Journal Article

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

Qi, Dahu, Zhao, Liming, Liu, Changyu, Xiao, Jun, Gao, Yutong, Liu, Hui, Zhao, Libo, Tao, Tenghui, Zhou, Chuankun, Sun, Xuying, Zhu, Yuanli, Guo, Fengjing

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13/2 / 13/21 / 13/51 / 13/95 / 14/35 / 38/77 / 42/89 / 64/60 / 692/420/256/2515 / 692/699/1670/498 / 82/1 / 82/29 / 96/31 / Agonists / Animals / Antibodies / Antirheumatic Agents - pharmacology / Arthritis, Experimental - genetics / Arthritis, Experimental - metabolism / Arthritis, Experimental - pathology / Arthritis, Experimental - prevention & control / Arthritis, Rheumatoid - genetics / Arthritis, Rheumatoid - metabolism / Arthritis, Rheumatoid - pathology / Autoimmune diseases / Biochemistry / Biomedical and Life Sciences / Bone growth / Bone Remodeling / Cartilage / Case-Control Studies / Cell activation / Cell Biology / Cell Culture / Cells, Cultured / Collagen / Humans / Hyperplasia / IL-1β / Immunology / Inflammation / Inflammation Mediators - metabolism / Kinases / Knee Joint - metabolism / Knee Joint - pathology / Life Sciences / Macrophages / Male / MAP kinase / Matrix metalloproteinase / Matrix Metalloproteinases - metabolism / Mice, Inbred DBA / NF-κB protein / Nuclear Receptor Subfamily 1, Group D, Member 1 - agonists / Nuclear Receptor Subfamily 1, Group D, Member 1 - genetics / Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism / Osteoclastogenesis / Protein kinase / Pyrrolidines - pharmacology / Reactive oxygen species / Reactive Oxygen Species - metabolism / Rheumatoid arthritis / Signal Transduction / Synovial Membrane - metabolism / Synovial Membrane - pathology / Synoviocytes / Synoviocytes - metabolism / Synoviocytes - pathology / Synovitis - genetics / Synovitis - metabolism / Synovitis - pathology / Thiophenes - pharmacology