Multifunctional Roles of Magnesium Ions in Modulating Bone Regeneration-Related Cells

Magnesium ions (Mg²⁺) play pivotal roles in bone regeneration by regulating the biological functions of multiple bone repair-related cells. However, the effective concentration ranges and optimal concentration of Mg²⁺ for different cell types remain incompletely defined, which limits the precise design of Mg-containing biomaterials with controllable ion release for repairing of bone defects. In this study, the concentration-dependent effects of Mg²⁺ on the biological functions of bone regeneration-related cells were systematically investigated. Human bone marrow mesenchymal stem cells (hBMSCs), human umbilical vein endothelial cells (HUVECs), rat Schwann cells (RSCs), and RAW264.7 macrophage were selected to evaluate the effective concentration of Mg²⁺ for promoting osteogenesis, angiogenesis, neuroregulation, and immunomodulation, respectively. The results demonstrated that Mg²⁺ concentrations ranging from to 16 mM, particularly 8 mM, significantly upregulated the expression of M2 macrophage-related markers, thereby promoting the polarization of RAW264.7 macrophages toward the anti-inflammatory M2 phenotype. Moreover, Mg²⁺ concentrations between 2 and 8 mM effectively enhanced the osteogenic activity of hBMSCs, the angiogenic activity of HUVECs, and the neuroregulatory function of RSCs, as confirmed by immunofluorescence staining and quantitative PCR analysis of osteogenic, angiogenic, and neuroregulation-related marker expression. These findings provide a comprehensive understanding of the concentration-dependent biological effects of Mg²⁺ on bone regeneration-related cells and establish a theoretical basis for the rational design of next-generation Mg²⁺-releasing biomaterials with precise biological regulation.