甲基化在运动干预骨质疏松中的作用机制

背景：成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的动态平衡是维持机体骨组织稳定的基础，当两者代谢平衡紊乱时造成骨质流失和骨微细结构退化，导致骨质疏松发生。

目的：综述DNA甲基化在骨质疏松中的作用，探讨运动影响DNA甲基化及DNA甲基化调控骨代谢的机制。

方法：检索2002年1月至2020年4月CNKI和PubMed等外文生物医学、生物学、体育学期刊系统相关文献，中文关键词：DNA甲基化；骨质疏松；运动干预；机械应力；成骨分化；英文关键词：DNA methylation; Osteoporosis; Exercise intervention; Mechanical stress; Osteogenic differentiation。排除不符合纳入标准的文献，对入选的52条文献进行归纳总结。

结果与结论：①DNA甲基化是一种相对保守、稳定的表观修饰，其调控基因表达、沉默以及疾病发生；②研究表明，β-catenin、Runx2、骨桥蛋白等基因甲基化水平降低能促进其表达进而活化Wnt通路；而硬化蛋白、核因子κB受体活化因子配体等基因甲基化水平降低则会促进其表达，抑制Wnt通路以及降低OPG/RANKL比例，进而对成骨细胞和破骨细胞的增殖、分化及功能产生影响，从而调节骨形成和骨吸收动态平衡；③成骨细胞和破骨细胞为力学刺激敏感细胞，骨骼能将运动产生的机械负荷转变为生物学刺激作用于相关骨细胞分化及功能的发挥，进而调节骨代谢；④体外实验表明，不同形式的机械应力刺激可以改变骨桥蛋白、GNAS1等基因甲基化水平进而调节其表达，从而对骨形成产生积极作用；⑤骨组织是力学敏感组织，而DNA甲基化能通过调节多种因子来调节骨代谢。

BACKGROUND:The dynamic balance between bone formation mediated by osteoblasts and bone resorption mediated by osteoclasts is the basis for maintaining the stability of the body’s bone tissue. The metabolic imbalance between them can cause bone loss and fine structure degeneration of the bone cells, leading to osteoporosis.

OBJECTIVE:To review the role of DNA methylation in osteoporosis and to explore the mechanism of exercise affecting DNA methylation and DNA methylation regulating bone metabolism.

METHODS:A computer-based search of PubMed and CNKI databases was performed for relevant articles published from January 2002 to April 2020 with “DNA methylation; Osteoporosis; Exercise intervention; Mechanical stress; Osteogenic differentiation” as key words in English and Chinese, respectively. Initially,finally 52 eligible articles were included for result analysis.

RESULTS AND CONCLUSION:DNA methylation is a relatively conservative and stable apparent modification, which regulates gene expression, silencing and disease occurrence. Studies have shown that reduced methylation levels of genes such as β-catenin, Runx2, osteopontin (OPG) can promote their expression and activate Wnt Pathway, whereas the reduction of methylation level of Sclerosin, receptor activator of nuclear factor kappa B ligand (RANKL) and other genes can promote their expression, and inhibit Wnt pathway and reduce the ratio of OPG/RANKL, thereby affecting the proliferation, differentiation and function of osteoblasts and osteoclasts, and accordingly regulating dynamic equilibrium between bone formation and bone resorption. Osteoblasts and osteoclasts act as sensitive cells for mechanical stimulation. Bone can transform the mechanical load generated by exercise into biological stimulation that acts on the differentiation and function of related bone cells, thereby regulating bone metabolism. In vitro experiments have indicated that different forms of mechanical stress stimulations can change the methylation level of genes such as OPN and GNAS1 to regulate their expression, which has a positive effect on bone formation. Bone tissue is a mechanically sensitive tissue, and DNA methylation can regulate bone metabolism by regulating a variety of factors.

0 引言 Introduction

骨质疏松症是代谢性骨病，其分子网络机制研究一直是生命医学领域的研究热点[1]。成骨细胞介导的骨形成与破骨细胞介导的骨吸收之间的动态平衡是保持人体骨代谢稳定的基础，维持着机体骨骼的完整性。当此种平衡被打破，即骨吸收速率大于骨形成时，会出现骨质流失、骨密度下降、骨微结构被破坏进而导致骨脆性增加，最终产生骨质疏松症[2]。骨质疏松症的产生由多因素引起，遗传因素则是研究较多的一种。目前已经证实，存在一种更为复杂的遗传机制——表观遗传参与了骨代谢的调节过程。表观遗传是指在不改变 DNA序列前提下，使基因发生稳定表达且可遗传，并介导环境暴露对基因表达的影响。

DNA甲基化是研究较为广泛的一种表观遗传修饰机制，在基因印记、基因失活以及X染色体失活等方面起重要作用。研究证实，β-catenin、Frizzled等基因甲基化水平升高会抑制其表达，进而抑制Wnt信号通路激活并减弱骨形成，而活化核因子κB受体活化因子配体(receptor activator of nuclear factor kappa B ligand, RANKL)，Notch1、硬化蛋白 (sclerostin,SOST)等基因甲基化水平降低会促进其表达，在抑制骨形成的同时还能够增加骨吸收，进而导致骨代谢失调并导致骨质疏松症产生[3]。体外研究表明，诱导间充质干细胞成骨分化后，经染色质免疫共沉淀法检测到成骨特异性转录因子(runt related transcription factor2, Runx2)甲基化程度降低了50%以上，且Runx2 mRNA表达显著上升[4]，此外诸如锌指结构转录因子(osterix, Osx)、骨钙素、碱性磷酸酶、骨桥蛋白等与骨代谢密切相关的基因，其启动子区域甲基化改变也能调节基因表达，进而影响成骨细胞、破骨细胞活性和功能，与骨质疏松症密切相关。

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