Atf3 + senescent chondrocytes mediate meniscus degeneration in aging

作者：Jingyi Wang, Yaohui Liu, Xiao Wang, Min Ma, Zhangyi Pan, Ao-Yuan Fan, Lei Lü, Zheng Liu, Kun Tao, Feng Yin · 发表于：Arthritis Research & Therapy · 年份：2025 · DOI：10.1186/s13075-025-03566-z · 被引用次数：4 · 研究领域：Osteoarthritis Treatment and Mechanisms、Tendon Structure and Treatment、Knee injuries and reconstruction techniques

BACKGROUND: 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. METHODS: 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. RESULTS: 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) ex...