Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant
Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant
复制标题
DOI：
10.1016/j.actbio.2017.08.051
复制
发表时间：
2017-11-01
影响因子：
9.7
通讯作者：
Zhang, Zhaodong
中科院分区：
文献类型：
--
作者：
Zhang, Xiuzhi;Zu, Haiyue;Zhang, Zhaodong
镁基合金作为一种潜在的骨科植入物，可以自降解，避免二次手术取出，并能够促进骨修复，但其分子机制尚不清楚。本研究通过观察镁离子对hFOB 1.19人成骨细胞成骨、趋化和抗碱性应激的影响，模拟可生物降解镁基合金植入体的骨修复作用，并探讨了瞬时受体电位melastatin 7（TRPM 7）/磷酸肌醇3-激酶（PI 3 K）的调节作用通过敲低TRPM 7和拮抗PI 3 K活性，在镁离子诱导的骨修复过程中的信号通路。结果表明，镁离子通过TRPM 7/PI 3 K信号通路上调Runx 2和碱性磷酸酶（ALP）的表达，从而显着增强人成骨细胞的成骨活性。此外，MMP 2、MMP 9和血管内皮生长因子（VEGF）的表达水平通过TRPM 7/PI 3 K信号通路增加，该信号通路通过诱导细胞迁移将成骨细胞从低镁离子环境招募到高镁离子环境。虽然碱性环境具有抗菌作用，但碱性应激可引起细胞毒性并诱导细胞死亡。最后，我们发现镁离子可以激活PI 3 K磷酸化，促进细胞生长和存活，保护细胞免受镁基合金植入物降解引起的碱性应激诱导的细胞毒性。本研究不仅揭示了镁促进骨修复的分子机制，而且解释了镁离子在碱性环境下对成骨细胞的保护作用，为镁基合金植入材料在骨科固定和骨肉瘤治疗中的应用提供了理论依据和新的方向。生物可降解镁具有自身降解和促进骨修复的优点，但其调控骨修复的分子机制和有效浓度尚不清楚。本研究揭示了Mg离子及其有效浓度通过TRPM 7激活PI 3 K磷酸化，从而导致影响骨修复的三个过程，即成骨细胞募集、成骨和人成骨细胞对碱性应力的抵抗。因此，我们的研究结果提供了深入了解潜在的分子生物学基础，并指导操纵降解速率，如表面改性，骨科镁基植入物。(C)2017 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Mg-based alloys, as the potential orthopaedic implant, can self-degrade to avoid second operation for its remove, and enable to promote bone repair; however, the underlying molecular mechanisms remain unclear. In the present study, we examined the effect of Mg ions on osteogenesis, chemotaxis and anti-alkaline stress in hFOB1.19 human osteoblast cells to simulate bone-repairing effect of a biodegradable Mg-based alloy implant in vitro, and explored the regulatory role of the transient receptor potential melastatin 7 (TRPM7)/phosphoinositide 3-kinase (PI3K) signalling pathway in the process of Mg ion induced bone repair by knockdown of TRPM7 and antagonizing PI3K activity. Results indicate that Mg ions up-regulated the expression of Runx2 and alkaline phosphatase (ALP) through TRPM7/PI3K signalling pathway, which could significantly enhance the osteogenic activity of human osteoblasts. Furthermore, the expression levels of MMP2, MMP9 and vascular endothelial growth factor (VEGF) were increased by TRPM7/PI3K signalling pathway, which recruits osteoblasts from low- to high-Mg ion environments by inducing cell migration. Although an alkaline environment has antibacterial effects, alkaline stress can cause cytotoxicity and induce cell death. Finally, we found that Mg ions could activate PI3K phosphorylation to promote cell growth and survival, protecting cells against the alkaline-stress induced cytotoxicity caused by the degradation of Mg-based alloy implants. Our study not only revealed the molecular mechanism of Mg in promoting bone repair but also explained the protective effects of Mg ions on osteoblasts in an alkaline environment, which provides a theoretical basis and new directions for the application of Mg-based alloy implant material in orthopaedics fixations and osteosarcoma treatment.Statements of SignificanceAs a potential biomaterial for orthopaedic implant, biodegradable magnesium has several advantages including self-degradation and bone repair promotion; however, the underlying mechanisms and effective concentration by which molecular regulates the bone repair remain unclear. The present study revealed that Mg ion and its effective concentration for activating PI3K phosphorylation via TRPM7, which causes three processes affecting bone repair, namely, osteoblast recruitment, osteogenesis and resistance to alkaline stress in human osteoblast. Therefore, our results have provided insight into the underlying molecular biological basis, and guidance for manipulating degradation rate, such as surface modification, of orthopaedic Mg-based implants. (C) 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.