Skatole通过巨噬细胞极化重编程和保护软骨细胞减轻骨关节炎。

IF 10.7 1区 综合性期刊 Q1 Multidisciplinary
Research Pub Date : 2025-02-03 eCollection Date: 2025-01-01 DOI:10.34133/research.0604
Weiyun Wang, Yaru Chu, Yunkun Lu, Jie Xu, Weixuan Zhao, Zhuo Liang, Xueqiang Guo, Lingling Xi, Tao Han, Yaping Shen, Wenjuan Song, Yanhua Tang, Mengnan Wen, Zhuang Qian, Lei Wang, Zhenlin Fan, Guangdong Zhou, Wenjie Ren
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引用次数: 0

摘要

骨关节炎(OA)是最常见的关节疾病,但有效的改善疾病的OA药物(DMOADs)仍然难以捉摸。靶向巨噬细胞极化已成为OA治疗的一个有前途的途径。本研究通过高通量筛选发现粪臭素是巨噬细胞极化的有效调节剂。体内实验表明,在内侧半月板失稳(DMM)诱导的OA小鼠和碘乙酸钠(MIA)诱导的OA大鼠中,施卡妥可显著减轻滑膜炎和软骨损伤。在机制上,角鲨素激活信号转换器和转录激活因子6 (Stat6)信号通路,促进M2巨噬细胞极化,同时抑制核因子-κB (NFκB)和丝裂原活化蛋白激酶(MAPK)信号通路,抑制M1极化。rna测序分析、靶向代谢组学和线粒体应激测试进一步表明,粪毒唑治疗使巨噬细胞转向氧化磷酸化以产生能量。此外,它上调与谷胱甘肽代谢和活性氧(ROS)途径相关的基因,减少细胞内ROS的产生。CUT&Tag分析结果表明,NFκB下游转录因子p65可直接结合炎症、氧化磷酸化和谷胱甘肽代谢相关基因位点,从而调控基因表达。这种调节过程被粪臭素抑制。在软骨细胞水平,skatole处理的M1巨噬细胞条件培养基平衡小鼠软骨细胞的合成代谢和分解代谢,并抑制细胞凋亡。在il - 1β处理的软骨细胞中,粪甲素抑制炎症和分解代谢,而不影响细胞凋亡或合成代谢。总体而言,角鲨素通过调节关节内巨噬细胞极化维持免疫微环境稳态,通过平衡软骨细胞合成代谢和分解代谢维持软骨功能,有效缓解骨关节炎。这些发现表明,skatole有可能成为一种DMOAD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Skatole Alleviates Osteoarthritis by Reprogramming Macrophage Polarization and Protecting Chondrocytes.

Osteoarthritis (OA) is the most prevalent joint disease, yet effective disease-modifying OA drugs (DMOADs) remain elusive. Targeting macrophage polarization has emerged as a promising avenue for OA treatment. This study identified skatole through high-throughput screening as an efficient modulator of macrophage polarization. In vivo experiments demonstrated that skatole administration markedly reduced synovitis and cartilage damage in both destabilization of medial meniscus (DMM)-induced OA mice and monosodium iodoacetate (MIA)-induced OA rats. Mechanistically, skatole activated signal transducer and activator of transcription 6 (Stat6) signaling, promoting M2 macrophage polarization, while inhibiting nuclear factor-κB (NFκB) and mitogen-activated protein kinase (MAPK) signaling pathways to suppress M1 polarization. RNA-sequencing analysis, targeted metabolomics, and mitochondrial stress tests further revealed that skatole treatment shifted macrophages toward oxidative phosphorylation for energy production. Additionally, it up-regulated genes associated with glutathione metabolism and reactive oxygen species (ROS) pathways, reducing intracellular ROS production. The CUT&Tag assay results indicated that the downstream transcription factor p65 of NFκB can directly bind to gene loci related to inflammation, oxidative phosphorylation, and glutathione metabolism, thereby modulating gene expression. This regulatory process is inhibited by skatole. At the chondrocyte level, conditional medium from skatole-treated M1 macrophages balanced anabolism and catabolism in mouse chondrocytes and inhibited apoptosis. In IL1β-treated chondrocytes, skatole suppressed inflammation and catabolism without affecting apoptosis or anabolism. Overall, skatole maintains immune microenvironment homeostasis by modulating macrophage polarization in joints and preserves cartilage function by balancing chondrocyte anabolism and catabolism, effectively alleviating OA. These findings suggest skatole's potential as a DMOAD.

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来源期刊
Research
Research Multidisciplinary-Multidisciplinary
CiteScore
13.40
自引率
3.60%
发文量
0
审稿时长
14 weeks
期刊介绍: Research serves as a global platform for academic exchange, collaboration, and technological advancements. This journal welcomes high-quality research contributions from any domain, with open arms to authors from around the globe. Comprising fundamental research in the life and physical sciences, Research also highlights significant findings and issues in engineering and applied science. The journal proudly features original research articles, reviews, perspectives, and editorials, fostering a diverse and dynamic scholarly environment.
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