Dataset Information

FOXM1/LINC00152 feedback loop regulates proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via Wnt/?-catenin signaling pathway.

ABSTRACT: Rheumatoid arthritis (RA), a chronic systemic disease, is featured with inflammatory synovitis, which can lead to destruction on bone and cartilage and even cause disability. Emerging studies demonstrated that Fibroblast-like synoviocytes (FLS) is a vital cellular participant in RA progression. Long non-coding RNAs (lncRNAs) are also reported to participate in the pathogenesis of RA. In our present study, lncRNA microarray analysis was applied to screen out lncRNAs differentially expressed in RA FLS. Among which, cytoskeleton regulator RNA (LINC00152) presented biggest fold change. Gain- or loss-of function assays were further carried out in RA FLS, and the results revealed that LINC00152 promoted proliferation but induced apoptosis in RA FLS. Furthermore, up-regulation of LINC00152 may induce promotion of Wnt/?-catenin signaling pathway in RA FLS. Mechanistically, we found that forkhead box M1 (FOXM1) transcriptionally activated LINC00152 in RA FLS. Additionally, LINC00152 positively regulated FOXM1 via sponging miR-1270. In conclusion, the present study focused on elucidating the function of FOXM1/LINC00152 positive feedback loop in RA FLS and its association with Wnt/?-catenin signaling.

SUBMITTER: Wang W

PROVIDER: S-EPMC6974425 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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FOXM1/LINC00152 feedback loop regulates proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via Wnt/β-catenin signaling pathway.

Wang Wenlong W Guo Piaopiao P Chen Mengjie M Chen Die D Cheng Yongjun Y He Long L

Bioscience reports 20200101 1

Rheumatoid arthritis (RA), a chronic systemic disease, is featured with inflammatory synovitis, which can lead to destruction on bone and cartilage and even cause disability. Emerging studies demonstrated that Fibroblast-like synoviocytes (FLS) is a vital cellular participant in RA progression. Long non-coding RNAs (lncRNAs) are also reported to participate in the pathogenesis of RA. In our present study, lncRNA microarray analysis was applied to screen out lncRNAs differentially expressed in RA ...[more]

PMID: 31854447

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Project description:ObjectiveUp-regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in rheumatoid arthritis (RA), particularly in fibroblast-like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage.MethodsSynovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA). The rate of glycolysis after stimulation of FLS with lipopolysaccharide and platelet-derived growth factor BB was measured using glycolysis stress test technology. FLS function was evaluated using a glycolysis inhibitor, 2-deoxy-d-glucose (2-DG). After stimulation of the FLS, a migration scratch assay, MTT assay, and enzyme-linked immunosorbent assay were performed to measure the effect of 2-DG on FLS migration, viability of the FLS, and cytokine secretion, respectively. IRDye 800CW 2-DG was used to assess glucose uptake in the arthritic joints and stromal cells of mice after K/BxN mouse serum transfer. The mice were injected daily, intraperitoneally, with 3-bromopyruvate (BrPa; 5 mg/kg) to assess the effect of inhibition of glycolysis in vivo.ResultsCompared to human OA FLS, the balance between glycolysis and oxidative phosphorylation was shifted toward glycolysis in RA FLS. Glucose transporter 1 (GLUT1) messenger RNA (mRNA) expression correlated with baseline functions of the RA FLS. Glucose deprivation or incubation of the FLS with glycolytic inhibitors impaired cytokine secretion and decreased the rate of proliferation and migration of the cells. In a mouse model of inflammatory arthritis, GLUT1 mRNA expression in the synovial lining cells was observed, and increased levels of glucose uptake and glycolytic gene expression were detected in the stromal compartment of the arthritic mouse joints. Inhibition of glycolysis by BrPa, administered in vivo, significantly decreased the severity of arthritis in this mouse model.ConclusionTargeting metabolic pathways is a novel approach to understanding the mechanisms of disease. Inhibition of glycolysis may directly modulate synoviocyte-mediated inflammatory functions and could be an effective treatment strategy for arthritis.

Project description:ObjectiveRheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) derived from hip and knee have distinctive DNA methylation and transcriptome patterns in interleukin (IL)-6 signaling and Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. To determine the functional effects of these joint-specific signatures, we evaluated how RA hip and knee FLS differ in their response to IL-6.MethodsHip or knee RA FLS were obtained after arthroplasty. Previously published datasets on epigenetic landscape of FLS were mined to identify joint-specific IL-6-related epigenomic differences. RNA sequencing was performed on five RA hip and five knee FLS treated with or without IL-6. Differential gene expression was determined using edgeR software. STAT3 phosphorylation was measured using bead assays. Sensitivity to tofacitinib was evaluated by measuring CCL2 inhibition using quantitative polymerase chain reaction.ResultsAssay for Transposase-Accessible Chromatin sequencing and histone chromatin immunoprecipitation sequencing datasets from RA FLS were analyzed to identify epigenomic differences between hip and knee. Differential chromatin accessibility was associated with IL-6,IL-6R, and JAK1 genes. H3K27ac was also differentially marked at other JAK-STAT-related genes, including STAT3-STAT5A region. Principal component analysis of RNA sequencing data confirmed segregation between RA hip and knee FLS under basal conditions, that persisted following IL-6 treatment. STAT3 phosphorylation after IL-6 was significantly higher in knee than hip FLS and was highly correlated with JAK1 protein levels. Knee FLS were less sensitive to the JAK inhibitor tofacitinib than hip FLS.ConclusionRA hip and knee FLS have distinct transcriptomes, epigenetic marks, and STAT3 activation patterns in the IL-6 pathway. These joint-specific differences might contribute to a differential clinical response in individual joints to targeted therapies such as JAK inhibitors.

Dataset Information

FOXM1/LINC00152 feedback loop regulates proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via Wnt/?-catenin signaling pathway.

Publications

FOXM1/LINC00152 feedback loop regulates proliferation and apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via Wnt/β-catenin signaling pathway.

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