Synovial expression of glucocorticoid receptor parallels fibroblast activation in patients with rheumatoid arthritis.

IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL European Journal of Clinical Investigation Pub Date : 2024-08-06 DOI:10.1111/eci.14298
Nikolaos I Vlachogiannis, Kleio-Maria Verrou, Maria P Yavropoulou, Maria Tektonidou, George P Chrousos, Petros P Sfikakis
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Abstract

Background: Hypocortisolemia is associated with increased expression of NR3C1 (glucocorticoid receptor, GR) in blood cells. As endogenous cortisol production is decreased in some RA patients, we tested the hypothesis that GR may be aberrantly expressed in rheumatoid synovium.

Methods: We defined the cellular pattern of NR3C1 synovial expression using human and mouse single-cell RNA-sequencing data. Bulk synovial RNA-sequencing data from early (n = 57) or established (n = 94) RA were compared to osteoarthritis (n = 22) and healthy synovium (n = 28).

Results: GR was expressed in all synovial cell types in both human and experimental arthritis. GR synovial expression, as well as 11β-HSD1/11β-HSD2 enzyme ratio, were higher in RA than healthy and osteoarthritic tissue, regardless of disease duration or treatment. Given that GR expression varied across samples, we searched for differences between RA patients with higher versus lower GR expression. Indeed, the synovial transcriptome of RA patients with high versus low GR expression (1st quartile, 30,517 ± 4876 vs. 4th quartile, 19,382 ± 2523 normalized counts) was enriched for proinflammatory gene-sets, including 'inflammatory response', 'IFN-γ response' and 'IL6/JAK/STAT3 signalling'. High synovial GR expression was also associated with increased JAK2 and PTPRK expression, denoting activation of the proinflammatory sublining fibroblasts. In contrast, low GR expression was associated with increased COMP and COL6A2 expression, denoting a resting synovial state.

Conclusions: GR is overexpressed in the synovium of some RA patients in association with proinflammatory gene expression and activated sublining fibroblast status. Further studies should examine whether GR overexpression may act as a compensatory mechanism sensitizing synovial tissue to glucocorticoid action in RA.

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类风湿性关节炎患者滑膜中糖皮质激素受体的表达与成纤维细胞的活化平行。
背景:低皮质醇血症与NR3C1(糖皮质激素受体,GR)在血细胞中的表达增加有关。由于部分类风湿关节炎患者的内源性皮质醇分泌减少,我们测试了类风湿滑膜中 GR 可能异常表达的假设:方法:我们利用人类和小鼠单细胞 RNA 序列数据确定了 NR3C1 滑膜表达的细胞模式。将早期(n = 57)或已确诊(n = 94)RA 的大量滑膜 RNA 序列数据与骨关节炎(n = 22)和健康滑膜(n = 28)进行比较:结果:GR在人类和实验性关节炎的所有滑膜细胞类型中均有表达。无论病程长短或治疗方法如何,GR滑膜表达以及11β-HSD1/11β-HSD2酶比率在RA中均高于健康组织和骨关节炎组织。鉴于不同样本的 GR 表达不同,我们寻找 GR 表达较高和较低的 RA 患者之间的差异。事实上,GR表达量高与低的RA患者的滑膜转录组(第1四分位数,30517 ± 4876 vs. 第4四分位数,19382 ± 2523归一化计数)富含促炎基因组,包括 "炎症反应"、"IFN-γ反应 "和 "IL6/JAK/STAT3信号"。滑膜 GR 的高表达还与 JAK2 和 PTPRK 表达的增加有关,这表明促炎性下层成纤维细胞被激活。相反,GR的低表达与COMP和COL6A2的表达增加有关,表示滑膜处于静止状态:结论:GR在一些RA患者的滑膜中过度表达,这与促炎基因表达和激活的下层成纤维细胞状态有关。进一步的研究应探讨 GR 的过度表达是否可作为一种代偿机制,使 RA 患者的滑膜组织对糖皮质激素的作用敏感。
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来源期刊
CiteScore
9.50
自引率
3.60%
发文量
192
审稿时长
1 months
期刊介绍: EJCI considers any original contribution from the most sophisticated basic molecular sciences to applied clinical and translational research and evidence-based medicine across a broad range of subspecialties. The EJCI publishes reports of high-quality research that pertain to the genetic, molecular, cellular, or physiological basis of human biology and disease, as well as research that addresses prevalence, diagnosis, course, treatment, and prevention of disease. We are primarily interested in studies directly pertinent to humans, but submission of robust in vitro and animal work is also encouraged. Interdisciplinary work and research using innovative methods and combinations of laboratory, clinical, and epidemiological methodologies and techniques is of great interest to the journal. Several categories of manuscripts (for detailed description see below) are considered: editorials, original articles (also including randomized clinical trials, systematic reviews and meta-analyses), reviews (narrative reviews), opinion articles (including debates, perspectives and commentaries); and letters to the Editor.
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