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Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia.

ABSTRACT: Synovial hyperplasia is the main cause of chronic rheumatoid arthritis (RA), but the mechanism of synovial hyperplasia is still unclear. Etodolac (ETD) is a selective COX-2 inhibitor for relieving pain and stiffness in RA, but the disease modifying effect is still lack of evidence. Proteomics method was used to study the differential proteome of synovial tissue in collagen induced arthritis (CIA) in rats. With the help of STRING analysis, the upregulated proteins enriched in the cluster of complement and coagulation cascades and platelet degranulation were highlighted, these proteins with fibrogenic factors Lum, CIV, CXI and Tgfbi participated in the synovial inflammation, fibrosis and hyperplasia in CIA. Based on KOG function class analysis, the proteins involved in the events of the central dogma was explored. They might be hyperplasia related proteins for most of them are related to the proliferation of cancer. ETD significantly attenuated synovial inflammation, fibrosis and hyperplasia in CIA rats by downregulating these proteins. Several proteins have not been observed in RA so far, such as Tmsb4x, Pura, Nfic, Ruvbl1, Snrpd3, U2af2, Srrm2, Srsf7, Elavl1, Hnrnph1, Wars, Yars, Bzw2, Mcts1, Eif4b, Ctsh, Lamp1, Dpp7, Ptges3, Cdc37 and Septin9, they might be potentials targets for RA. Blood biochemistry tests showed the safety of 7 months use of ETD on rats. In conclusion, present study displayed a comprehensive mechanism of synovial hyperplasia in CIA rats, on this basis, the clinical value of ETD in the treatment of RA was well confirmed.

SUBMITTER: Feng Q

PROVIDER: S-EPMC8607370 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia.

Feng Qin Q Xia Wenkai W Wang Shenglan S Dai Guoxin G Jiao Weimei W Guo Na N Li Honghua H Zhang Guimin G

Molecular biomedicine 20211025 1

Synovial hyperplasia is the main cause of chronic rheumatoid arthritis (RA), but the mechanism of synovial hyperplasia is still unclear. Etodolac (ETD) is a selective COX-2 inhibitor for relieving pain and stiffness in RA, but the disease modifying effect is still lack of evidence. Proteomics method was used to study the differential proteome of synovial tissue in collagen induced arthritis (CIA) in rats. With the help of STRING analysis, the upregulated proteins enriched in the cluster of compl ...[more]

PMID: 35006449

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Project description:ObjectiveRheumatoid arthritis synovial fibroblasts (RASFs) are crucial mediators of synovial inflammation and joint destruction. However, their intrinsic immunoregulatory mechanisms under chronic inflammation remain unclear. Thus, the present study was undertaken to understand the role of a newly identified GTPase, guanylate binding protein 5 (GBP-5), in RA pathogenesis.MethodsThe expression of GBP1-GBP7 transcripts was evaluated using quantitative reverse transcription-polymerase chain reaction in RA synovial tissue or synovial tissue unaffected by RA. Our investigation on transient small interfering RNA (siRNA) knockdown and lentiviral overexpression in human RASFs examined the regulatory role of GBP-5 on proinflammatory cytokine signaling pathways. Unbiased whole transcriptome RNA sequencing analysis was used to assess the impact of GBP-5 on RASF molecular functions. These findings were confirmed using a rat model of adjuvant-induced arthritis (AIA) in vivo.ResultsAmong different GBPs evaluated, GBP-5 was selectively up-regulated in RA synovial tissue (P < 0.05; n = 4) and in the joints of rats with AIA (P < 0.05; n = 6) and was significantly induced in human RASFs by interleukin-1β (IL-1β), tumor necrosis factor (TNF), and/or interferon-γ (IFNγ) (P < 0.05; n = 3). Bioinformatics analysis of RNA sequencing data identified cytokine-cytokine receptor signaling as a major function altered by GBP-5, with IL-6 signaling as a primary target. Knockdown of GBP-5 amplified IL-1β-induced IL-6, IL-8, and epithelial neutrophil-activating peptide 78/CXCL5 production by 44%, 54%, 45%, respectively, and matrix metalloproteinase 1 (MMP-1) production by several-fold-effects that reversed with exogenously delivered GBP-5. Lack of GBP-5 increased IFNγ-induced proliferation and migration of human RASFs. GBP-5 knockdown in vivo using intraarticular siRNA exacerbated disease onset, severity, synovitis, and bone destruction in rat AIA.ConclusionExpressed by RASFs in response to cytokine stimulation, GBP-5 has potential to restore cellular homeostasis and blunt inflammation and tissue destruction in RA.

Dataset Information

Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia.

Publications

Etodolac improves collagen induced rheumatoid arthritis in rats by inhibiting synovial inflammation, fibrosis and hyperplasia.

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