Wang Jing-Yi, Liu Yao-Hui, Wang Xiao, Ma Min, Pan Zhang-Yi, Fan Ao-Yuan, Lu Lai-Ya, Liu Zheng, Tao Kun, Yin Feng
Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Joint Surgery, Ningbo No.6 Hospital, Ningbo, Zhejiang, China.
Arthritis Res Ther. 2025 May 15;27(1):105. doi: 10.1186/s13075-025-03566-z.
Meniscus degeneration contributes to knee arthritis progression, but the cellular and molecular mechanisms of meniscus aging remain poorly understood. We aimed to characterize age-related changes in the rat meniscus using single-cell RNA sequencing (scRNA-seq) and identify key pathogenic cell populations and pathways.
Meniscal tissues from young (12 weeks) and aged (24 months) rats were processed for histology, flow cytometry, and scRNA-seq. Bioinformatics tools, including Seurat, Monocle 2, and CellChat, were used to analyze cellular composition, pseudotime trajectories, and intercellular communication. Senescence-related features and signaling pathways were evaluated.
Knee joint of aged rats exhibited higher Osteoarthritis Research Society International (OARSI) scores and synovial inflammation. scRNA-seq revealed three major chondrocyte subpopulations: Sox9 + stable chondrocytes, Fndc1 + fibrochondrocytes, and Atf3 + senescent chondrocytes. Aging caused a significant increase in Atf3 + senescent chondrocytes, characterized by the expression of senescence markers (Cdkn1a/Cdkn2a) and activation of inflammatory pathways such as tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB). These cells were predominantly located at the endpoint of differentiation trajectories. CellChat analysis identified the ANGPTL4-SDC4 axis as a key signaling pathway mediated by Atf3 + cells. Immunostaining confirmed elevated Angiopoietin-Like Protein 4 (ANGPTL4) expression in aged menisci.
We identified Atf3 + senescent chondrocytes as a key pathogenic population in the aging meniscus, driving degeneration via the ANGPTL4 pathway. Targeting Atf3 + cells or ANGPTL4 signaling may offer new therapeutic strategies for age-related meniscus degeneration and arthritis.
半月板退变会导致膝关节骨关节炎进展，但半月板老化的细胞和分子机制仍知之甚少。我们旨在通过单细胞RNA测序（scRNA-seq）来表征大鼠半月板与年龄相关的变化，并确定关键的致病细胞群和信号通路。
对年轻（12周）和老年（24个月）大鼠的半月板组织进行组织学、流式细胞术和scRNA-seq分析。使用包括Seurat、Monocle 2和CellChat在内的生物信息学工具来分析细胞组成、伪时间轨迹和细胞间通讯。评估衰老相关特征和信号通路。
老年大鼠的膝关节表现出更高的国际骨关节炎研究学会（OARSI）评分和滑膜炎症。scRNA-seq揭示了三种主要的软骨细胞亚群：Sox9+稳定软骨细胞、Fndc1+纤维软骨细胞和Atf3+衰老软骨细胞。衰老导致Atf3+衰老软骨细胞显著增加，其特征是衰老标志物（Cdkn1a/Cdkn2a）的表达以及肿瘤坏死因子（TNF）和核因子-κB（NF-κB）等炎症通路的激活。这些细胞主要位于分化轨迹的终点。CellChat分析确定ANGPTL4-SDC4轴是由Atf3+细胞介导的关键信号通路。免疫染色证实老年半月板中血管生成素样蛋白4（ANGPTL4）表达升高。
我们确定Atf3+衰老软骨细胞是老化半月板中的关键致病群体，通过ANGPTL4途径驱动退变。靶向Atf3+细胞或ANGPTL4信号通路可能为与年龄相关的半月板退变和骨关节炎提供新的治疗策略。
