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

Abstract

The use of magnesium ion (Mg 2+ )-modified biomaterials in bone regeneration is a promising and cost-effective therapeutic. Despite the widespread observation on the osteogenic effects of Mg 2+ , the diverse roles played by Mg 2+ in the complex biological process of bone healing have not been systematically dissected. Here, we reveal a previously unknown biphasic mode of action of Mg 2+ in bone repair. In the early inflammation phase, Mg 2+ primarily targets the monocyte-macrophage lineage to promote their recruitment, activation, and polarization.We showed that an increase in extracellular 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 like IL-8, leading to the formation of a pro-osteogenic immune microenvironment. In the later active repair/remodeling phase of bone healing, however, continued exposure of Mg 2+ and IL-8 leads to over activation of NF-κB signaling in macrophages, turning the immune microenvironment into pro-osteoclastogenesis. Moreover, the presence of Mg 2+ at this stage also decelerates bone maturation through the suppression of hydroxyapatite precipitation. The negative effects of Mg 2+ on osteogenesis can override the initial pro-osteogenic benefits of Mg 2+ , as we found prolonged delivery of Mg 2+ compromises overall bone formation. Taken together, this study establishes a paradigm shift in understanding the diverse and multifaceted roles of Mg 2+ in bone healing.

Early osteoimmunomodulatory effects of magnesium–calcium–zinc alloys

“…However, the osteo-promoting functions of magnesium only is affective during the early phase of osteogenesis as the continued stimulation of magnesium over activates the nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling pathway and prevents mineralization of extracellular matrix. 25 Our results supported their findings indicating that ZX00 alloy could potentially modulate the early inflammatory responses after implantation toward tissue healing. We found that the alloy could significantly regulate the polarization of macrophages toward higher expression of type 2 macrophages, 5 and 10 days after implantation, which could stimulate tissue healing and reduce the immune responses against the alloy degradation products.…”

“…Because macrophages and other inflammatory immune cells play key roles in determining the biomaterial's success after implantation, biomaterials with immunomodulatory potential have gained much attention over the past few years. [90][91][92] Qiao et al 25 Have more recently demonstrated that the influx of magnesium through the transient receptor potential cation channel member 7 (TRPM7) channel and the nuclear translocation of TRPM7-cleaved kinase fragments (M7CKs) lead to the polarization of macrophages into a pro-osteogenic subtype. 25 This further stimulates the osteogenic differentiation of MSC, which is distinct from the classical macrophage type 1/2 phenotypes.…”

“…[90][91][92] Qiao et al 25 Have more recently demonstrated that the influx of magnesium through the transient receptor potential cation channel member 7 (TRPM7) channel and the nuclear translocation of TRPM7-cleaved kinase fragments (M7CKs) lead to the polarization of macrophages into a pro-osteogenic subtype. 25 This further stimulates the osteogenic differentiation of MSC, which is distinct from the classical macrophage type 1/2 phenotypes. Their data supported that the initial immune response to bone injuries, regulated by cell types in the monocyte-macrophage-preosteoclast lineage, could be controlled to enhance tissue regeneration through different signals such as magnesium ion signaling pathways.…”

“…This is largely owing to their high plasticity in response to environmental signals and their multiple roles in bone homeostasis. 25 Over the past few years, biomedical scientists and engineers have developed biodegradable metallic materials to improve the regenerative capability of biomaterials and stimulate the desirable immune system responses leading to the biomaterial's success. 23,[26][27][28] Such materials are developed to adjust their function in the body based on the biochemical and biomechanical properties of bone tissue.…”

The effects of a biodegradable Mg-based alloy on the function of VSMCs via immunoregulation of macrophages through Mg-induced responses

“…Numerous signaling pathways have been demonstrated in previous studies to be involved in M2 macrophage polarization, including the NF-κB, JAK-STAT, Akt-p18-mTOR-LXR, and PTEN/PI3k/AKT pathways, among others (41)(42)(43). Of note, the transient receptor potential cation channel subfamily M member 7 (TRPM7), which is a predominant Mg 2+ channel in mammalian cells, plays a pivotal role in regulating the functions of macrophages (44). Our previous studies reported that Mg from the degradation products of JDBM inhibited the inflammatory response of THP-1 cellderived macrophages through the TRPM7-PI3K-AKT1 signaling axis.…”