PMID- 32068606 OWN - NLM STAT- MEDLINE DCOM- 20210121 LR - 20210211 IS - 2542-5641 (Electronic) IS - 0366-6999 (Print) IS - 0366-6999 (Linking) VI - 133 IP - 6 DP - 2020 Mar 20 TI - Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA. PG - 679-686 LID - 10.1097/CM9.0000000000000697 [doi] AB - 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)-1beta, IL-6, IL-8, matrix metalloproteinase (MMP) 2, MMP3, MMP9, transforming growth factor (TGF)-beta1, TGF-beta2 and monocyte chemoattractant protein (MCP)-1 levels in the cell culture supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Invasion assay and H 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)-kappaB, interleukin-1 receptor-associated kinase (IRAK)1, extracellular regulated protein kinases (ERK)1, Jun N-terminal kinase (JNK) and beta-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, beta-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. FAU - Liu, Yan-Ying AU - Liu YY AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Wang, Shi-Yao AU - Wang SY AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Li, Ying-Ni AU - Li YN AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Bian, Wen-Jie AU - Bian WJ AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Zhang, Lin-Qi AU - Zhang LQ AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Li, Yu-Hui AU - Li YH AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Long, Li AU - Long L AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Liu, Xia AU - Liu X AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Zhang, Xue-Wu AU - Zhang XW AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. FAU - Li, Zhan-Guo AU - Li ZG AD - Department of Rheumatology and Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing 100044, China. AD - Center of Clinical Immunology, Peking University, Beijing 100044, China. LA - eng PT - Journal Article PL - China TA - Chin Med J (Engl) JT - Chinese medical journal JID - 7513795 RN - 0 (DKK1 protein, human) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Interleukin-8) RN - 0 (RNA, Small Interfering) RN - 0 (Transforming Growth Factor beta1) RN - 0 (Transforming Growth Factor beta2) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Adult MH - Arthritis, Rheumatoid/genetics/*metabolism MH - Blotting, Western MH - Cell Proliferation/genetics/physiology MH - Cells, Cultured MH - Female MH - Fibroblasts/*cytology/*metabolism MH - Humans MH - Intercellular Signaling Peptides and Proteins/genetics/*metabolism MH - Interleukin-1beta/metabolism MH - Interleukin-6/metabolism MH - Interleukin-8/metabolism MH - Male MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 3/metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Middle Aged MH - RNA, Small Interfering MH - Synoviocytes/*cytology/*metabolism MH - Transforming Growth Factor beta1/metabolism MH - Transforming Growth Factor beta2/metabolism PMC - PMC7190238 COIS- The authors declare that they have no conflicts of interest. EDAT- 2020/02/19 06:00 MHDA- 2021/01/22 06:00 PMCR- 2020/03/20 CRDT- 2020/02/19 06:00 PHST- 2020/02/19 06:00 [pubmed] PHST- 2021/01/22 06:00 [medline] PHST- 2020/02/19 06:00 [entrez] PHST- 2020/03/20 00:00 [pmc-release] AID - 00029330-202003200-00008 [pii] AID - CMJ-2019-1726 [pii] AID - 10.1097/CM9.0000000000000697 [doi] PST - ppublish SO - Chin Med J (Engl). 2020 Mar 20;133(6):679-686. doi: 10.1097/CM9.0000000000000697.