Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity - Evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis
Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity - Evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis
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DOI：
10.1002/art.20811
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发表时间：
2005-02-01
影响因子：
--
通讯作者：
Verweij, CL
中科院分区：
文献类型：
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作者：
Kasperkovitz, PV;Timmer, TCG;Verweij, CL
Objective.鉴于类风湿性关节炎（RA）滑膜组织之间的基因表达模式和细胞分布的异质性，我们试图确定这种变异性是否也反映在从RA滑膜组织培养的成纤维细胞样滑膜细胞（FLS）的水平上。采用互补DNA微阵列和层次聚类分析法分析了19例RA患者滑膜组织培养FLS的基因表达谱。为了验证子分类，我们进行了预测分析和主成分分析。使用微阵列统计分析软件选择在FLS培养物之间表达显著不同的基因。实时定量聚合酶链反应进行验证微阵列数据。应用免疫细胞化学方法研究FLS和滑液组织中目的基因的表达。结果。层次聚类确定了2个主要的FLS组，其特征在于独特的基因表达谱。来自高度炎症的滑膜组织的FLS揭示了转化生长因子β/激活素A诱导的基因谱的表达增加，该基因谱是肌成纤维细胞的特征，肌成纤维细胞是一种被认为参与伤口愈合的细胞类型，而生长因子的产量增加（胰岛素样生长因子2/胰岛素样生长因子结合蛋白5）似乎构成了来自低胰岛素血症的FLS的特征性特征。滑膜组织炎症。定义肌成纤维细胞样表型的分子特征反映为异质FLS群体中肌成纤维细胞样细胞比例增加。滑膜组织免疫组化染色可见肌纤维母细胞样细胞。我们的研究结果支持滑膜组织之间的异质性反映在FLS作为一个稳定的性状的概念，并提供了FLS的行为和RA滑膜的炎症状态之间可能存在联系的证据。
Objective. Given the heterogeneity of gene expression patterns and cellular distribution between rheumatoid arthritis (RA) synovial tissues, we sought to determine whether this variability was also reflected at the level of the fibroblast-like synoviocyte (FLS) cultured from RA synovial tissues.Methods. Gene expression profiles in FLS cultured from synovial tissues obtained from 19 RA patients were analyzed using complementary DNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal components analysis. Genes that differed significantly in their expression between FLS cultures were selected using Statistical Analysis of Microarrays software. Real-time quantitative polymerase chain reaction was performed to validate the microarray data. Immunocytochemistry was applied to study the expression of the genes of interest in FLS and synovial tissues.Results. Hierarchical clustering identified 2 main groups of FLS characterized by distinctive gene expression profiles. FLS from high-inflammation synovial tissues revealed increased expression of a transforming growth factor beta/activin A-inducible gene profile that is characteristic of myofibroblasts, a cell type considered to be involved in wound healing, whereas increased production of growth factor (insulin-like growth factor 2/insulin-like growth factor binding protein 5) appeared to constitute a characteristic feature of FLS derived from low-inflammation synovial tissues. The molecular feature that defines the myofibroblast-like phenotype was reflected as an increased proportion of myofibroblast-like cells in the heterogeneous FLS population. Myofibroblast-like cells were also found upon inummohistochemical analysis of synovial tissue.Conclusion. Our findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium.