Melatonin Suppresses Ferroptosis Induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis.
Melatonin Suppresses Ferroptosis Induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis.
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DOI：
10.1155/2020/9067610
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发表时间：
2020
影响因子：
--
通讯作者：
Yang M
中科院分区：
文献类型：
--
作者：
Ma H;Wang X;Zhang W;Li H;Zhao W;Sun J;Yang M
铁凋亡是最近发现的一种铁和活性氧依赖的细胞死亡形式。本研究旨在明确2型糖尿病骨质疏松症发病机制中是否存在铁凋亡，并证实褪黑素可通过激活Nrf2/HO-1信号通路抑制成骨细胞的铁凋亡，从而改善骨组织的微观结构。我们用不同浓度的褪黑激素（1、10或100 μ M）处理MC3T3-E1细胞，并将其暴露于体外高糖（25.5 mM）48 h。我们的数据显示，高糖可诱导成骨细胞的细胞毒性和脂质过氧化物的积累，成骨细胞线粒体呈现与erastin处理组相同的形态学变化，并且亚铁代谢相关蛋白谷胱甘肽过氧化物酶4（GPX 4）和胱氨酸-谷氨酸反向转运体（SLC 7A11）的表达下调，但这些作用可被铁凋亡抑制剂ferrastatin-1和铁螯合剂去铁胺（DFO）逆转。Western blot和实时荧光定量PCR检测细胞核因子红细胞2相关因子2（Nrf2）和血红素氧合酶-1（HO-1）的表达水平，茜素红S染色检测成骨能力，骨保护素（OPG）、骨钙素（OCa）和碱性磷酸酶（ALP）的表达水平;结果显示，1、10或100 μ M褪黑素组成骨细胞中这些蛋白的表达水平显著高于高糖组，但使用Nrf2-SiRNA干扰后，褪黑激素的治疗作用被显著抑制。我们还在用两种浓度的褪黑激素（10、50 mg/kg）处理的糖尿病大鼠模型中进行了体内实验。采用动态骨组织形态计量学和micro-CT观察大鼠骨显微结构，免疫组化检测GPX 4和Nrf2的表达。在这里，我们首次报道了2型糖尿病骨质疏松症中高糖通过增加ROS/脂质过氧化/谷胱甘肽耗竭诱导铁凋亡。更重要的是，褪黑素通过激活体内和体外的Nrf2/HO-1通路，显著降低了MC3T3-E1的铁凋亡水平，提高了MC3T3-E1的成骨能力。
Ferroptosis is recently identified, an iron- and reactive oxygen species- (ROS-) dependent form of regulated cell death. This study was designed to determine the existence of ferroptosis in the pathogenesis of type 2 diabetic osteoporosis and confirm that melatonin can inhibit the ferroptosis of osteoblasts through activating Nrf2/HO-1 signaling pathway to improve bone microstructure in vivo and in vitro. We treated MC3T3-E1 cells with different concentrations of melatonin (1, 10, or 100 μM) and exposed them to high glucose (25.5 mM) for 48 h in vitro. Our data showed that high glucose can induce osteoblast cytotoxicity and the accumulation of lipid peroxide, the mitochondria of osteoblast show the same morphology changes as the erastin treatment group, and the expression of ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter (SLC7A11) is downregulated, but these effects were reversed by ferroptosis inhibitor ferrastatin-1 and iron chelator deferoxamine (DFO). Furthermore, western blot and real-time polymerase chain reaction were used to detect the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1); osteogenic capacity was evaluated by alizarin red S staining and the expression of osteoprotegerin, osteocalcin, and alkaline phosphatase; the results showed that the expression levels of these proteins in osteoblasts with 1, 10, or 100 μM melatonins were significantly higher than the high glucose group, but after using Nrf2-SiRNA interference, the therapeutic effect of melatonin was significantly inhibited. We also performed in vivo experiments in a diabetic rat model treated with two concentrations of melatonin (10, 50 mg/kg). Dynamic bone histomorphometry and micro-CT were used to observe the rat bone microstructure, and the expression of GPX4 and Nrf2 was determined by immunohistochemistry. Here, we first report that high glucose induces ferroptosis via increased ROS/lipid peroxidation/glutathione depletion in type 2 diabetic osteoporosis. More importantly, melatonin significantly reduced the level of ferroptosis and improved the osteogenic capacity of MC3T3-E1 through activating the Nrf2/HO-1 pathway in vivo and in vitro.
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3.6
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Liu F;Zhang WL;Meng HZ;Cai ZY;Yang MW
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