Targeting of hyperlipid- producing senescent synovial fibroblasts to ameliorate cartilage degeneration

• 成果类型: Article
• 署名作者: Hu, Jiajie; Yu, Dongsheng; Wang, Jiasheng; Guo, Peng; Chen, Mingming; Wu, Dongmei; Cai, Youzhi; Wang, Yixuan; Ji, Junfeng; Yao, Xudong; Ouyang, Hongwei
• 署名单位: Zhejiang University; Zhejiang University; Liangzhu Laboratory; Zhejiang University; Hangzhou Medical College; Zhejiang Provincial People's Hospital; Zhejiang University; Zhejiang University; Zhejiang University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8963
• DOI: 10.1073/pnas.2417708122
• 发表日期: 2025-06-10
• 关键词: secretory phenotype; cellular senescence; osteoarthritis; rcan1; cells; mtor; regulator; injury

摘要

Osteoarthritis (OA) is one of the most common causes of physical disability among older people and its incidence increases with age. Removal of the senescent cells (SNCs) delays OA pathologies, but little is known about the heterogeneity of SNCs and their roles in OA pathogenesis. Here, we identify a subpopulation of senescent synovial cells and proposed a molecular mechanism governing pathogenic synovium-cartilage crosstalk in OA progression. Using single-cell RNA sequencing and synovial organoids, we demonstrate that RCAN1+IL1 alpha+ senescent synovial fibroblasts, predominantly located in the lining layer of human OA synovium, exhibit proinflammatory phenotype, mitochondrial dysfunction, and promote cartilage degeneration. Mechanistically, RCAN1 stabilizes ATF4 mRNA and mediates saturated fatty acids (SFA) secretion from synovial fibroblasts, which could promote chondrocyte senescence and cartilage matrix degradation. Synovium-targeted delivery of anti-RCAN1 siRNA significantly ameliorated posttraumatic OA development in mice, reducing of SNC accumulation in synovium and increasing cartilage regeneration. Coculture experiments with human OA cartilage explants and synovial organoids confirm that RCAN1 silencing in synovial fibroblasts suppressess chondrocyte senescence and cartilage degradation. Our findings reveal a prodegenerative interaction between RCAN1+IL1 alpha+ senescent synovial fibroblasts and chondrocytes mediated by secreted lipid in OA progression. Targeted RCAN1 knockdown in senescent synovium could be a new treatment strategy for restoring the joint homeostasis.