Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK.
Computational Biology Facility, Liverpool Shared Research Facilities, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L7 8TX, UK.
Int J Mol Sci. 2023 Oct 4;24(19):14888. doi: 10.3390/ijms241914888.
Extracellular vesicles (EVs) contribute to osteoarthritis pathogenesis through their release into joint tissues and synovial fluid. Synovial fluid-derived EVs have the potential to be direct biomarkers in the causal pathway of disease but also enable understanding of their role in disease progression. Utilizing a temporal model of osteoarthritis, we defined the changes in matched synovial fluid and plasma-derived EV small non-coding RNA and protein cargo using sequencing and mass spectrometry. Data exploration included time series clustering, factor analysis and gene enrichment interrogation. Chondrocyte signalling was analysed using luciferase-based transcription factor activity assays. EV protein cargo appears to be more important during osteoarthritis progression than small non-coding RNAs. Cluster analysis revealed plasma-EVs represented a time-dependent response to osteoarthritis induction associated with supramolecular complexes. Clusters for synovial fluid-derived EVs were associated with initial osteoarthritis response and represented immune/inflammatory pathways. Factor analysis for plasma-derived EVs correlated with day post-induction and were primarily composed of proteins modulating lipid metabolism. Synovial fluid-derived EVs factors represented intermediate filament and supramolecular complexes reflecting tissue repair. There was a significant interaction between time and osteoarthritis for CRE, NFkB, SRE, SRF with a trend for osteoarthritis synovial fluid-derived EVs at later time points to have a more pronounced effect.
细胞外囊泡 (EVs) 通过释放到关节组织和滑液中参与骨关节炎发病机制。滑膜液衍生的 EVs 有可能成为疾病因果途径中的直接生物标志物，同时也能理解它们在疾病进展中的作用。我们利用骨关节炎的时间模型，使用测序和质谱法定义了匹配的滑膜液和血浆衍生 EV 小非编码 RNA 和蛋白质货物的变化。数据探索包括时间序列聚类、因子分析和基因富集询问。使用基于荧光素酶的转录因子活性测定分析软骨细胞信号。在骨关节炎进展过程中，EV 蛋白货物似乎比小非编码 RNA 更重要。聚类分析显示，血浆-EVs 代表了与超分子复合物相关的骨关节炎诱导的时间依赖性反应。滑膜液衍生 EV 的聚类与初始骨关节炎反应相关，代表免疫/炎症途径。血浆衍生 EV 的因子分析与诱导后天数相关，主要由调节脂质代谢的蛋白质组成。滑膜液衍生 EV 的因子代表中间丝和超分子复合物，反映组织修复。CRE、NFkB、SRE、SRF 的时间和骨关节炎之间存在显著相互作用，并且骨关节炎滑膜液衍生 EV 在后期时间点的影响更为明显。
