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

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 20; no. 33; pp. e2311344 - n/a
• Main Authors: Dai, Yuya, Wu, Jinhui, Wang, Junyou, Wang, Haoze, Guo, Bingqing, Jiang, Tao, Cai, Zhuyun, Han, Junjie, Zhang, Haoyu, Xu, Bangzhe, Zhou, Xuhui, Wang, Ce
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.08.2024
• Subjects: adaptive immunoinflammation; Animals; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone Regeneration - drug effects; bone repair; Cellular Microenvironment - drug effects; Chitosan; Chitosan - chemistry; Chitosan - pharmacology; dendritic cell; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Glycine - analogs & derivatives; Glycine - pharmacology; Hyaluronic acid; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunosuppression; Isoquinolines - pharmacology; Lymphocytes; Magnesium; Magnesium - pharmacology; magnesium ion; Mice; Mice, Inbred C57BL; Mustard Compounds; osteoimmunology; Phenylpropionates; Regeneration (physiology); Signal Transduction - drug effects; Transforming Growth Factor beta - metabolism; TRPM Cation Channels - metabolism; magnesium ion; adaptive immunoinflammation; dendritic cell; bone repair; osteoimmunology
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202311344

The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg2+ 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 Mg2+ (CSHA‐Mg) in bone‐deficient mice, it is shown that Mg2+ can inhibit the activation of CD4+ T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg2+ 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 Mg2+‐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. Mg2+ promotes bone regeneration by inducing imDC suppression of effector T cell‐mediated adaptive immune inflammation. Specifically, Mg2+ activates the MAPK signaling pathway through the TRPM7 channel on the DC surface, which in turn activates the HIF‐1α‐TGF‐β axis to inhibit effector T cell activation. Induction of key target HIF‐1α expression by roxadustat significantly promotes regeneration in bone‐deficient mice.