活性氧通过调节C/EBP同源蛋白和醛酮还原酶家族1成员A1的基因表达,调节人间充质干细胞的脂肪-成骨谱系承诺。

IF 6.2 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Chen Hao Chiang, Yu-Chieh Kao, Yi-Hui Lin, Yi-Shing Ma, Yu-Ting Wu, Bo-Yan Jian, Yau-Huei Wei, Chuan-Mu Chen, Ying-Ming Liou
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引用次数: 0

摘要

背景:骨源性间充质干细胞(BMSCs)是一种多能干细胞,能够分化为脂肪细胞和成骨细胞。以成骨细胞发生向脂肪发生转变为特征的功能失调分化与代谢性和老年性骨质疏松症密切相关。醛酮还原酶家族1成员A1 (Akr1A1)酶利用NADPH将醛基还原为醇,已成为一种潜在的调节剂。本研究探讨了活性氧(ROS)在人间充质干细胞向成骨细胞和脂肪细胞分化过程中调节Akr1A1表达的作用。结果:我们的研究结果表明,在成脂分化过程中,ROS水平的升高会增强C/EBP同源蛋白(CHOP)和Akr1A1的表达。相反,ROS水平降低会抑制成骨细胞中CHOP和Akr1A1的表达。涉及Akr1A1沉默和过表达的功能研究表明,Akr1A1表达水平决定MSC谱系承诺,而不改变ROS产生或CHOP表达。Akr1A1的下调抑制了脂肪的形成,同时促进成骨细胞的形成,并伴有SIRT1、PGC-1α、TAZ等成骨转录因子的上调。相反,过表达Akr1A1会降低SIRT1、PGC-1α和TAZ水平,从而促进脂肪形成,抑制成骨。这些发现将Akr1A1定位为ROS/CHOP信号通路的下游靶点。利用d -半乳糖诱导的骨髓间充质干细胞氧化应激细胞模型,我们证实了升高的ROS水平上调CHOP和Akr1A1的表达,优先推动脂肪细胞而非成骨细胞的分化。结论:我们的研究结果表明,细胞内ROS调节CHOP和Akr1A1的表达,从而调节脂肪和成骨谱系的承诺。这种调节似乎是通过抑制sirt1依赖途径发生的,揭示了代谢性和年龄相关性骨质疏松症的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reactive oxygen species regulate adipose-osteogenic lineage commitment of human mesenchymal stem cells by modulating gene expression of C/EBP homology protein and aldo-keto reductase family 1 member A1.

Background: Bone-derived mesenchymal stem cells (BMSCs) are multipotent stem cells capable of differentiating into adipocytes and osteoblasts. Dysfunctional differentiation, characterized by a shift from osteoblastogenesis to adipogenesis, is closely associated with metabolic and senile osteoporosis. The Aldo-keto reductase family 1 member A1 (Akr1A1) enzyme, which utilizes NADPH to reduce aldehyde groups to alcohols, has emerged as a potential regulator. This study investigates the role of reactive oxygen species (ROS) in modulating Akr1A1 expression during the lineage differentiation of human mesenchymal stem cells into osteoblasts and adipocytes.

Results: Our findings demonstrate that increased ROS levels enhance the expression of C/EBP homology protein (CHOP) and Akr1A1 during adipogenic differentiation. Conversely, reduced ROS levels suppress CHOP and Akr1A1 expression in osteogenically committed cells. Functional studies involving Akr1A1 silencing and overexpression revealed that Akr1A1 expression levels dictate MSC lineage commitment without altering ROS production or CHOP expression. Knockdown of Akr1A1 suppressed adipogenesis while promoting osteoblastogenesis, accompanied by upregulation of SIRT1, PGC-1α, TAZ, and other osteogenic transcription factors. In contrast, overexpression of Akr1A1 reduced SIRT1, PGC-1α, and TAZ levels, thereby enhancing adipogenesis and inhibiting osteogenesis. These findings position Akr1A1 as a downstream target of the ROS/CHOP signaling pathway. Using an oxidative stress cell model induced by D-galactose in BMSCs, we confirmed that elevated ROS levels upregulate CHOP and Akr1A1 expression, preferentially driving differentiation into adipocytes over osteoblasts.

Conclusions: Our results reveal that intracellular ROS modulate CHOP and Akr1A1 expression, which regulate commitment to adipogenic and osteogenic lineages. This regulation appears to occur through inhibiting SIRT1-dependent pathways, shedding light on potential therapeutic targets for metabolic and age-related osteoporosis.

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来源期刊
Cell and Bioscience
Cell and Bioscience BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
10.70
自引率
0.00%
发文量
187
审稿时长
>12 weeks
期刊介绍: Cell and Bioscience, the official journal of the Society of Chinese Bioscientists in America, is an open access, peer-reviewed journal that encompasses all areas of life science research.
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