-1 cells were exposed to Zol for 48 h after phorbol 12-myristate 13-acetate (PMA) treatment
Summary
Zoledronic acid (Zol), one of the bisphosphonates, is frequently utilized for the treatment of osteoporosis and bone metastasis. The onset of medication-related osteonecrosis of the jaw (MRONJ) following dental treatments has become a serious issue. M1 macrophages are involved in the induction and exacerbation of inflammation and express proinflammatory mediators including interleukin (IL)-1. Nitrogen-containing bisphosphonates, including zoledronic acid (Zol), are widely used as anti-bone-resorptive agents, primarily for the treatment of osteoporosis, Paget’s disease of the bone, multiple myeloma, hypercalcemia due to malignancy, and other bone-resorptive diseases. The onset of medication-related osteonecrosis of the jaw (MRONJ) has become a serious issue. Dental treatment such as tooth extraction triggers the MRONJ in the patients taking anti-bone-resorptive agents. Oral macrophages play important roles in the inflammatory response, as well as in signaling to resolve inflammation, and promote healing and regeneration [9].
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