BACKGROUND Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is well known that the formation of positive feedback between synovial hyperplasia and inflammatory infiltration is intimately associated with the occurrence and development of RA. However, the exact mechanisms still remain unknown, making the early diagnosis and therapy of RA difficult. This study was designed to identify prospective diagnostic and therapeutic biomarkers, as well as their-mediated biological mechanisms in RA. METHODS Three microarray datasets (GSE36700, GSE77298 and GSE153015) and two RNA-sequencing datasets (GSE89408 and GSE112656) of synovial tissues, as well as three other microarray datasets (GSE101193, GSE134087 and GSE94519) of peripheral blood were downloaded for integrated analysis. The differently expressed genes (DEGs) were identified by "limma" package of R software. Then, weight gene co-expression analysis and gene set enrichment analysis were performed to investigate synovial tissue-specific genes and their-mediated biological mechanisms in RA. The expression of candidate genes and their diagnostic value for RA were verified by quantitative real-time PCR and receiver operating characteristic (ROC) curve, respectively. Relevant biological mechanisms were explored through cell proliferation and colony formation assay. The suggestive anti-RA compounds were discovered by CMap analysis. RESULTS We identified a total of 266 DEGs, which were mainly enriched in cellular proliferation and migration, infection and inflammatory immune signaling pathways. Bioinformatics analysis and molecular validation revealed 5 synovial tissue-specific genes, which exhibited excellent diagnostic value for RA. The infiltration level of immune cells in RA synovial tissue was significantly higher than that in control individuals. Moreover, preliminary molecular experiments suggested that these characteristic genes may be responsible for the high proliferation potential of RA fibroblast-like synoviocytes (FLSs). Finally, 8 small molecular compounds with anti-RA potential were obtained. CONCLUSIONS We have proposed 5 potential diagnostic and therapeutic biomarkers (CDK1, TTK, HMMR, DLGAP5, and SKA3) in synovial tissues that may contribute to the pathogenesis of RA. These findings may shed light on the early diagnosis and therapy of RA.

中文翻译：

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滑膜组织特异性基因及其介导的类风湿性关节炎生物学机制的鉴定和初步验证。

背景技术类风湿性关节炎(RA)是一种慢性炎症性自身免疫性疾病。众所周知，滑膜增生与炎症浸润之间正反馈的形成与RA的发生发展密切相关。然而，确切的机制仍然未知，使得RA的早期诊断和治疗变得困难。本研究旨在确定前瞻性诊断和治疗生物标志物，以及它们在 RA 中介导的生物学机制。方法下载滑膜组织的三个微阵列数据集（GSE36700、GSE77298和GSE153015）和两个RNA测序数据集（GSE89408和GSE112656），以及外周血的其他三个微阵列数据集（GSE101193、GSE134087和GSE94519）进行整合分析。差异表达基因（DEGs）由R软件的“limma”包识别。然后，进行权重基因共表达分析和基因集富集分析，以研究滑膜组织特异性基因及其在RA中介导的生物学机制。分别通过定量实时PCR和受试者工作特征（ROC）曲线验证候选基因的表达及其对RA的诊断价值。通过细胞增殖和集落形成试验探索了相关的生物学机制。提示性抗 RA 化合物是通过 CMap 分析发现的。结果共鉴定出266个DEGs，主要富集于细胞增殖和迁移、感染和炎症免疫信号通路。生物信息学分析和分子验证揭示了 5 个滑膜组织特异性基因，对 RA 具有极好的诊断价值。RA滑膜组织中免疫细胞的浸润水平明显高于对照个体。此外，初步分子实验表明，这些特征基因可能与 RA 成纤维细胞样滑膜细胞 (FLS) 的高增殖潜能有关。最终获得了8个具有抗RA潜力的小分子化合物。结论 我们提出了滑膜组织中可能有助于 RA 发病机制的 5 种潜在诊断和治疗生物标志物（CDK1、TTK、HMMR、DLGAP5 和 SKA3）。这些发现可能有助于 RA 的早期诊断和治疗。RA滑膜组织中免疫细胞的浸润水平明显高于对照个体。此外，初步分子实验表明，这些特征基因可能与 RA 成纤维细胞样滑膜细胞 (FLS) 的高增殖潜能有关。最终获得了8个具有抗RA潜力的小分子化合物。结论 我们提出了滑膜组织中可能有助于 RA 发病机制的 5 种潜在诊断和治疗生物标志物（CDK1、TTK、HMMR、DLGAP5 和 SKA3）。这些发现可能有助于 RA 的早期诊断和治疗。RA滑膜组织中免疫细胞的浸润水平明显高于对照个体。此外，初步分子实验表明，这些特征基因可能与 RA 成纤维细胞样滑膜细胞 (FLS) 的高增殖潜能有关。最终获得了8个具有抗RA潜力的小分子化合物。结论 我们提出了滑膜组织中可能有助于 RA 发病机制的 5 种潜在诊断和治疗生物标志物（CDK1、TTK、HMMR、DLGAP5 和 SKA3）。这些发现可能有助于 RA 的早期诊断和治疗。初步分子实验表明，这些特征基因可能与 RA 成纤维细胞样滑膜细胞 (FLS) 的高增殖潜能有关。最终获得了8个具有抗RA潜力的小分子化合物。结论 我们提出了滑膜组织中可能有助于 RA 发病机制的 5 种潜在诊断和治疗生物标志物（CDK1、TTK、HMMR、DLGAP5 和 SKA3）。这些发现可能有助于 RA 的早期诊断和治疗。初步分子实验表明，这些特征基因可能与 RA 成纤维细胞样滑膜细胞 (FLS) 的高增殖潜能有关。最终获得了8个具有抗RA潜力的小分子化合物。结论 我们提出了滑膜组织中可能有助于 RA 发病机制的 5 种潜在诊断和治疗生物标志物（CDK1、TTK、HMMR、DLGAP5 和 SKA3）。这些发现可能有助于 RA 的早期诊断和治疗。