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Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis.

ABSTRACT: Background: Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis. Methods: Therapeutic effect of BRD4 specific inhibitor JQ-1 on acute gouty arthritis was evaluated in vivo and in vitro. Pyroptosis was analyzed by Caspase-1/PI double staining and cleavage of gasdermin D (GSDMD). Expression of key factors involved in BRD4/NF-?B/NLRP3/GSDMD signaling pathway were measured by western blot, and colocalization of NLRP3 and ASC was detected using immunofluorescence. In addition, the role of BRD4 on monosodium uric acid crystals (MSU)-induced pyroptosis was verified in BRD4 siRNA-transfected THP-1 cells. Results: Pretreatment of JQ1 and BRD4 siRNA significantly suppressed pyroptosis and inhibited activation of p65 NF-?B signaling as well as NLRP3 inflammasome in THP-1 cells exposed to MSU. In vivo, JQ-1 administration could effectively attenuate joint swelling and synovial inflammation in rats treated by intra-articular injection of MSU. More importantly, MSU led to macrophage pyroptosis and Brd4/NF-?B/NLRP3/GSDMD signaling induction in rat synoviums, which was improved by JQ-1. Conclusions: Our study identifies the role of BRD4 in MSU-induced pyroptosis through regulating NF-?B/NLRP3/GSDMD signaling pathways, which provides a potential target for treatment of acute gouty arthritis.

SUBMITTER: Hao K

PROVIDER: S-EPMC7645998 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis.

Hao Kun K Jiang Wenjiao W Zhou Mengze M Li Hanwen H Chen Yadong Y Jiang Fei F Hu Qinghua Q

International journal of biological sciences 20201017 16

<b>Background:</b> Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis. <b>Methods:</b> Therapeutic effect of BRD4 specific inhibitor JQ-1 on acute gouty arthritis was evaluated in vivo and in vitro. Pyroptosis was analyzed by Caspase-1/PI double ...[more]

PMID: 33162822

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Project description:OBJECTIVE:To assess the safety and efficacy of etoricoxib, a selective cyclo-oxygenase-2 inhibitor, in comparison with indometacin in the treatment of acute gouty arthritis. DESIGN:Randomised, double blind, active comparator controlled trial. SETTING:43 outpatient study centres in 11 countries. PARTICIPANTS:142 men and eight women (75 patients per treatment group) aged 18 years or over presenting with clinically diagnosed acute gout within 48 hours of onset. INTERVENTIONS:Etoricoxib 120 mg administered orally once daily versus indometacin 50 mg administered orally three times daily, both for 8 days. MAIN OUTCOME MEASURES:Patients' assessment of pain in the study joint over days 2 to 5 (primary end point); investigators' and patients' global assessments of response to treatment and tenderness of the study joint (key secondary end points). RESULTS:Etoricoxib showed efficacy comparable to indometacin. Patients' assessment of pain in the study joint (0-4 point Likert scale, "no pain" to "extreme pain") over days 2 to 5 showed a least squares mean change from baseline of -1.72 (95% confidence interval -1.90 to -1.55) for etoricoxib and -1.83 (-2.01 to -1.65) for indometacin. The difference between treatment groups met prespecified comparability criteria. All other efficacy end points, including those reflecting reduction in inflammation and analgesia, provided corroborative evidence of comparable efficacy. Significant pain relief was evident at the first measurement, 4 hours after the first dose of treatment. Prespecified safety analyses revealed that drug related adverse experiences occurred significantly less frequently with etoricoxib (22.7%) than with indometacin (46.7%) (P=0.003), although overall adverse experience rates were similar between the two treatment groups. CONCLUSION:Etoricoxib 120 mg once daily provides rapid and effective treatment for acute gouty arthritis comparable to indometacin 50 mg three times daily. Etoricoxib was generally safe and well tolerated in this study.

Project description:BackgroundGout is considered one of the most painful acute conditions caused by deposition of monosodium urate (MSU) crystals within joints. Recent studies have shown that interleukin (IL)-1β is a key inflammatory mediator in acute gouty arthritis (GA), and its level is regulated by microRNAs (miRNAs). However, the molecular mechanisms of the regulation remain unclear.MethodsA miRNA microarray was used to analyze the miRNA expression profiles in peripheral white blood cells (WBCs) of patients with GA. THP-1 cells were transfected with miRNA mimics, stimulated by MSU crystals, and then subjected to quantitative real-time polymerase chain reaction or Western blot analysis. Levels of IL-1β, IL-8, and tumor necrosis factor (TNF)-α in culture supernatants of THP-1 cells were measured by enzyme-linked immunosorbent assay. A luciferase reporter assay was conducted to confirm the interaction of miRNA and IL-1β 3'-untranslated regions (UTRs).ResultsCombining bioinformatics and miRNA expression profiles, we found five miRNAs (hsa-miR-30c-1-3p, hsa-miR-488-3p, hsa-miR-550a-3p, hsa-miR-663a, and hsa-miR-920) that possibly target IL-1β. Then, we demonstrated that miR-488 and miR-920 were significantly decreased in the WBCs of patients with GA and that MSU crystals could inhibit expression of miR-488 and miR-920. Upregulation of miR-488 and miR-920 could suppress MSU-induced IL-1β protein expression in THP-1 cells, but no significant difference in IL-1β messenger RNA levels was observed. Moreover, we found that miR-488 and miR-920 could directly target the 3'-UTR of IL-1β. Overexpression of miR-488 and miR-920 could significantly inhibit the gene and protein expression of IL-8 and TNF-α in MSU-induced THP-1 cells.ConclusionsThis study demonstrates the roles of miR-488 and miR-920 in regulating the production of proinflammatory cytokines in the pathogenesis of GA. These findings suggest that miR-488 and miR-920 could serve as potential therapeutic targets in the treatment of GA.

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Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis.

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Targeting BRD4 prevents acute gouty arthritis by regulating pyroptosis.

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