Research progress on osteoclast regulation by biodegradable magnesium and its mechanism

Abstract

Continuous advancements in medical technology and biomaterials have underscored the significant advantages of biodegradable implant materials for bone repair and remodelling over traditional inert metallic implants. Notably, biodegradable magnesium-based materials have gained much attention because of their optimal corrosion rates. Importantly, extensive clinical experience has resulted in the use of biodegradable magnesium-based orthopaedic implants. Both preclinical and clinical studies have consistently demonstrated that Mg has an excellent ability to promote bone tissue formation, a process that is closely associated with the release of Mg²⁺ and other degradation byproducts. Bone metabolism depends on a dynamic balance of bone formation and bone resorption. Mg²⁺ has been shown to increase osteoblast (OB) activity while suppressing osteoclast (OC) formation, thus playing a crucial role in bone remodelling and regeneration. In terms of osteolysis inhibition, Mg²⁺ plays a multifaceted role. First, Mg²⁺ inhibits OC formation by modulating the activity of mature OCs, their migratory behaviour and the activity of precursor cells. Second, Mg²⁺ influences OC production by regulating the expression of osteoprotegerin (OPG), receptor activator of nuclear factor kappa-Β ligand (RANKL) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Additionally, Mg²⁺ impacts bone resorption by altering the immune microenvironment and the levels of hormones and peptides within the body. Furthermore, the alkaline environment generated around the biodegradable magnesium implant and its degradation products (e.g. H₂) also significantly inhibit OC formation. Recent research on magnesium-based implants has focused predominantly on their osteogenic properties, with few systematic reviews addressing the mechanisms through which biodegradable magnesium alloys suppress osteoclastic activity. This article summarizes the latest clinical research progress concerning biodegradable magnesium implant materials and their significant regulatory effects and discusses recent advances in the understanding of the regulatory mechanisms of action Mg-based biomaterials on OCs, with the aim of providing a more theoretical basis for the clinical application of biodegradable magnesium-based implants.

Keywords: biodegradable magnesium alloys; bone remodelling; osteoblast; osteoclast; regulatory mechanisms.

Graphical abstract

Figure 1.

Mechanism by which magnesium promotes osteogenesis. (A) Schematic showing how the TRPM7/PI3K signalling pathway mediated by magnesium ions promotes osteogenesis and resistance to alkaline stress-induced cytotoxicity in human osteoblasts. Adapted and reproduced from Ref. [1] Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd All rights reserved. (B) Schematics showing the release of Mg²⁺ through Mg²⁺ transporters or channels (i.e. MAGT 1 and TRPM 7) and the promotion of CGRP-vesicle accumulation and exocytosis. The CGRP released by DRGs in turn activates the CGRP receptor (composed of CALCRL and RAMP 1) in PDLSCs, which triggers the phosphorylation of CREB 1 via cAMP and promotes the expression of genes that contribute to osteogenic differentiation. Adapted and reproduced from Ref. [2]. (C) Schematic showing the mechanism by which Mg²⁺ regulates macrophages and mesenchymal stem cells during bone healing. Figure is licenced under CC by-NC-ND 4.0 [3]. Copyright © 2021, the Author(s).

Figure 2.

Preparation process of magnesium-based biomaterials and their mechanism of action on osteoclasts. (A) The continuous release of Mg²⁺ inhibits osteoclast formation by regulating AKT phosphorylation through intra-articular injection of MgO&SA@PlGA. Figure is licenced under CC by-NC-ND 4.0 [29]. Copyright © 2024, the American Association for the Advancement of Science. (B) For the preparation process of a composite scaffold composed of piezoelectric WH (PWH) and poly(ε-caprolactone) (PCL). (C) Schematic diagram showing the PWH scaffold prepared from WH NPs using 3D printing and PCL/PWH composite filaments. It inhibits osteoclast differentiation through the continuous and stable release of Mg²⁺. It also promotes the formation of nerves and blood vessels. Figure is licenced under CC by-NC-ND 4.0 [34]. Copyright © 2022 the Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. (D) Collagen is assembled on the surface of an electrospun fibre membrane coated with MgO nanoparticles to form a magnesium-based artificial bandage structure. (E) A magnesium-based artificial bandage attached to the surface of a mouse femur promotes the differentiation of macrophages into the M2 phenotype by releasing Mg²⁺. Adapted and reproduced from Ref. [30] Copyright © 2022, American Chemical Society.

Figure 3.

(A) The alkaline environment generated by the degradation of magnesium-based materials has been found to partially inhibit the expression of factors associated with osteoclast absorption and the bone resorption activity of osteoclasts. (B) Schematic diagram showing osteoclasts capable of α2, αV, β1, β3 and β5. By increasing the expression of αV and β3, TNF-α can enhance the adhesion ability of osteoclasts. Mg²⁺ inhibits bone resorption by inhibiting TNF-α.

Figure 4.

Biodegradable magnesium-based implants inhibit osteoclast differentiation through multiple mechanisms. First, magnesium ions (Mg²⁺) promote the binding of OPG secreted by osteoblasts to RANKL during material degradation, competitively inhibiting the binding of RANK to RANKL. Second, the alkaline environment generated by the degradation of magnesium-based materials further inhibits the binding of RANK and RANKL and reduces the formation of osteoclasts. In addition, magnesium ions inhibit the activation of inflammatory factors (such as TNF-α), affect the expression of downstream signalling molecules (such as JNK, ERK, NF-κB and AP-1), reduce the expression of NFATc1 and inhibit osteoclast differentiation. Finally, magnesium ions (Mg²⁺) significantly inhibit calcium ion (Ca²⁺) influx, thereby inhibiting osteoclast differentiation by inactivating the nuclear factor κB (NF-κB) and activated T nuclear factor c1 (NFATc1) signalling pathways.

Figure 5.

The effect of an alkaline microenvironment resulting from the degradation of magnesium-based materials on osteoclasts. (A, B) Inhibitory effect on osteoclasts, as determined by TRAP staining. (C, D) At different pH values (7.4, 7.7 and 8.0), the Mg (1 mm) group is more abundant than the NAOH group. (E, F) Inhibitory effect on osteocytes at the same pH (7.4). Adapted and reproduced from Ref. [33]. Copyright © 2014 Elsevier Ltd All rights reserved. (G) Changes in the Mg²⁺ concentration released during the degradation of NT-Mg1 and NT-Mg3 with time. (H) Relationships between the alkaline environments generated during the degradation of NT, NT-Mg1 and NT-Mg3 with time. (I, J) Inhibitory effects on osteoclasts, as determined by TRAP staining. Adapted and reproduced from Ref. [28]. Copyright © 2019, American Chemical Society.

Figure 6.

The effect of Mg²⁺ on genes related to osteoclast formation. (A) Western blot analysis confirmed that MLL inhibited the phosphorylation and degradation of the RANKL-induced NF-kB inhibitory subunit (IkBa). (B) The effect of MLL on NF-κB activity was assessed using luciferase gene assays. (C) The blockade of p65 nuclear transport. (D) The effect of MLL on NFATc1 activity was assessed using luciferase gene assays. (E, F) MLL inhibited the expression of genes related to osteoclast generation at both the mRNA and protein levels. Adapted and reproduced from Ref. [33] Copyright © 2014 Elsevier Ltd All rights reserved. (G, H) Representative Western blots and the corresponding quantification showing the concentration-dependent effect of Mg²⁺. Figure is licenced under CC by-NC-ND 4.0 [3]. Copyright © 2021, the Author(s). (I, J) The influence of FTY720 or TRPM7 siRNA on the activation ofNF-κB signalling in THP1-derived macrophages. Figure is licenced under CC by-NC-ND 4.0 [3]. Copyright © 2021, the Author(s).

Figure 7.

The mechanism by which Mg²⁺ affects immunomodulation in vivo. (A) Compared with the other groups, the bone cement (MMSC) group containing magnesium microspheres presented higher CD206 and CCR7 expression. (B) Compared with the other groups, the MMSC group containing magnesium microspheres presented higher IL-10 expression and lower IL-6 expression. (C) The IL-10 concentration in the MMSC group was significantly greater than that in the B and MPC groups. Figure is licenced under CC by-NC-ND 4.0 [36]. Copyright © 2021 the Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. (D) Quantitative and qualitative analyses of immunofluorescence and HE staining between the PLGA/MgO-alendronate sodium group and other groups. (E) Results of the quantitative and qualitative analyses of iNOS (green, M1 phenotype) and Arg 1 (red, M2 phenotype) expression via immunofluorescence and HE staining in 4D postoperative skin tissue sections. Figure is licenced under CC by-NC-ND 4.0 [35]. Copyright © 2021 the Authors. Production and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.

Figure 8.

(A) PTH reduces the binding of RANKL to OPG by inhibiting the secretion of OPG from osteoblasts and acting on the cAMP-PKA-CREB and PP1/PP2A-CRTC3 pathways. Therefore, it regulates osteoclast generation. Mg²⁺ indirectly promotes the formation of osteoclasts by inhibiting PTH production. (B) PGE₂ promotes osteoclast generation through the cAMP/PKA signalling pathway. Mg²⁺ inhibits osteoclast generation by inhibiting PGE₂ production.

Figure 9.

(A) Schematic of the mechanism by which degradable Mg@PEG-PLGA hydrogel effectively promotes osteoplastic bone regeneration. Figure is licenced under CC by-NC-ND 4.0. [121]. (B) The Mg-@PEg-PLga hydrogel exerts significant anti-inflammatory effects by modulating macrophage polarization and inhibiting the IκBα/NF-κB pathway. Figure is licenced under CC by-NC-ND 4.0 [121]. (C) Hydrogen inhibits NF-κB by clearing the ROS BB and MAPK signalling pathways and then downregulates the expression of inflammatory factors (TNF-α, IL-6, MMP-13, etc). Adapted and reproduced from Ref. [120]. Copyright © 2024 Wiley‐VCH GmbH.