Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA  

作　　者：Yan-Ying Liu 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 

机构地区：[1]Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis(BZ0135),Peking University People's Hospital,Beijing 100044,China [2]Center of Clinical Immunology,Peking University,Beijing 100044,China

出　　处：《Chinese Medical Journal》2020年第6期679-686,共8页中华医学杂志（英文版）

基　　金：This work was supported by grants from the National Key R&D Program of China(No.2017YFA0105802);National Natural Science Foundation of China(Nos.81771678,81801617);Peking University People's Hospital Research and Development Funds(No.RDH 2017-02&RDX 2019-02).

摘　　要：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)-pi,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)-kB,interleukin-1 receptor-associared kinase(IRAK)1,extracellular regulated protein kinases(ERK)1,Jun N-terminal kinase(JNK)and p-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 IRAKI 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.

关 键 词：DICKKOPF-1 Fibroblast-like SYNOVIOCYTES RHEUMATOID ARTHRITIS small interfering RNAS 

分 类 号：R593.22[医药卫生—内科学]