Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA
10.1097/CM9.0000000000000697
- VernacularTitle:Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA
- Author:
Yan-Ying LIU
1
;
Shi-Yao WANG
;
Ying-Ni LI
;
Wen-Jie BIAN
;
Lin-Qi ZHANG
;
Yu-Hui LI
;
Li LONG
;
Xia LIU
;
Xue-Wu ZHANG
;
Zhan-Guo LI
Author Information
1. Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China;Center of Clinical Immunology, Peking University, Beijing 100044, China.
- Keywords:
Dickkopf-1;
Fibroblast-like synoviocytes;
Rheumatoid arthritis;
small interfering RNAs
- From:
Chinese Medical Journal
2020;133(6):679-686
- CountryChina
- Language:Chinese
-
Abstract:
Background::Fibroblast-like synoviocytes (FLSs), resident mesenchymal cells of synovial joints, play an important role in the pathogenesis of rheumatoid arthritis (RA). Dickkopf-1 (DKK-1) has been proposed to be a master regulator of bone remodeling in inflammatory arthritis. Here, potential impairation on the activity of FLSs derived from RA to small interfering RNAs (siRNAs) targeting DKK-1 was investigated.Methods::siRNAs targeting DKK-1 were transfected into FLSs of patients with RA. Interleukin (IL)-1β, IL-6, IL-8, matrix metalloproteinase (MMP) 2, MMP3, MMP9, transforming growth factor (TGF)-β1, TGF-β2 and monocyte chemoattractant protein (MCP)-1 levels in the cell culture supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Invasion assay and 3H incorporation assay were utilized to investigate the effects of siRNAs targeting DKK-1 on FLSs invasion and cell proliferation, respectively. Western blotting was performed to analyze the expression of nuclear factor (NF)-κB, interleukin-1 receptor-associated kinase (IRAK)1, extracellular regulated protein kinases (ERK)1, Jun N-terminal kinase (JNK) and β-catenin in FLSs. Results::DKK-1 targeting siRNAs inhibited the expression of DKK-1 in FLSs ( P < 0.01). siRNAs induced a significant reduction of the levels of IL-6, IL-8, MMP2, MMP3 and MMP9 in FLSs compared to the control group ( P < 0.05). DKK-1 targeting siRNAs inhibited the proliferation and invasion of FLSs ( P < 0.05). Important molecules of pro-inflammatory signaling in FLSs, including IRAK1 and ERK1, were decreased by the inhibition of DKK-1 in FLSs. In contrast, β-catenin, a pivotal downstream molecule of the Wnt signaling pathway was increased. Conclusions::By inhibiting DKK-1, we were able to inhibit the proliferation, invasion and pro-inflammatory cytokine secretion of FLSs derived from RA, which was mediated by the ERK or the IRAK-1 signaling pathway. These data indicate the application of DKK-1 silencing could be a potential therapeutic approach to RA.
