DNA甲基化调控衰老相关骨代谢失衡的机制与干预研究进展^*

Research Advances on Mechanisms and Interventions of DNA Methylation-Regulated Aging-Related Imbalance in Bone Metabolism

摘要

衰老可诱发骨质疏松等增龄性骨病。DNA甲基化是一类核心表观遗传调控方式，能够通过表观遗传层面的基因表达调控，参与衰老诱导骨代谢失衡的病理过程。它以S-腺苷甲硫氨酸作为甲基供体，随着年龄增长，呈现出基因组重复区域低甲基化以及骨代谢关键基因启动子CpG岛异常甲基化的特征。基于这些特征构建的“表观遗传时钟”能够高精度地预测个体的生理年龄。在骨代谢中，DNA甲基化通过靶向核心因子打破成骨-破骨平衡。此类异常由衰老相关炎症和氧化应激驱动，同时骨质流失会反馈加重表观遗传紊乱，形成恶性循环。靶向干预策略在应对骨代谢相关问题方面已展现出显著潜力。低剂量的DNA甲基转移酶抑制剂能够通过调节相关酶活性，有效改善骨代谢的紊乱状态；叶酸、钴胺素等营养素可通过优化一碳代谢途径，维持DNA甲基化的稳态平衡；而CRISPR/dCas技术凭借其高精度特性，在细胞和动物水平可实现对特定基因位点的精准调控，进而影响骨代谢过程。然而，当前现有的靶向干预策略仍面临诸多挑战，如脱靶效应、递送效率低下等问题，需要进一步深入探究相关作用机制，优化现有的干预手段，从而推动这些策略向骨质疏松的临床防治领域有效转化。

Abstract

Aging can induce age-related bone diseases such as osteoporosis. DNA methylation, a core epigenetic regulatory mechanism, participate in the pathological process of aging-induced bone metabolism imbalance by modulating gene expression at the epigenetic level. Using S-adenosylmethionine as a methyl donor, it exhibits characteristics of hypomethylation in genomic repetitive regions and abnormal methylation in CpG islands of promoters of key bone metabolism genes with advancing age. The "epigenetic clock" constructed based on these features can accurately predict an individual's biological age. In bone metabolism, DNA methylation disrupts the osteoblast-osteoclast balance by targeting key factors. Such abnormalities are driven by aging-related inflammation and oxidative stress, while bone loss feedback exacerbates epigenetic disorders, forming a vicious cycle. Targeted intervention strategies have demonstrated significant potential in addressing bone metabolism-related issues. Low-dose DNA methyltransferase inhibitors can improve bone metabolism; nutrients such as folate and cobalamin maintain methylation homeostasis by optimizing one-carbon metabolism pathways; while CRISPR/dCas technology enables precise regulation in the cellular and animal levels, thereby affecting bone metabolism. However, existing strategies still face challenges such as off-target effects and low delivery efficiency. Future research needs to deepen mechanistic studies, optimize intervention methods, and promote their translation into clinical prevention and treatment of osteoporosis.

关键词

DNA甲基化 / 骨质疏松症 / 衰老 / 成骨细胞 / 破骨细胞 / 表观遗传时钟

Key words

DNA methylation / Osteoporosis / Aging / Osteoblasts / Osteoclasts / Epigenetic clock

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基金资助

*国家自然科学基金(82502940)

深圳市医学研究专项资金(B2504003)

深圳市医学研究专项资金(A2503003)