Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41467-021-23005-2
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Funding
- National Key R&D Program of China [2018YFA0703100]
- General Research Fund of Hong Kong Research Grant Council [17214516, N_HKU725/16]
- Sanming Project of Medicine in Shenzhen Team of Excellence in Spinal Deformities and Spinal Degeneration Disease [SZSM201612055]
- Shenzhen Science and Technology Funds [JSGG20180507183242702]
- Hong Kong Innovation Technology Fund [ITS/287/17, ITS/405/18]
- Science and Technology Commission of Shanghai Municipality [18410760600]
- International Partnership Program of Chinese Academy of Sciences [GJHZ1850]
- National Natural Science Foundation of China [81970975]
- Guangdong Financial Fund for Hige-Caliber Hospital Construction [174-2018-XMZC-0001-03-2125/D-10]
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This study reveals a biphasic mode of action of magnesium ion (Mg2+) in bone repair. During the early inflammation phase, Mg2+ can contribute to pro-osteogenic effects by promoting an immune microenvironment for bone formation; however, in the later remodeling phase, Mg2+ has negative effects on bone maturation and repair.
Despite 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-kappa B 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. 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.
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