IRS2/FOXO1 mitigates osteoarthritis by regulating chondrocyte autophagy and mitochondrial function.

IF 6.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Medicine Pub Date : 2025-09-26 DOI:10.1186/s10020-025-01346-8

Chaoren Qin, Kai Chen, Yingchun Sun, Changjiang Wang, Yaohui Yu, Hao Zhu, Guoyou Zou

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引用次数: 0

Abstract

Purpose: Osteoarthritis (OA) is a debilitating joint disease with no effective cure. This study investigates the role of Insulin Receptor Substrate 2 (IRS2) in OA and its potential as a therapeutic target.

Methods: Transcriptomic analysis of OA-related datasets (GSE178557, GSE169077, GSE64394, GSE57218) was conducted to identify differentially expressed genes (DEGs), with KEGG pathway analysis highlighting the PI3K/AKT pathway. In vivo, the destabilization of the medial meniscus (DMM) OA mouse model was used to assess IRS2 expression through histology, qPCR, and Western blot. IRS2 was overexpressed in primary mouse chondrocytes via adenoviral transfection, with proliferation, apoptosis, and autophagy assessed by EdU, Annexin V/PI staining, and autophagy-related protein analysis. Adenovirus expressing Irs2 was injected intra-articularly into DMM mice, and cartilage integrity was assessed using histology and micro-CT.

Results: IRS2 expression was significantly reduced in OA cartilage, correlating with PI3K/AKT pathway inhibition. IRS2 overexpression restored AKT activation, FOXO1 phosphorylation, and mitochondrial autophagy. Intra-articular IRS2 injection improved cartilage matrix integrity, reduced MMP13, and alleviated subchondral bone changes in DMM mice.

Conclusion: IRS2 plays a key role in OA pathogenesis and targeting it may provide a promising therapeutic approach for OA.

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IRS2/ fox01通过调节软骨细胞自噬和线粒体功能减轻骨关节炎。

目的：骨关节炎（OA）是一种使人衰弱的关节疾病，没有有效的治疗方法。本研究探讨了胰岛素受体底物2 （IRS2）在OA中的作用及其作为治疗靶点的潜力。方法：对oa相关数据集（GSE178557、GSE169077、GSE64394、GSE57218）进行转录组学分析，鉴定差异表达基因（DEGs）， KEGG通路分析突出PI3K/AKT通路。在体内，采用内侧半月板（DMM） OA小鼠模型的不稳定性，通过组织学、qPCR和Western blot来评估IRS2的表达。通过腺病毒转染，IRS2在小鼠原代软骨细胞中过表达，通过EdU、Annexin V/PI染色和自噬相关蛋白分析评估其增殖、凋亡和自噬情况。将表达Irs2的腺病毒注射到DMM小鼠关节内，通过组织学和显微ct评估软骨完整性。结果：IRS2在OA软骨中表达显著降低，与PI3K/AKT通路抑制有关。IRS2过表达恢复AKT激活、FOXO1磷酸化和线粒体自噬。关节内注射IRS2可改善DMM小鼠软骨基质完整性，降低MMP13，减轻软骨下骨改变。结论：IRS2在OA发病中起关键作用，靶向IRS2可能是OA治疗的重要途径。

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

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.