Acod1-mediated inhibition of aerobic glycolysis suppresses osteoclast differentiation and attenuates bone erosion in arthritis.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-14 DOI:10.1136/ard-2023-224774

Katerina Kachler, Darja Andreev, Shreeya Thapa, Dmytro Royzman, Andreas Gießl, Shobika Karuppusamy, Mireia Llerins Perez, Mengdan Liu, Jörg Hofmann, Arne Gessner, Xianyi Meng, Simon Rauber, Alexander Steinkasserer, Martin Fromm, Georg Schett, Aline Bozec

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引用次数: 0

Abstract

Objectives: Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss.

Methods: Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development.

Results: Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis.

Conclusion: Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis.

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Acod1 介导的有氧糖酵解抑制破骨细胞分化并减轻关节炎的骨侵蚀。

目的：代谢变化是破骨细胞发育的关键因素，并可能导致类风湿性关节炎（RA）的骨质退化。据了解，醋酸脱羧酶1（Acod1）可将单核巨噬细胞的细胞功能与其代谢状态联系起来。由于破骨细胞来源于单核细胞系，我们推测 Acod1 及其代谢产物伊他康酸在破骨细胞分化和关节炎相关骨质流失中发挥作用：方法：通过质谱法测量 RA 患者和健康对照组的人外周血单核细胞（PBMC）中的伊他康酸水平。在体外用它肯酸衍生物 4-辛基-它肯酸（4-OI）处理人类和小鼠破骨细胞。我们使用 K/BxN 血清诱导的关节炎和人类 TNF 转基因（hTNFtg）小鼠研究了 Acod1 缺失和 4-OI 处理对小鼠骨侵蚀的影响。SCENITH 和细胞外通量分析用于评估破骨细胞和破骨细胞祖细胞的代谢活动。通过 RNA 测序确定了破骨细胞转录组中 Acod1 依赖性和 itaconate 依赖性的变化。利用CRISPR/Cas9基因编辑技术研究了低氧诱导因子（Hif）-1α在Acod1介导的破骨细胞发育调控中的作用：结果：RA患者PBMC中的伊他康酸水平与疾病活动性成反比。Acod1缺陷小鼠在实验性关节炎中表现出破骨细胞数量增加和骨侵蚀，而4-OI治疗可减轻体内炎性骨质流失，并抑制体外人和小鼠破骨细胞分化。从机理上讲，Acod1 通过抑制琥珀酸脱氢酶依赖性活性氧的产生和 Hif1α 介导的有氧糖酵解诱导来抑制破骨细胞的分化：Acod1和itaconate是炎症性关节炎破骨细胞分化和骨质流失的关键调节因子。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.