Department of Orthopedics, First Hospital of China Medical University, Shenyang, China.
Cell Death Dis. 2024 Nov 6;15(11):795. doi: 10.1038/s41419-024-07177-5.
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.
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意识的局限性，骨质疏松症治疗的目的更多是延缓进一步恶化，而不是从根本上纠正骨量。我们旨在阐明绝经后骨质疏松症的发病机制，并优化治疗方案。我们的实验基于先前的研究结果，即氧化应激介导雌激素缺乏后骨代谢失衡。通过针对能量代谢的代谢组学研究，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，这一机制通过使用来自人类数据库的机器学习数据得到了验证。我们使用黄嘌呤和黄嘌呤氧化酶处理成骨细胞，构建嘌呤代谢紊乱模型。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，自噬通量损伤参与嘌呤代谢诱导的成骨细胞氧化应激。此外，我们进行了血清代谢组学结合网络药理学研究，以确定二甲双胍治疗绝经后骨质疏松症的药理机制。从枢纽基因中筛选出 HPRT1 是潜在的靶标，FoxO1 信号通路是介导二甲双胍在成骨细胞中作用的关键途径。我们还揭示了 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 的上调促进嘌呤合成，并防止嘌呤分解代谢引起的 ROS 积累，从而逆转成骨细胞的氧化损伤。我们提出嘌呤代谢紊乱诱导的氧化应激是绝经后骨质疏松症发病机制的重要因素。应该通过后续的药物优化和开发研究来确认二甲双胍的治疗机制，以改善绝经后妇女的骨骼健康。
