Journal Article

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

Shen, Jie, Qiao, Wei, Lin, Zhengjie, Liu, Xuanyong, Lam, Yun Wah, Wu, Shuilin, Li, Jinhua, Wong, Karen H. M., Zheng, Yufeng, Wu, Jun, Lai, Keng Po, Cheung, Kenneth M. C., Chen, Zetao, Yeung, Kelvin W. K., Wang, Wenhao, Chen, Zhuofan, Matinlinna, Jukka P.

2021

Overview

Despite the widespread observations on the osteogenic effects of magnesium ion (Mg 2+ ), the diverse roles of Mg 2+ during bone healing have not been systematically dissected. Here, we reveal a previously unknown, biphasic mode of action of Mg 2+ in bone repair. During the early inflammation phase, Mg 2+ contributes to an upregulated expression of transient receptor potential cation channel member 7 (TRPM7), and a TRPM7-dependent influx of Mg 2+ 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 Mg 2+ 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 Mg 2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg 2+ . Taken together, this study establishes a paradigm shift in the understanding of the diverse and multifaceted roles of Mg 2+ in bone healing. Supplementation of magnesium (Mg2+) or its inclusion in biomaterials has beneficial effects for bone formation, but it has also been reported that it can have detrimental effects. Here, the authors analyse dose- and time-dependent effects of Mg2+ on bone regeneration and show that it can stimulate monocyte-macrophage lineage cells to support bone formation in the early phases of repair, but inhibit bone repair and mineralization in later stages by promoting a pro-inflammatory environment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/21 / 13/51 / 14/19 / 45/77 / 49/31 / 49/88 / 631/250/808 / 631/80/86/2372 / 639/301/54/990 / 64/86 / 692/698/1671/63 / 82/51 / Animals / Biomaterials / Biomedical materials / Bone biomaterials / Bone growth / Bone healing / Bone Regeneration - drug effects / Cell Differentiation - drug effects / Cells, Cultured / Cytokines / Cytokines - immunology / Cytokines - metabolism / Deceleration / Femur - drug effects / Femur - metabolism / Femur - pathology / Gene Expression - drug effects / Healing / Histone H3 / Histones / Homeostasis / Hospitals / Humanities and Social Sciences / Humans / Hydrogels / Hydroxyapatite / Immunomodulation / Immunomodulation - drug effects / Inflammation / Inflammation - metabolism / Ion channels / Kinases / Laboratories / Macrophages / Macrophages - cytology / Macrophages - immunology / Macrophages - metabolism / Magnesium / Magnesium - administration & dosage / Magnesium - metabolism / Magnesium - pharmacology / Materials science / Metabolism / Microenvironments / Mineralization / Mode of action / Monocytes / multidisciplinary / NF-κB protein / Orthopedics / Osteoclasts / Osteoclasts - cytology / Osteoclasts - drug effects / Osteogenesis / Osteogenesis - drug effects / Osteogenesis - genetics / Phosphorylation / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Rats / Rats, Sprague-Dawley / Regeneration / Regeneration (physiology) / Repair / Roles / Science / Science (multidisciplinary) / Serine / THP-1 Cells / Titanium alloys / Transient receptor potential proteins / Transplants & implants / TRPM Cation Channels - genetics / TRPM Cation Channels - metabolism