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中华老年病研究电子杂志 ›› 2024, Vol. 11 ›› Issue (04) : 38 -45. doi: 10.3760/cma.j.issn.2095-8757.2024.04.007

综述

类端粒沉默干扰体1 对骨骼相关疾病的调控作用
朱颖1, 李汉兵1, 高延盼2,()   
  1. 1. 310014 杭州,浙江工业大学药学院
    2. 310015 杭州,浙大城市学院医学院
  • 收稿日期:2024-09-27 出版日期:2024-11-28
  • 通信作者: 高延盼
  • 基金资助:
    浙江省自然科学基金资助项目(LTGD24H090003)浙江省自然科学基金重点项目(LZ24H310002)

Disrupter of telomeric silencing 1-like in bone-related diseases

Ying Zhu1, Hanbing Li1, Yanpan Gao2,()   

  1. 1. College of Pharmacy,Zhejiang University of Technology,Hangzhou 310014,China
    2. Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province,School of Medicine,Hangzhou City University,Hangzhou 310015,China
  • Received:2024-09-27 Published:2024-11-28
  • Corresponding author: Yanpan Gao
引用本文:

朱颖, 李汉兵, 高延盼. 类端粒沉默干扰体1 对骨骼相关疾病的调控作用[J/OL]. 中华老年病研究电子杂志, 2024, 11(04): 38-45.

Ying Zhu, Hanbing Li, Yanpan Gao. Disrupter of telomeric silencing 1-like in bone-related diseases[J/OL]. Chinese Journal of Geriatrics Research(Electronic Edition), 2024, 11(04): 38-45.

近年来,越来越多的研究表明,表观遗传调控因子在骨骼发育及骨质疏松等骨骼疾病的病理机制中扮演重要作用。其中,组蛋白甲基化水平的调控是热点之一。类端粒沉默干扰体1(DOT1L)是已知催化组蛋白H3K79 发生甲基化的唯一酶,其在骨代谢及相关疾病中的作用受到越来越多的关注。DOT1L 的表达异常往往引起一系列骨骼系统疾病,例如骨关节炎、骨质疏松症和骨骼发育障碍等,这表明DOT1L 在维持骨骼发育及功能稳态方面具有重要作用。此外,也有初步证据表明DOT1L 在骨肿瘤发生的潜在作用。从机制上来说,骨关节炎的发病与DOT1L 调节的Sirt1/Wnt 通路密切相关;骨质疏松的发病与DOT1L 对氧化环境调节和对miR-181 介导的KAT2B 降解调控密不可分。本文综述DOT1L 在骨发育进程及骨骼疾病中的作用,以期进一步了解骨骼相关疾病治疗的新靶点和新策略。

In recent years, more and more studies have shown that epigenetic regulatory factors play an important role in bone development and bone diseases.Among them, the regulation of histone methylation level is one of the hot topics.Disrupter of telomeric silencing 1-like (DOT1L) is the only enzyme known to catalyze the methylation of histone H3K79.Recently, the role of DOT1L in bone metabolism and related diseases has received much attention.The abnormal expression of DOT1L often causes a series of bone diseases, such as osteoarthritis, osteoporosis and skeletal developmental disorders,which indicates that DOT1L plays an important role in maintaining bone development and functional homeostasis.In addition, there is also preliminary evidence for a potential role of DOT1L in bone tumorigenesis.In terms of mechanism, the pathogenesis of osteoarthritis is closely related to DOT1Lregulated Sirt1/Wnt pathway; the pathogenesis of osteoporosis is closely related to the regulation of oxidative environment and mir181-mediated KAT2B degradation by DOT1L.This article reviews the role of DOT1L in bone development and bone diseases, which provides a new target and treatment strategy for the treatment of bone diseases.

图1 DOT1L 在保护骨关节炎中的作用机制 注:DOT1L 指类端粒沉默干扰体1;SIRT1 指沉默信息调节因子1;LEF1 指淋巴增强结合因子1;TCF1 指T 细胞因子1;HIF1A 指缺氧诱导因子1α;PPARGC1A 指过氧化物酶体增殖物激活受体γ 辅激活因子1α;GCN5 又名KAT2A,赖氨酸乙酰转移酶2A
图2 敲低DOT1L 或抑制其酶活性增加破骨细胞活性的作用机制 注:敲低DOT1L 或抑制DOT1L 酶活性可通过路径①、②、③增加破骨细胞活性。DOT1L 指类端粒沉默干扰体1;CD9 指白细胞分化抗原9;MMP9 指基质金属蛋白酶9:miR-181 指微小RNA-181;KAT2B:指赖氨酸乙酰转移酶2B;SRSF1 指富丝氨酸和精氨酸的剪接因子1;NFATc1 指活化T 细胞核因子1;c-Fos 为AP-1 转录因子基因;Ctsk 指组织蛋白酶K;Acp5 指酒石酸酸性磷酸酶5
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