Magnesium enhances the chondrogenic differentiation of mesenchymal stem cells by inhibiting activated macrophage-induced inflammation

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.

Exosomes derived from M0, M1 and M2 macrophages exert distinct influences on the proliferation and differentiation of mesenchymal stem cells

“…Apart from proliferation and osteogenic and adipogenic differentiation, Mφs are also involved in the chondrogenic differentiation of stem cells. Several studies have confirmed the negative effect of M1 Mφs on chondrogenesis and the chondrogenesis-inductive effect of M2 Mφs (Han et al, 2014;Dai et al, 2018;Hu et al, 2018). However, the exact mechanism for these effects remains unclear.…”

A Review of the Action of Magnesium on Several Processes Involved in the Modulation of Hematopoiesis

“…In addition, low Mg 2+ concentration showed an increase in NF-κB activity in RAW264.7 cells, in addition to alterations in the production and expression of high-mobility group box 1 (HMGB1), a molecule with inflammatory properties [ 43 ]. On the other hand, studies showed that increased Mg 2+ concentration is able to decrease the proinflammatory cytokine production in mononuclear cells from human and animal sources, by inhibiting the nuclear translocation and phosphorylation of NFκB and the rise in basal IĸBα levels [ 44 , 120 ]. Moreover, the effects of preventing inflammation by increased Mg 2+ concentration in macrophages also include modulation of PI3K/Akt pathway activity, downregulation of TNF-α and IL-1β, enhanced M2 macrophage phenotype, and BMP2 and VEGF expression, with the latter seen in cell subject biomaterials coated with Mg 2+ [ 121 , 122 , 123 ] ( Figure 1 ).…”

Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis

“…Given that M1Mφ is involved mainly in the initiation of inflammation, yet M2Mφ is involved mainly in the regression of inflammation, this phenomenon indicated that the failure of transformation from M1Mφ to M2Mφ may result in persistent chronic inflammation. At present, the implications of the alteration of the Mφ polarization state for OA treatment are not clear, but several relevant studies have shown that infiltrative M1Mφ and M2Mφ exert different effects on cells within the joint, thus playing a key role in the orchestration of inflammation and regeneration (Blom et al, 2007 ; Fahy et al, 2014 ; Fichadiya et al, 2016 ; Utomo et al, 2016 ; Samavedi et al, 2017 ; Hu et al, 2018 ; Chen et al, 2020 ).…”