NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis
NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis
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NR1D1 调节类风湿性关节炎的滑膜炎症和骨质破坏
DOI：
10.1038/s41419-020-2314-6
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发表时间：
2020-02-18
影响因子：
9
通讯作者：
Xiao, Jun
中科院分区：
文献类型：
--
作者：
Liu, Hui;Zhu, Yuanli;Xiao, Jun
类风湿性关节炎（RA）是一种以滑膜增生、血管翳形成、软骨和骨破坏为特征的慢性自身免疫性疾病。核受体亚家族1 D组成员1（NR 1D 1）作为转录抑制因子发挥功能，并在炎症反应中发挥重要作用。然而，NR 1D 1是否参与RA发病过程中的滑膜炎症和关节破坏尚不清楚。在本研究中，我们发现NR 1D 1在RA患者的滑膜组织中表达增加，而在体外用IL-1β刺激的RA成纤维样滑膜细胞（FLS）中表达减少。我们发现，NR 1D 1激活降低了促炎细胞因子和基质金属蛋白酶（MMPs）的表达，而NR 1D 1沉默产生相反的效果。此外，NR 1D 1激活减少了活性氧（ROS）的产生，并增加了核转录因子E2相关因子2（Nrf 2）相关酶的产生。丝裂原活化蛋白激酶（MAPK）和核因子κB（NF-κB）通路被NR 1D 1激动剂SR9009阻断，但被NR 1D 1沉默激活。NR 1D 1激活还抑制M1巨噬细胞极化，并抑制破骨细胞生成和破骨细胞相关基因表达。NR 1D 1激动剂SR9009治疗胶原诱导性关节炎（CIA）小鼠，可显著抑制CIA小鼠滑膜增生、炎性细胞浸润及软骨和骨破坏。我们的研究结果表明NR 1D 1在RA中的重要作用，并表明其治疗潜力。
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia, pannus formation, and cartilage and bone destruction. Nuclear receptor subfamily 1 group D member 1 (NR1D1) functions as a transcriptional repressor and plays a vital role in inflammatory reactions. However, whether NR1D1 is involved in synovial inflammation and joint destruction during the pathogenesis of RA is unknown. In this study, we found that NR1D1 expression was increased in synovial tissues from patients with RA and decreased in RA Fibroblast-like synoviocytes (FLSs) stimulated with IL-1β in vitro. We showed that NR1D1 activation decreased the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs), while NR1D1 silencing exerted the opposite effect. Furthermore, NR1D1 activation reduced reactive oxygen species (ROS) generation and increased the production of nuclear transcription factor E2-related factor 2 (Nrf2)-associated enzymes. Mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways were blocked by the NR1D1 agonist SR9009 but activated by NR1D1 silencing. NR1D1 activation also inhibited M1 macrophage polarization and suppressed osteoclastogenesis and osteoclast-related genes expression. Treatment with NR1D1 agonist SR9009 in collagen-induced arthritis (CIA) mouse significantly suppressed the hyperplasia of synovial, infiltration of inflammatory cell and destruction of cartilage and bone. Our findings demonstrate an important role for NR1D1 in RA and suggest its therapeutic potential.