NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

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

doi:10.1038/s41419-020-2314-6

Abstract

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.

Highlights

Rheumatoid arthritis (RA) is a chronic complicated autoimmune disease characterized by synovial hyperplasia, pannus formation, and bone and cartilage destruction
Western blotting showed that the protein levels of COX-2, IL-1β, MMP3, and MMP13 were elevated, while that of NR1D1 was consistent with its mRNA level (Fig. 1c, d)
Annexin V/propidium iodide (PI) double staining was performed to assess the proapoptotic effect of the NR1D1 agonist SR9009 on RA Fibroblast-like synoviocytes (FLSs); SR9009 had no obvious pro-apoptotic effect on cells (Fig. 1e, f)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic complicated autoimmune disease characterized by synovial hyperplasia, pannus formation, and bone and cartilage destruction. Liu et al Cell Death and Disease (2020)11:129 identification of a factor with anti-inflammatory and antibone destruction activity would promote the development of novel agents for RA. NR1D1, known as REV-ERBα, is a member of the nuclear receptor 1D subfamily and functions as a transcriptional repressor[9,10]. It inhibits transcription of a target gene by binding to the REV-ERB response element. Studies have shown that NR1D1 is closely related to various physiological processes of cells, including cell differentiation, metabolism, mitochondrial biosynthesis, and inflammatory responses, making it a potential therapeutic target for cancer, dyslipidemia, and inflammatory diseases[13,14,15]

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Results

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