缺乏 Lif 会导致全身性铁代谢紊乱,并增加成骨细胞对铁变态反应的易感性。

IF 3.5 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Bone Pub Date : 2024-09-26 DOI:10.1016/j.bone.2024.117266
Yu Zhang , Yaqi Cong , Juan Du , Donghua Guo , Jing Huang , Junchen Pan , Youde Liang , Jiali Zhang , Zhou Ye , Yi Liu , Yi Zhou
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引用次数: 0

摘要

白血病抑制因子(LIF)是一种多功能细胞因子,在各种生物过程中发挥着至关重要的作用。然而,LIF 在铁代谢中的参与几乎仍未被探索。本研究旨在探讨 LIF 对全身铁运输的影响及其在成骨细胞铁变态反应中的潜在作用。我们观察到,与野生型(WT)小鼠相比,Lif 缺陷(Lif-/-)小鼠的特点是骨量减少和骨矿物质密度降低。能量色散 X 射线光谱显示,Lif-/- 小鼠股骨表面的铁含量明显增加。同时,铁储存测试显示,Lif-/-小鼠脾脏中的铁含量较低,而股骨中的铁含量较高。此外,与 WT 小鼠相比,Lif-/- 小鼠的血清铁、总铁结合力、不饱和铁结合力、转铁蛋白饱和度和血清铁蛋白水平均有所提高。Lif-/- 小鼠肝脏中的 Hepcidin mRNA 表达减少。Lif-基因敲除后,AML-12 肝细胞系中的情况也是如此。免疫组化和 RT-PCR 发现 Lif-/- 小鼠十二指肠细胞中的铁蛋白(FPN)升高。Lif缺陷会降低成骨细胞中SLC7A11的水平。此外,过表达 LIF 会下调 CD71、DCYTB 和 DMT1,从而减少铁过载细胞对铁的吸收。股骨免疫组化(IHC)显示,ACSL4增加,GPX4和SLC7A11减少,表明Lif-/-小鼠成骨细胞的铁变态反应增加。全转录组测序显示,Lif-基因敲除后基因表达发生变化,与涉及长链脂肪酸转运、线粒体组织和 p38 MAPK 信号通路的基因呈负相关。这些结果表明,Lif 缺失会改变全身铁代谢,并增加成骨细胞对铁变态反应的易感性。
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Lif-deficiency promote systemic Iron metabolism disorders and increases the susceptibility of osteoblasts to ferroptosis
Leukemia inhibitory factor (LIF) is a multifunctional cytokine that plays a crucial role in various biological processes. However, LIF involvement in iron metabolism remains almost unexplored. This study aimed to explore the impact of LIF on systemic iron transportation and its potential role in ferroptosis in osteoblasts. We observed that the Lif-deficient (Lif−/−) mice is characterized by a reduction in bone mass and a decrease in bone mineral density compared with wild-type (WT) mice. Energy-dispersive X-ray spectroscopy revealed a marked increase in iron content on the surface of femurs from Lif−/− mice. Meanwhile, iron stores test lower iron levels in the spleens and higher levels in the femurs of Lif−/− mice. Besides, Lif−/− mice display increased levels of serum iron, total iron-binding capacity, unsaturated iron-binding capacity, and transferrin saturation and serum ferritin relative to WT mice. Hepcidin mRNA expression reduction in the liver of Lif−/− mice. It also holds true in the AML-12 hepatocyte cell line after Lif-knockdown. Immunohistochemistry and RT-PCR revealed elevated ferroportin (FPN) in duodenal cells of Lif−/− mice. Lif-deficiency decreases SLC7A11 levels in osteoblasts. In addition, overexpression of LIF downregulates CD71, DCYTB, and DMT1, thereby reducing iron uptake in iron-overloaded cells. Femur immunohistochemistry (IHC) revealed increased ACSL4 and decreased GPX4 and SLC7A11, indicating an increase in ferroptosis of osteoblasts in Lif−/− mice. Whole-transcriptome sequencing showed gene expression changes after Lif-knockdown, exhibiting a negative correlation with genes involved in long-chain fatty acid transport, mitochondrial organization, and the p38 MAPK signaling pathway. These results demonstrate that Lif-deficiency alter systemic iron metabolism and increases the susceptibility of osteoblasts to ferroptosis.
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来源期刊
Bone
Bone 医学-内分泌学与代谢
CiteScore
8.90
自引率
4.90%
发文量
264
审稿时长
30 days
期刊介绍: BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.
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