TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion-induced bone regeneration

• DOI: 10.1038/s41467-021-23005-2
• Publication Date: 2021-05-17T10:04:53Z
• Authors: Wei Qiao; Karen H. M. Wong; Jie Shen; Wenhao Wang; Jun Wu; Jinhua Li; Zhengjie Lin; Zetao Chen; Jukka P. Matinlinna; Yufeng Zheng; Shuilin Wu; Xuanyong Liu; Keng Po Lai; Zhuofan Chen; Yun Wah Lam; Kenneth M. C. Cheung; Kelvin W. K. Yeung
• Keywords: 0301 basic medicine; Kinase; Bone Regeneration; Osteoclasts/cytology; THP-1 Cells; Gene Expression; Osteoclasts; FOS: Health sciences; Signal transduction; Femur/drug effects; Monocyte; Bone Regeneration/drug effects; Biochemistry; Rats, Sprague-Dawley; Osteogenesis; Magnesium; Femur; Phosphorylation; Cells, Cultured; Bone healing; 0303 health sciences; Magnesium/administration & dosage; Nutrition and Dietetics; Inflammation/metabolism; Q; RANKL; Cell Differentiation; Activator (genetics); Osteogenesis/drug effects; Chemistry; Physical Sciences; Cytokines; Protein Serine-Threonine Kinases/genetics; Anatomy; Receptor; Cell biology; Magnesium Alloys for Biomedical Applications; Science; Materials Science; Immunology; TRPM7; TRPM Cation Channels; Gene Expression/drug effects; Nursing; Protein Serine-Threonine Kinases; Transient receptor potential channel; Article; Immunomodulation; Biomaterials; 03 medical and health sciences; Cytokines/immunology; Copper and Zinc in Health and Disease; Health Sciences; Animals; Humans; Role of Magnesium in Health and Disease; Biology; Immunomodulation/drug effects; Inflammation; Macrophages; FOS: Clinical medicine; Macrophages/cytology; Rats; Cell Differentiation/drug effects; Osteoimmunology; TRPM Cation Channels/genetics

AbstractDespite the widespread observations on the osteogenic effects of magnesium ion (Mg2+), the diverse roles of Mg2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg2+ in bone repair. During the early inflammation phase, Mg2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg2+ in the monocyte-macrophage lineage, resulting in the cleavage and nuclear accumulation of TRPM7-cleaved kinase fragments (M7CKs). This then triggers the phosphorylation of Histone H3 at serine 10, in a TRPM7-dependent manner at the promoters of inflammatory cytokines, leading to the formation of a pro-osteogenic immune microenvironment. In the later remodeling phase, however, the continued exposure of Mg2+ not only lead to the over-activation of NF-κB signaling in macrophages and increased number of osteoclastic-like cells but also decelerates bone maturation through the suppression of hydroxyapatite precipitation. Thus, the negative effects of Mg2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg2+. Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg2+ in bone healing.