二甲双胍通过调节 FoxO1 核胞质穿梭改善 HPRT1 靶向嘌呤代谢并修复 NR4A1 介导的自噬通量,从而治疗绝经后骨质疏松症。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Keda Yang, Xiaochuan Wang, Chi Zhang, Dian Liu, Lin Tao
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引用次数: 0

摘要

骨质疏松症是一种严重的退行性代谢性骨病,威胁着绝经后妇女的生命和健康。由于检测方法和预防策略认识的局限性,骨质疏松症治疗的目的更多的是延缓进一步恶化,而不是从根本上纠正骨量。我们的目的是阐明绝经后骨质疏松症的发病机制,优化治疗方案。我们的实验基于之前的发现,即氧化应激介导了雌激素缺乏后的骨代谢失衡。通过能量代谢靶向代谢组学研究,我们揭示了嘌呤代谢紊乱是诱导骨组织氧化损伤的主要机制,这一点通过使用来自人类数据库的机器学习数据得到了验证。利用黄嘌呤和黄嘌呤氧化酶处理成骨细胞,构建了嘌呤代谢紊乱模型。X/XO处理后,成骨细胞的活性和分化能力下降。转录组测序表明,自噬通路损伤参与了嘌呤代谢诱导的成骨细胞氧化应激。此外,我们还进行了血清代谢组学与网络药理学相结合的研究,以确定二甲双胍治疗绝经后骨质疏松症的药理机制。HPRT1是从中枢基因中筛选出的潜在靶点,而FoxO1信号传导是二甲双胍对成骨细胞产生作用的关键途径。我们还发现,SIRT3 介导的去乙酰化促进了 FoxO1 的核定位,从而增加了 HPRT1 的表达。HPRT1 的上调促进了嘌呤的合成代谢,阻止了嘌呤分解代谢引起的 ROS 的积累,从而逆转了成骨细胞的氧化损伤。我们认为,嘌呤代谢紊乱诱导的氧化应激是绝经后骨质疏松症的重要发病机制。二甲双胍的治疗机制应通过后续的药物优化和开发研究加以证实,以改善绝经后妇女的骨健康。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Metformin improves HPRT1-targeted purine metabolism and repairs NR4A1-mediated autophagic flux by modulating FoxO1 nucleocytoplasmic shuttling to treat postmenopausal osteoporosis.

Osteoporosis is a major degenerative metabolic bone disease that threatens the life and health of postmenopausal women. Owing to limitations in detection methods and prevention strategy awareness, the purpose of osteoporosis treatment is more to delay further deterioration rather than to fundamentally correct bone mass. We aimed to clarify the pathogenesis of postmenopausal osteoporosis and optimize treatment plans. Our experiments were based on previous findings that oxidative stress mediates bone metabolism imbalance after oestrogen deficiency. Through energy metabolism-targeted metabolomics, we revealed that purine metabolism disorder is the main mechanism involved in inducing oxidative damage in bone tissue, which was verified via the use of machine-learning data from human databases. Xanthine and xanthine oxidase were used to treat osteoblasts to construct a purine metabolism disorder model. The activity and differentiation ability of osteoblasts decreased after X/XO treatment. Transcriptomic sequencing indicated that autophagic flux damage was involved in purine metabolism-induced oxidative stress in osteoblasts. Additionally, we performed serum metabolomics combined with network pharmacology to determine the pharmacological mechanism of metformin in the treatment of postmenopausal osteoporosis. HPRT1 was the potential target filtered from the hub genes, and FoxO1 signalling was the key pathway mediating the effect of metformin in osteoblasts. We also revealed that SIRT3-mediated deacetylation promoted the nuclear localization of FoxO1 to increase the expression of HPRT1. HPRT1 upregulation promoted purine anabolism and prevented the accumulation of ROS caused by purine catabolism to reverse oxidative damage in osteoblasts. We propose that purine metabolism disorder-induced oxidative stress is important for the pathogenesis of postmenopausal osteoporosis. The therapeutic mechanism of metformin should be confirmed through subsequent drug optimization and development studies to improve bone health in postmenopausal women.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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