【摘要】 背景:随着高通量测序技术的发展,研究发现骨髓间充质干细胞、成骨细胞、脂肪细胞、破骨细胞、软骨细胞和骨肉瘤细胞等均可检测到m~6A修饰的存在,m~6A修饰可通过调控细胞RNA水平的甲基化,影响相关基因的mRNA和(或)非编码RNA的翻译等过程,从而激活细胞信号转导通路,影响细胞的增殖、分化、迁移、侵袭、凋亡及DNA损伤修复等,进而调控骨骼发育、关节退变、骨折愈合及骨肿瘤的发生、发展等生理病理过程。目的:总结近年来m~6A修饰在骨质疏松症、骨关节炎等骨科疾病中的最新研究成果和作用机制,为开发骨科相关疾病的新型治疗策略提供启发。方法:以中文关键词"N6-甲基腺嘌呤,骨质疏松症,骨关节炎,骨科疾病"检索CNKI数据库,以英文关键词"m~6A,osteoporosis,osteoarthritis,orthopedic disease"检索PubMed数据库,全网检索自建库至2020年6月有关m~6A修饰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61篇文献进行综述。结果与结论:(1)在骨质疏松症进展过程中,METTL3/m~6A介导的RNA甲基化以及FTO/m~6A介导的RNA去甲基化动态调控相关基因的表达,进一步影响相关信号通路的激活,影响骨髓间充质干细胞的成骨及成脂分化;(2)METTL3/m~6A通过调节软骨细胞中的核因子κB信号传导和细胞外基质合成,在骨关节炎进展中"扮演"了重要的角色;(3)METTL3/m~6A通过靶向调控成骨细胞相关的miR-7212-5p来抑制骨折愈合过程中的成骨机制;(4)METTL3通过调节淋巴增强因子1的m~6A水平从而激活Wnt/β-catenin信号以及通过调节ATAD2基因的m~6A甲基化来加速骨肉瘤的恶化;(5)在骨质疏松症、骨关节炎等骨科疾病中,m~6A修饰均参与了多系统疾病的进程,m~6A修饰的深入研究为进一步了解骨科相关疾病的发病机制提供了理论依据,并提供了基于表观遗传学基础的骨科疾病治疗思路以及参考依据。更多还原

【Abstract】 BACKGROUND: With the development of high-throughput sequencing technology, recent studies have found that the presence of N6-methyladenosine(m~6A) modification can be detected in bone marrow mesenchymal stem cells, osteoblasts, adipocytes, osteoclasts, chondrocytes, and osteosarcoma cells. It can affect the translation of mRNA and/or non-coding RNA of related genes by regulating the methylation of RNA in cells, which can activate cell signal transduction pathways, regulating cell proliferation, differentiation, migration, invasion, apoptosis and DNA damage repair. In turn, it can regulate the physiological and pathological processes such as bone development, joint degeneration, fracture healing, and the occurrence and development of bone tumors.OBJECTIVE: To summarize the latest research results and specific mechanisms of m~6A modification in osteoporosis, osteoarthritis and other orthopedic diseases in recent years, and to offer inspiration for the development of new treatment strategies for orthopedic diseases.METHODS: CNKI and PubMed were searched with the keywords of "N-6 methyladenine, osteoporosis, osteoarthritis, orthopedic diseases" for literatures regarding m~6A methylation modification in orthopedic diseases from their inception date to June 2020. According to the established inclusion and exclusion criteria, 61 articles were finally included for review.RESULTS AND CONCLUSION: During the accelerated development of osteoporosis, METTL3-mediated m~6A methylation and FTO-mediated m~6A demethylation affect the expression of related genes and further regulate the bone formation and adipogenic differentiation of bone marrow mesenchymal stem cells. METTL3-mediated m~6A methylation plays an important role in the development of osteoarthritis by regulating nuclear-κB signaling in chondrocytes and extracellular matrix synthesis. METTL3/m~6A inhibits the osteogenic mechanism in the fracture healing process by targeting the regulation of osteoblast-related miR-7212-5 p. METTL3 activates Wnt/β-catenin signals by regulating the m~6A level of lymphoid enhancer binding factor 1 and accelerates the progression of osteosarcoma by regulating the m~6A methylation of ATAD2 gene. Therefore, m~6A modification is involved in the pathological progresses of osteoporosis, osteoarthritis and other orthopedic diseases. The in-depth study of m~6A modification provides a theoretical basis for further understanding the pathogenesis of orthopedic related diseases, and provides therapeutic thoughts and references for orthopedic diseases based on epigenetics.更多还原