Activity of fibroblast-like synoviocytes in rheumatoid arthritis was impaired by dickkopf-1 targeting siRNA.
Chin Med J (Engl)
; (6): 679-686, 2020 Mar 20.
Article
em En
| MEDLINE
| ID: mdl-32068606
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)-1ß, IL-6, IL-8, matrix metalloproteinase (MMP) 2, MMP3, MMP9, transforming growth factor (TGF)-ß1, TGF-ß2 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)-κB, interleukin-1 receptor-associated kinase (IRAK)1, extracellular regulated protein kinases (ERK)1, Jun N-terminal kinase (JNK) and ß-catenin in FLSs.RESULTS:
DKK-1 targeting siRNAs inhibited the expression of DKK-1 in FLSs (Pâ<â0.01). siRNAs induced a significant reduction of the levels of IL-6, IL-8, MMP2, MMP3 and MMP9 in FLSs compared to the control group (Pâ<â0.05). DKK-1 targeting siRNAs inhibited the proliferation and invasion of FLSs (Pâ<â0.05). Important molecules of pro-inflammatory signaling in FLSs, including IRAK1 and ERK1, were decreased by the inhibition of DKK-1 in FLSs. In contrast, ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
/
Peptídeos e Proteínas de Sinalização Intercelular
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Fibroblastos
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Sinoviócitos
Limite:
Adult
/
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Chin Med J (Engl)
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China