Abstract
Magnesium deficiency increases the generation of pro-inflammatory cytokines, which is consistently accompanied by the sensitization of cells such as neutrophils, macrophages and endothelial cells. We investigated the potential of magnesium to regulate macrophage polarization and macrophage-induced inflammation with or without lipopolysaccharide (LPS) and interferon-γ (IFN-γ) activation and further elucidated whether these effects impact the inhibitory functions of activated macrophage-induced inflammation on cartilage regeneration. The results showed that magnesium inhibited the activation of macrophages, as indicated by a significant reduction in the percentage of CCR7-positive cells, while the percentage of CD206-positive cells decreased to a lesser degree. After activation, both pro-inflammatory and anti-inflammatory cytokines were down-regulated at the mRNA level and certain cytokines (IL-1β, IL-6 and IL-10) were decreased in the cell supernatant with the addition of magnesium. Moreover, magnesium decreased the nuclear translocation and phosphorylation of nuclear factor-κB (NF-κB) to impede its activation. A modified micromass culture system was applied to assess the effects of activated macrophage-conditioned medium with or without magnesium treatment on the chondrogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). Magnesium enhanced the chondrogenic differentiation of hBMSCs by reversing the adverse effects of activated macrophage-induced inflammation.
Highlights
Due to a limited ability to achieve self-repair and regeneration as well as a lack of effective therapeutic options, the degeneration and injury of articular cartilage may result in severe consequences[1]
A lactate dehydrogenase (LDH) release assay was performed to investigate the cytotoxic effects of magnesium on RAW cells in the absence or presence of LPS and IFN-γ
Several studies have shown that magnesium deficiency increases the production of many pro-inflammatory cytokines and that this effect is accompanied by the sensitization of cells such as neutrophils, macrophages and endothelial cells[14,17,24,25,26]
Summary
Due to a limited ability to achieve self-repair and regeneration as well as a lack of effective therapeutic options, the degeneration and injury of articular cartilage may result in severe consequences[1]. Whether the immunoregulatory effects of magnesium on macrophages affect inflammation-induced chondrocyte regeneration has not been fully investigated to date. According to previous studies[10,13] indicating that magnesium plays a positive role in the chondrogenic differentiation of MSCs, whereas macrophages with a pro-inflammatory phenotype have the opposite effect, we wondered whether magnesium affects the inflammation induced by macrophages and, whether this effect influences the chondrogenic differentiation of MSCs. In the present study, we first examined the potential effects of magnesium on the phenotypic changes in macrophages and their release of inflammatory cytokines with or without lipopolysaccharide (LPS) and interferon-γ (IFN-γ) activation. We investigated the chondrogenic differentiation of human bone marrow MSCs (hBMSCs) co-cultured with activated macrophage cell-conditioned medium and the potential effects of magnesium addition on this process. The results elucidate a novel immunoregulatory pathway for magnesium in chondrogenesis and provide foundational data for the application of magnesium-containing implants in cartilage regeneration to achieve better clinical outcomes
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