Quercetin attenuates the symptoms of osteoarthritis in vitro and in vivo by suppressing ferroptosis via activation of AMPK/Nrf2/Gpx4 signaling.

IF 3.4 3区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular medicine reports Pub Date : 2025-03-01 Epub Date: 2024-12-24 DOI:10.3892/mmr.2024.13425
Shiyu Dong, Xiaoliang Li, Genrong Xu, Liming Chen, Jiyang Zhao
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Abstract

Osteoarthritis (OA) is a common joint disorder involving the cartilage and other joint tissues. Quercetin (QCT) serves a protective role in the development of OA. However, to the best of our knowledge, the regulatory mechanisms of QCT in the progression of OA have not yet been fully elucidated. In order to mimic a model of OA in vitro, IL‑1β was used to stimulate chondrocytes. Furthermore, an in vivo animal model of OA was induced by anterior cruciate ligament transection (ACLT). 5‑Ethynyl‑2'‑deoxyuridine assays, TUNEL assays, ELISAs, western blotting and immunohistochemical assays were conducted to assess the chondroprotective properties of QCT in the development of OA. The results revealed that 100 µM QCT significantly promoted the proliferation, reduced the apoptosis and inflammation, and inhibited the extracellular matrix (ECM) degradation in IL‑1β‑stimulated chondrocytes. Additionally, QCT attenuated the IL‑1β‑induced ferroptosis of chondrocytes, as demonstrated by the reduced lipid reactive oxygen species and Fe2+ levels. Conversely, the inhibitory effects of QCT on the apoptosis and inflammatory responses were reversed by the activation of ferroptosis by erastin in IL‑1β‑stimulated chondrocytes. Furthermore, QCT significantly elevated the level of phosphorylated (p‑)5' AMP‑activated protein kinase (AMPK) and the levels of two negative regulators of ferroptosis [nuclear factor erythroid 2‑related factor 2 (Nrf2) and glutathione peroxidase 4 (Gpx4)] in IL‑1β‑stimulated chondrocytes. The AMPK inhibitor compound C notably reversed the promoting effects of QCT on phosphorylated‑AMPK, Nrf2 and Gpx4 expression in IL‑1β‑stimulated chondrocytes. Additionally, QCT markedly ameliorated the destruction and degradation of articular cartilage, and elevated the p‑AMPK, Nrf2 and Gpx4 levels in the mouse model of ACLT‑induced OA. Overall, the present study demonstrated that QCT inhibited the development of OA by suppressing ferroptosis via the activation of the AMPK/Nrf2/Gpx4 signaling pathway. These findings provide novel insights into the regulatory mechanisms of QCT for the treatment of patients with OA.

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槲皮素通过激活AMPK/Nrf2/Gpx4信号抑制铁下垂,在体外和体内减轻骨关节炎的症状。
骨关节炎(OA)是一种常见的关节疾病,涉及软骨和其他关节组织。槲皮素(QCT)在OA的发生发展中起保护作用。然而,据我们所知,QCT在OA进展中的调控机制尚未完全阐明。为了在体外模拟OA模型,使用IL - 1β刺激软骨细胞。采用前交叉韧带横断法(ACLT)建立骨关节炎动物模型。采用5‑乙炔‑2‑脱氧尿苷法、TUNEL法、elisa法、western blotting法和免疫组化法评估QCT在骨性关节炎发展中的软骨保护作用。结果显示,100µM QCT能显著促进IL - 1β刺激的软骨细胞增殖,减少细胞凋亡和炎症,抑制细胞外基质(ECM)降解。此外,通过降低脂质活性氧和Fe2+水平,QCT可以减弱IL - 1β诱导的软骨细胞铁下垂。相反,QCT对凋亡和炎症反应的抑制作用被IL - 1β刺激的软骨细胞中erastin激活的铁凋亡逆转。此外,QCT显著提高了IL - 1β刺激的软骨细胞中磷酸化(p -)5' AMP激活的蛋白激酶(AMPK)水平和两种铁凋亡负调节因子[核因子-红细胞2相关因子2 (Nrf2)和谷胱甘肽过氧化物酶4 (Gpx4)]的水平。AMPK抑制剂化合物C显著逆转了QCT对IL - 1β刺激的软骨细胞中磷酸化AMPK、Nrf2和Gpx4表达的促进作用。此外,在ACLT诱导的OA小鼠模型中,QCT显著改善了关节软骨的破坏和退化,并提高了p - AMPK、Nrf2和Gpx4的水平。总体而言,本研究表明,QCT通过激活AMPK/Nrf2/Gpx4信号通路抑制铁下垂,从而抑制OA的发展。这些发现为QCT治疗OA患者的调控机制提供了新的见解。
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来源期刊
Molecular medicine reports
Molecular medicine reports 医学-病理学
CiteScore
7.60
自引率
0.00%
发文量
321
审稿时长
1.5 months
期刊介绍: Molecular Medicine Reports is a monthly, peer-reviewed journal available in print and online, that includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.
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