Yeremenko Nataliya, Noordenbos Troy, Cantaert Tineke, van Tok Melissa, van de Sande Marleen, Cañete Juan D, Tak Paul P, Baeten Dominique
Department of Clinical Immunology and Rheumatology, Academic Medical Center and University of Amsterdam, Amsterdam, The Netherlands.
Arthritis Rheum. 2013 Jan;65(1):174-85. doi: 10.1002/art.37704.
The molecular processes driving the distinct patterns of synovial inflammation and tissue remodeling in spondylarthritis (SpA) as compared to rheumatoid arthritis (RA) remain largely unknown. Therefore, we aimed to identify novel and unsuspected disease-specific pathways in SpA by a systematic and unbiased synovial gene expression analysis.
Differentially expressed genes were identified by pan-genomic microarray and confirmed by quantitative polymerase chain reaction and immunohistochemical analyses of synovial tissue biopsy samples from patients with SpA (n=63), RA (n=28), and gout (n=9). The effect of inflammation on gene expression was assessed by stimulating fibroblast-like synoviocytes (FLS) with synovial fluid and by analysis of synovial tissue samples at weeks 0 and 12 of etanercept treatment.
Using very stringent statistical thresholds, microarray analysis identified 64 up-regulated transcripts in patients with SpA synovitis as compared to those with RA synovitis. Pathway analysis revealed a robust myogene signature in this gene set. The myogene signature was technically and biologically reproducible, was specific for SpA, and was independent of disease duration, treatment, and SpA subtype (nonpsoriatic versus psoriatic). Synovial tissue staining identified the myogene expressing cells as vimentin-positive, prolyl 4-hydroxylase β-positive, CD90+, and CD146+ mesenchymal cells that were significantly overrepresented in the intimal lining layer and synovial sublining of inflamed SpA synovium. Neither in vitro exposure to synovial fluid from inflamed SpA joints nor in vivo blockade of tumor necrosis factor modulated the SpA-specific myogene signature.
These data identify a novel and disease-specific myogene signature in SpA synovitis. The fact that this stromal alteration appeared not to be downstream of local inflammation warrants further analysis of its functional role in the pathogenesis of the disease.
与类风湿关节炎（RA）相比，脊柱关节炎（SpA）中驱动滑膜炎症和组织重塑独特模式的分子过程在很大程度上仍不清楚。因此，我们旨在通过系统且无偏倚的滑膜基因表达分析来鉴定SpA中新型且未被怀疑的疾病特异性途径。
通过全基因组微阵列鉴定差异表达基因，并通过定量聚合酶链反应以及对SpA患者（n = 63）、RA患者（n = 28）和痛风患者（n = 9）的滑膜组织活检样本进行免疫组织化学分析来进行确认。通过用滑液刺激成纤维样滑膜细胞（FLS）以及分析依那西普治疗第0周和第12周的滑膜组织样本，评估炎症对基因表达的影响。
使用非常严格的统计阈值，微阵列分析确定与RA滑膜炎患者相比，SpA滑膜炎患者中有64种转录本上调。通路分析显示该基因集中存在强大的肌生成特征。该肌生成特征在技术和生物学上均可重复，对SpA具有特异性，且独立于疾病持续时间、治疗和SpA亚型（非银屑病性与银屑病性）。滑膜组织染色将表达肌生成基因的细胞鉴定为波形蛋白阳性、脯氨酰4 - 羟化酶β阳性、CD90 +和CD146 +间充质细胞，这些细胞在炎症性SpA滑膜的内膜层和滑膜下层中显著富集。无论是体外暴露于炎症性SpA关节的滑液，还是体内阻断肿瘤坏死因子，均未调节SpA特异性肌生成特征。
这些数据确定了SpA滑膜炎中一种新型的疾病特异性肌生成特征。这种基质改变似乎并非局部炎症的下游这一事实，值得进一步分析其在疾病发病机制中的功能作用。
