中国组织工程研究

中国组织工程研究 ›› 2022, Vol. 26 ›› Issue (10): 1588-1596.doi: 10.12307/2022.208

• 生物材料综述 biomaterial review • 上一篇    下一篇

医用金属植入材料促进骨再生的分子机制

周宏博1，喻正文2，3，刘建国1，2，3   

  1. 1遵义医科大学口腔医学院，贵州省遵义市  563099；2贵州省普通高等学校口腔疾病研究特色重点实验室，贵州省遵义市  563006；3遵义市口腔疾病研究重点实验室，贵州省遵义市  563006
  • 收稿日期:2021-05-10 修回日期:2021-05-12 接受日期:2021-06-09 出版日期:2022-04-08 发布日期:2021-10-27
  • 通讯作者: 刘建国，博士，教授，主任医师，遵义医科大学口腔医学院，贵州省遵义市 563099
  • 作者简介:周宏博，男，1995年生，贵州省贵阳市人，汉族，遵义医科大学在读硕士
  • 基金资助:
    国家重点研发计划项目(2016YFC1102800)，项目参与人：刘建国，喻正文；贵州省医用生物材料研发人才基地(黔人领发[2018]3号)，项目负责人：刘建国；项目参与人：喻正文；遵义市医用生物材料研发创新人才基地(遵委[2019]69号)，项目负责人：刘建国；项目参与人：喻正文；遵义市科学技术局、遵义医科大学附属口腔医院联合科技研发资金项目(遵市科合社字(2018)240号)，项目负责人：喻正文；遵义医科大学学术新苗培养及创新探索专项项目(黔科合平台人才[2017]5733-057)，项目负责人：喻正文

Molecular mechanism of bone regeneration promoted by medical metal implant materials

Zhou Hongbo1, Yu Zhengwen2, 3, Liu Jianguo1, 2, 3   

  1. 1School of Stomatology, Zunyi Medical University, Zunyi 563099, Guizhou Province, China; 2Key Laboratory of Oral Disease Research, Guizhou Institution of Higher Education, Zunyi 563006, Guizhou Province, China; 3Key Laboratory of Oral Disease Research of Zunyi City, Zunyi 563006, Guizhou Province, China
  • Received:2021-05-10 Revised:2021-05-12 Accepted:2021-06-09 Online:2022-04-08 Published:2021-10-27
  • Contact: Liu Jianguo, MD, Professor, Chief physician, School of Stomatology, Zunyi Medical University, Zunyi 563099, Guizhou Province, China; Key Laboratory of Oral Disease Research, Guizhou Institution of Higher Education, Zunyi 563006, Guizhou Province, China; Key Laboratory of Oral Disease Research of Zunyi City, Zunyi 563006, Guizhou Province, China
  • About author:Zhou Hongbo, Master candidate, School of Stomatology, Zunyi Medical University, Zunyi 563099, Guizhou Province, China
  • Supported by:
    National Key R&D Program Project of the Ministry of Science and Technology, No. 2016YFC1102800 (to LJG and YZW); Talent Base of Medical Biomaterials Research of Guizhou Province, No. QRLF[2018]3) (to LJG and YZW); Innovative Talent Base of Medical Biomaterials Research and Development of Zunyi, No. ZW[2019]69) (to LJG and YZW);  Project of Zunyi Science and Technology Bureau, No. ZSKHSZ(2018)240 (to YZW); Academic Talents and Innovation Program of Zunyi Medical University, No. QKHPTRC[2017]5733-057) (to YZW)

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摘要： 文题释义：
医用金属植入材料：是一类由人工合成，具有良好的理化特性(如机械强度高、弹性模量与人体骨组织相近等)和生物学特性(如无生物毒性、可吸收降解、能诱导骨髓间充质干细胞成骨分化等)，植入体内能促进骨再生和骨结合的新型骨修复材料。
骨再生：在骨缺损处植入骨修复材料，通过调控骨发生的多种生物活性物质，主要包括细胞因子及其受体，局部形成适合细胞生长并利于恢复原有的骨形态及骨连续性的微环境和框架结构，调控并诱导细胞成骨分化，从而形成新骨修复骨缺损。

背景：研究不同医用金属植入材料诱导骨髓间充质干细胞成骨分化的分子机制，整理分析多条成骨信号通路的综合性基因调控网络，对于医用金属植入材料的设计、加工及临床应用具有重要意义。
目的：综述医用金属植入材料诱导骨髓间充质干细胞成骨分化的可能分子机制，以期为临床应用不同医用金属植入材料提供理论基础。
方法：检索PubMed、万方数据和中国知网数据库收录的相关文献。英文检索词为“osteogenic differentiation，signaling pathways，bone marrow mesenchymal stem cells，bone defect，bone repair materials，oral and maxillofacial restoration，implant，alloys”，中文检索词为“成骨分化、信号通路、骨髓间充质干细胞、骨缺损、骨修复材料、口腔颌面修复、种植体、合金”，最终纳入51篇文献进行归纳总结。

结果与结论：①骨髓间充质干细胞是一种多能成体干细胞，是组织工程重要的干细胞来源之一，Wnt/β-catenin通路、MAPK通路及骨形态发生蛋白/Smad通路等能调控诱导骨髓间充质干细胞成骨分化，医用金属植入材料植入人体后通过释放金属离子或刺激人体产生各种细胞因子，产生级联效应，促进骨髓间充质干细胞的成骨分化，从而促进骨再生进行骨缺损的修复。②文章总结分析了近年来不同医用金属植入材料及经过不同表面处理的骨修复材料促进骨髓间充质干细胞成骨分化所涉及的相关成骨信号通路(Wnt/β-catenin通路、MAPK通路、骨形态发生蛋白/Smad通路、整合素通路、磷脂酰肌醇3-激酶通路、骨保护素/RANKL/RANK通路)。③目前许多学者对医用金属材料体外及体内促进骨髓间充质干细胞成骨分化的研究主要以单一信号通路为主，而成骨分化相关的多条通路相互联系相互作用，构成了一个复杂的网络，目前的研究还未彻底地揭示成骨分化的具体机制。④从骨髓间充质干细胞成骨分化层面来看，不同新型医用金属植入材料调节诱导骨髓间充质干细胞成骨分化的可能分子机制和多条信号通路间的联系及作用，例如Wnt/β-catenin信号通路在被激活的同时，会刺激细胞产生MAPK通路及骨形态发生蛋白/Smad通路的启动因子，如表皮生长因子和骨形态发生蛋白等，此3条信号通路同时作用，进入细胞核后诱导成骨效应基因的转录，从而促进骨髓间充质干细胞的成骨分化，以此形成了多条成骨信号通路的综合性基因调控网络机制。

https://orcid.org/0000-0001-8397-2152 (周宏博)

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

关键词: 成骨分化, 信号通路, 骨髓间充质干细胞, 骨缺损, 骨修复材料, 口腔颌面修复, 种植体, 合金

Abstract: BACKGROUND:  It is of great significance for the design, processing and clinical application of medical metal implant materials to study the molecular mechanism of bone marrow mesenchymal stem cell osteogenic differentiation induced by different medical metal implant materials and to organize and analyze the comprehensive gene regulatory network of multiple osteogenic signaling pathways. 
OBJECTIVE: To review possible molecular mechanisms of bone marrow mesenchymal stem cell osteogenic differentiation induced by medical metal implant materials to provide theoretical basis for clinical application of different medical metal implant materials.
METHODS: The articles were searched in PubMed, CNKI, and Wanfang databases with the key words of “osteogenic differentiation, signaling pathways, bone marrow mesenchymal stem cells, bone defect, bone repair materials, oral and maxillofacial restoration, implant, alloys” in Chinese and English, separately. Finally, 51 articles met the criteria for review.
RESULTS AND CONCLUSION: (1) Bone marrow mesenchymal stem cells are a kind of pluripotent adult stem cells and an important source of stem cells for tissue engineering. The Wnt/β-catenin pathway, MAPK pathway and bone morphogenetic protein/Smad pathway can regulate and induce osteogenic differentiation of bone marrow mesenchymal stem cells. After implanted into human body, medical metal implant materials can release metal ions or stimulate the body to produce various cytokines and produce cascading effects to promote osteogenic differentiation of bone marrow mesenchymal stem cells, so as to promote bone regeneration and repair bone defects. (2) This review summarized and analyzed the osteogenic signaling pathways (Wnt/β-catenin pathway, MAPK pathway, bone morphogenetic protein/Smad pathway, integrin pathway, phosphatidylinositol 3-kinase pathway, osteoprotegerin/RANKL/RANK pathway) involved in the promotion of osteogenic differentiation of bone marrow mesenchymal stem cells by different medical metal implant materials and bone repair materials with different surface treatments. (3) At present, many researches on the promotion of bone marrow mesenchymal stem cell osteogenic differentiation by medical metal materials in vitro and in vivo are mainly focused on a single signaling pathway, while multiple pathways related to osteogenic differentiation interact with each other and constitute a complex network. Current studies have not been able to fully reveal the specific mechanism of osteogenic differentiation. (4) From the perspective of osteogenic differentiation of bone marrow mesenchymal stem cells, we discussed and summarized the possible molecular mechanisms of different new medical metal implants regulating the induction of osteogenic differentiation of bone marrow mesenchymal stem cells, as well as the relationships among multiple signaling pathways and their roles. For example, when the Wnt/β-catenin signaling pathway is activated, it will stimulate cells to produce MAPK pathway and bone morphogenetic protein/Smad pathway initiating factors, such as epidermal growth factor and bone morphogenetic protein. These three signaling pathways work simultaneously. After entering the nucleus, it induces the transcription of osteogenic effect genes, thereby promoting the osteogenic differentiation of bone marrow mesenchymal stem cells, and forming a comprehensive gene regulatory network mechanism of multiple osteogenic signal pathways.

Key words: osteogenic differentiation, signaling pathways, bone marrow mesenchymal stem cells, bone defect, bone repair materials, oral and maxillofacial restoration, implant, alloys