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| 骨碎补总黄酮介导Nrf2信号通路调控BMSCs铁死亡和成骨分化的机制 |
| Mechanism of Nrf2 signaling pathway mediated by total flavonoids of bone fragment tonics in regulating iron death and osteogenic differentiation of BMSCs |
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| DOI：10.3969/j.issn.1006-7108.2025.06.001 |
| 中文关键词: 骨碎补总黄酮 Nrf2信号通路 铁死亡 成骨分化 骨质疏松症 |
| 英文关键词:total flavonoids of osteoblast Nrf2 signaling pathway iron death osteogenic differentiation osteoporosis |
| 基金项目:国家自然科学基金项目-基于氧化应激-自噬探讨酒精性骨重构的机制及中药干预（81904222）；哈尔滨市科学技术局-骨碎补中柚皮苷对酒精性骨重构的干预作用机制的研究（2023ZCZJNS064）；黑龙江省中医药学会青年人才托举工程项目-从成骨分化角度解析骨碎补中柚皮苷对骨质疏松的干预作用（2022-QNRC1-12） |
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| 中文摘要: |
| 目的 旨在评估骨碎补总黄酮（RD）通过Nrf2信号通路对骨髓间充质干细胞（BMSCs）铁死亡和成骨分化的影响，并探讨其在治疗糖尿病相关骨质疏松症中的潜在作用。鉴于全球人口老龄化和2型糖尿病的高发态势，糖尿病相关骨质疏松症已成为一个日益严峻的公共卫生问题。骨质疏松症不仅影响患者的生活质量，也给医疗保健系统带来沉重负担。因此，寻找有效的干预措施具有重要意义。骨碎补作为传统中药，其总黄酮成分因其潜在的治疗骨质疏松症的天然产物特性，受到了研究者的关注。方法 采用高糖高脂饮食联合链脲佐菌素腹腔注射诱导的骨质疏松症动物模型，通过HE染色和micro-CT分析评估骨微结构变化。体外实验，采用CCK-8检测BMSCs细胞活力，FerroOrange染色和DHE检测法评估细胞内铁离子和活性氧水平，Western blot检测铁死亡相关蛋白ACSL4、GPX4及成骨分化标志蛋白COL1A1、RUNX2、OCN的表达，茜素红染色检测钙化结节，并通过慢病毒转染抑制Nrf2基因表达以探究RD的作用机制。结果 RD显著改善了动物模型的骨微结构参数，如增加骨体积比例、小梁厚度和小梁数量，减少小梁间隙。体外实验显示，RD能够增加BMSCs的细胞活力，降低细胞内铁离子和ROS水平，抑制BMSCs的铁死亡并促进其成骨分化。Western blot及茜素红染色结果显示，RD通过激活Nrf2信号通路，增强了抗氧化酶GPX4的表达，促进成骨分化，而慢病毒转染抑制Nrf2表达后，RD的保护作用减弱。结论 骨碎补总黄酮通过激活Nrf2信号通路，增强GPX4的表达，有效抑制BMSCs的铁死亡，促进其成骨分化，显示出对骨质疏松症的治疗潜力。 |
| 英文摘要: |
| Objective To evaluate the effects of total flavonoids from Drynaria fortunei (RD) on ferroptosis and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through the Nrf2 signaling pathway, and to explore its potential role in the treatment of diabetes-associated osteoporosis. In view of the global aging population and the high incidence of type 2 diabetes, diabetes related osteoporosis has become an increasingly serious public health problem. Osteoporosis not only affects the quality of life of patients but also places a heavy burden on the healthcare system. Therefore, finding effective intervention measures is of great significance. As a traditional Chinese medicine, Drynaria fortunei, and its total flavonoids have attracted the attention of researchers for their potential natural product characteristics in treating osteoporosis. Methods The animal model of osteoporosis induced by high-sugar and high-fat diet combined with streptozotocin injection was evaluated by HE staining and micro-CT analysis. In vitro, CCK-8 was used to detect the cell viability of BMSCs, FerroOrange staining and DHE detection were used to evaluate the levels of iron ions and reactive oxygen species in the cells, and Western blot was used to detect the expressions of iron death related proteins ACSL4 and GPX4 and the markers of osteogenic differentiation COL1A1, RUNX2 and OCN. Alizarin red staining was used to detect calcified nodules, and lentivirus transfection inhibited Nrf2 gene expression to explore the mechanism of RD. Results RD significantly improved bone microstructure parameters in animal models, such as increasing bone volume ratio, trabecular thickness and trabecular number, and reducing trabecular space. In vitro experiments have shown that RD can increase the cell viability of BMSCs, reduce intracellular iron ion and ROS levels, inhibit iron death of BMSCs and promote osteogenic differentiation. Western blot and alizarine red staining showed that RD enhanced the expression of antioxidant enzyme GPX4 and promoted osteogenic differentiation by activating Nrf2 signaling pathway, while the protective effect of RD was weakened after lentiviral transfection inhibited Nrf2 expression. Conclusion By activating Nrf2 signaling pathway, total flavonoids of osteoblast can enhance GPX4 expression, effectively inhibit iron death of BMSCs, and promote osteogenic differentiation of BMSCS, which shows therapeutic potential for osteoporosis. |
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