N6-甲基腺苷甲基转移酶样3调控骨代谢及其相关疾病的作用

Roles of N6-methyladenosine methyltransferase-like 3 in regulating bone metabolism and related diseases

背景:作为最普遍RNA修饰类型之一,N6-甲基腺苷甲基化已成为通过干扰RNA剪接、翻译、核输出和衰变来调节各种疾病的亮点。然而,甲基转移酶样3介导的N6-甲基腺苷甲基化表观遗传学修饰对骨代谢的研究尚未得到总结。目的:总结骨代谢中N6-甲基腺苷核心的甲基转移酶样3的潜在分子机制及其调节成骨分化、破骨分化、软骨凋亡、细胞外基质退变、骨代谢相关疾病等方面的最新进展和未来展望,为骨代谢相关疾病的病理机制研究提供新的见解,并随之对疾病的早期诊断、临床治疗、预后判断等提供理论参考。方法:以中文关键词“N6-甲基腺嘌呤,甲基转移酶样3,成骨细胞,破骨细胞,软骨细胞,间充质干细胞,骨代谢,骨质疏松症,骨关节炎,骨科疾病,治疗”等检索CNKI数据库,以英文关键词“m^(6)A,METTL3,osteoblast,osteoclasts,chondrocyte,mesenchymalstem cells,bone metabolism,osteoporosis,osteoarthritis,orthopedic disease,therapy”等检索PubMed数据库,全网检索自建库至2022年3月有关甲基转移酶样3/N6-甲基腺苷介导的RNA甲基化在骨科疾病中研究成果的文献,严格按照纳入和排除标准筛选,最后选定35篇文献进行综述。结果与结论:(1)甲基转移酶样3在成骨方面的作用存在一定争议,还有待进一步的深入研究;(2)甲基转移酶样3/N6-甲基腺苷介导的RNA甲基化能够通过多种机制调控骨髓间充质干细胞的成骨及成脂分化,然而其具体机制尚不明确;(3)甲基转移酶样3调控破骨细胞分化功能对于维持骨稳态以及保持骨骼完整性至关重要;(4)甲基转移酶样3在骨代谢相关疾病的发生发展中发挥着重要作用,使甲基转移酶样3过表达可能会成为治疗人类骨代谢相关疾病如骨质疏松症的一种新的替代疗法。

BACKGROUND:As one of the most prevalent types of RNA modification,N6-methyladenosine(m~6A)methylation has emerged as a bright spot for regulating various diseases by interfering with RNA splicing,translation,nuclear export and decay.However,studies of methyltransferase-like 3(METTL3)-mediated epigenetic modification of m~6A methylation on bone metabolism have not been summarized.OBJECTIVE:To summarize the potential molecular mechanism of m~6A core methyltransferase METTL3 in bone metabolism and its latest progress and future prospects in regulating osteogenic differentiation,osteoclastic differentiation,cartilage apoptosis,extracellular matrix degene ration,and bone metabolismrelated diseases,there by offering new insights into the study of the pathological mechanism of bone metabolism-related diseases and then providing a theoretical reference for the early diagnosis,clinical treatment,and prognosis of the diseases.METHODS:The CNKI database was searched with the Chinese keywords of"N6-methyladenin e,methyltransfe rase-like 3,osteoblasts,osteoclasts,chondrocytes,mesenchymal stem cells,bone metabolis m,osteoporosis,osteoarthritis,orthopedic diseases,treatment."The PubMed database was searched with the English keywords of"m^(6)A,METTL3,Osteoblast,osteoclasts,chondrocyte,mesenchymal stem cells,bone metabolis m,osteoporosis,osteoarthritis,orthopedic disease,therapy."Literature on METTL3/m6A-mediated RNA methylation in orthopedic diseases was retrieved from database establishment to March 2022.As per the inclusion and exclusion crite ria,35 articles were finally selected for review.RESULTS AND CONCLUSION:The role of METTL3 in osteogenesis is controve rsial and remains to be further studied in depth.METTL3/m6A-mediated RNA methylation can regulate osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells through a variety of mechanisms,but the specific mechanism is not clear.METT3 regulation of osteoclast differentiation function is essential for maintaining bone homeostasis as well as maintaining bone integrity.METTL3 plays an important role in the development of bone metabolism-related diseases;therefore,METTL3 ove rexpression may become a new alternative therapy for the treatment of human bone metabolism-related diseases such as osteoporosis.