First Department of Propaedeutic and Internal Medicine and Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Eur J Clin Invest. 2024 Dec;54(12):e14298. doi: 10.1111/eci.14298. Epub 2024 Aug 6.
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.
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).
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.
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.
皮质醇减少与血液细胞中 NR3C1（糖皮质激素受体，GR）的表达增加有关。由于一些 RA 患者的内源性皮质醇生成减少，我们检验了 GR 在类风湿滑膜中可能异常表达的假设。
我们使用人类和小鼠单细胞 RNA-seq 数据定义了 NR3C1 滑膜表达的细胞模式。将早期（n=57）或已建立的（n=94）RA 的批量滑膜 RNA-seq 数据与骨关节炎（n=22）和健康滑膜（n=28）进行比较。
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。无论疾病持续时间或治疗如何，RA 组织中的 GR 滑膜表达以及 11β-HSD1/11β-HSD2 酶比值均高于健康和骨关节炎组织。鉴于 GR 表达在不同样本之间存在差异，我们在 RA 患者中寻找 GR 表达较高与较低的患者之间的差异。事实上，GR 表达较高（第 1 四分位数，30517±4876 与第 4 四分位数，19382±2523 标准化计数）与较低（第 1 四分位数，30517±4876 与第 4 四分位数，19382±2523 标准化计数）的 RA 患者的滑膜转录组富含促炎基因集，包括“炎症反应”、“IFN-γ 反应”和“IL6/JAK/STAT3 信号转导”。高滑膜 GR 表达还与 JAK2 和 PTPRK 表达增加相关，表明促炎亚衬里成纤维细胞激活。相反，低 GR 表达与 COMP 和 COL6A2 表达增加相关，表明滑膜处于静止状态。
在一些 RA 患者的滑膜中，GR 过度表达与促炎基因表达和激活的亚衬里成纤维细胞状态有关。进一步的研究应该检查 GR 过度表达是否可能作为一种代偿机制，使滑膜组织对 RA 中糖皮质激素的作用敏感。
