Transcriptomic analyses of joint tissues during osteoarthritis development in a rat model reveal dysregulated mechanotransduction and extracellular matrix pathways

Transcriptomic changes in joint tissues during the development of osteoarthritis (OA) are of interest for the discovery of biomarkers and mechanisms of disease. The objective of this study was to use the rat medial meniscus transection (MMT) model to discover stage and tissue-specific transcriptomic changes. Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed for RNA-sequencing. Differentially expressed genes (DEG) were used to identify pathways and mechanisms. Published transcriptomic datasets from animal models and human OA were used to confirm and extend present findings. The total number of DEGs was already high at 2 weeks (723 in meniscus), followed by cartilage (259) and synovium (42) and declined to varying degrees in meniscus and synovium but increased in cartilage at 6 weeks. The most upregulated genes included tenascins. The 'response to mechanical stimulus' and extracellular matrix-related pathways were enriched in both cartilage and meniscus. Pathways that were enriched in synovium at 4 weeks indicate processes related to synovial hyperplasia and fibrosis. Synovium also showed upregulation of IL-11 and several MMPs. The mechanical stimulus pathway included upregulation of the mechanoreceptors PIEZO1, PIEZO2 and TRPV4 and nerve growth factor. Analysis of data from prior RNA-sequencing studies of animal models and human OA support these findings. These results indicate several shared pathways that are affected during OA in cartilage and meniscus and support the role of mechanotransduction and other pathways in OA pathogenesis. The objective of this study was to use the rat medial meniscus transection (MMT) model to discover stage and tissue-specific transcriptomic changes. Sham or MMT surgeries were performed in mature rats. Cartilage, menisci and synovium were scored for histopathological changes at 2, 4 and 6 weeks post-surgery and processed for RNA-sequencing.

骨关节炎（OA）发病过程中关节组织的转录组改变，对于疾病生物标志物的发掘与致病机制研究具有重要意义。本研究旨在利用大鼠内侧半月板截断（MMT）模型，筛选疾病不同阶段及组织特异性的转录组变化。对成熟大鼠施行假手术或MMT手术，于术后2、4、6周分别采集软骨、半月板及滑膜样本进行组织病理学评分，并开展RNA测序（RNA-sequencing）。借助差异表达基因（DEG）筛选相关通路与致病机制，并采用已发表的动物模型及人类OA转录组数据集对本研究结果进行验证与拓展。
术后2周时，差异表达基因总数已处于较高水平（半月板中达723个），其次为软骨（259个）与滑膜（42个）；至术后6周，半月板与滑膜的差异表达基因数呈不同程度下降，而软骨中的该数值则有所上升。上调表达最为显著的基因包括腱糖蛋白（tenascins）家族。软骨与半月板中均富集到“机械刺激应答”及细胞外基质相关通路。术后4周，滑膜中富集的通路则与滑膜增生及纤维化过程相关。滑膜组织中还可见白细胞介素11（IL-11）及多种基质金属蛋白酶（MMPs）的上调表达。机械刺激应答通路中，机械感受器PIEZO1、PIEZO2、TRPV4及神经生长因子的表达均呈上调趋势。对既往动物模型及人类OA的RNA测序研究数据进行分析，结果支持本研究结论。本研究结果揭示了OA发病过程中软骨与半月板共有的多条受累通路，并证实了机械转导及其他通路在OA发病机制中的作用。
本研究旨在利用大鼠内侧半月板截断（MMT）模型，筛选疾病不同阶段及组织特异性的转录组变化。对成熟大鼠施行假手术或MMT手术，于术后2、4、6周分别采集软骨、半月板及滑膜样本进行组织病理学评分，并开展RNA测序（RNA-sequencing）。