Magnesium Ions Promote the Induction of Immunosuppressive Bone Microenvironment and Bone Repair through HIF‐1α‐TGF‐β Axis in Dendritic Cells

Abstract The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg 2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid‐coated Mg 2+ (CSHA‐Mg) in bone‐deficient mice, it is shown that Mg 2+ can inhibit the activation of CD4 + T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg 2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF‐1α expression, a transcription factor that amplifies TGF‐β production and inhibits the effective T cell function. In vivo, knock‐out of HIF‐1α in DCs or using a HIF‐1α inhibitor PX‐478 reverses inhibition of bone inflammation and repair promotion upon Mg 2+ ‐treatment. Moreover, roxadustat, which stabilizes HIF‐1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA‐Mg. Thus, the findings identify a key mechanism for DCs and its HIF‐1α‐TGF‐β axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration.