Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1158331 | ENA |
REPOSITORIES: ENA
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Project description:To address the regulation of interferon-stimulated genes expression by VGLL3 in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) patients, VGLL3 was overexpressed in RA-FLS via a lentiviral vector. After four days of transfection, VGLL3-overexpressed RA-FLS and vector-transfected RA-FLS were subjected to RNA sequencing.
2022-08-17 | GSE200030 | GEO
Project description:Huntingtin-interacting protein 1 Related (HIP1R) protein, shares some function similarities with HIP1, and HIP1 regulates arthritis and RA fibroblast-like synoviocytes (FLS) invasiveness. Therefore, we hypothesized that HIP1R might be involved in the regulation of FLS phenotypes and molecular processes relevant to RA. siRNA was used to knockdwon HIP1R, HIP1 or control in RA FLS followed by cell studies for invasion in Matrigel, migration, proliferation and adhesion. RNA was sequenced and analyzed. HIP1R knockdown significantly reduced RA FLS invasiveness and migration (P<0.05). The DEGs in siRNA HIP1R had an enrichment for GO processes “astrocyte and glial cell projection”, “small GTPase signaling” and “PDGFR signaling”. The most significantly DEGs had decreased expression in siRNA HIP1R and included AKT1S1, GABBR2, GPR56, and TXNDC12. siRNA HIP1 RA FLS had an enrichment for the “Rap1 signaling pathway” and “Growth factor receptor binding”. The most significantly DEGs in HIP1 siRNA included FGF2, PGF, and SLC39A8. HIP1R and HIP1 DEG lists had a greater than expected number of similar genes (P=0.0015), suggesting that, despite the major differences detected, both have partially overlapping functions in RA FLS. The most significant DEGs in both HIP1R and HIP1 analyses are involved in cancer cell behaviors and outcomes. HIP1R is a new gene implicated in RA FLS invasiveness and migration, and regulates unique pathways and cell processes relevant to both RA as well as cancer biology. Our study provides new insight into processes implicated in FLS invasiveness, which is relevant for joint damage in RA, and identify new potential gene targets for FLS-specific treatments.
2024-11-21 | GSE278613 | GEO
Project description:Fibroblast-like synoviocytes (FLS) are crucial in promoting articular inflammation and destruction in rheumatoid arthritis (RA). As the most abundant RNA modification, the function of m6A in RA FLS is still unclear. Here, we constructed FTO-knockdown FLS to explore the mechanism of FTO in regulating the aggressive behavior of RA FLS.
2024-12-31 | GSE241249 | GEO
Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS
2014-01-09 | E-GEOD-49604 | biostudies-arrayexpress
Project description:Rheumatoid arthritis (RA) is an inflammatory autoimmune disease affecting synovial joints and leading to cartilage damage and bone loss. This destruction is promoted by activated fibroblast-like synoviocytes (FLS) that show an invasive and migratory phenotype. The mechanisms of FLS activation are unknown, but evidence suggests that pre-damaged extracellular matrix (ECM) of the cartilage can trigger FLS activation. Integrin α11β1 might be involved in the activation, as it is highly increased in the synovium of RA patients and hTNFtg mice, an RA mouse model. Since TNFα is the major cytokine induced in RA, we treated murine chondrocytes with TNFα to produce a damaged, RA-like matrix. Comparison to healthy chondrocyte matrix revealed decreased ECM proteins, including several collagens and proteoglycans, increased matrix-degrading proteins and elevated levels of inflammatory cytokines. FLS responded to those differences in the damaged chondrocyte matrix with a matrix-remodeling and pro-inflammatory phenotype characterized by expressing genes involved in matrix degradation and increased production of CLL11 and CCL19. Damaged chondrocyte matrix induced increased Itga11 expression in FLS, which correlates with the increased α11β1 amounts in RA patients. FLS deficient in integrin α11β1 released lower amounts of inflammation-associated cytokines but did not reveal significant differences from the response of wild type FLS to a damaged, RA-like matrix. Our results demonstrate differences in healthy and RA-like chondrocyte ECM and distinctly different responses of wt FLS to damaged versus healthy ECM.
2025-01-14 | PXD049800 | Pride
Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions.
2014-01-09 | GSE49604 | GEO
Project description:Fibroblast-like synoviocyte (FLS) constitutes a major cell subset of rheumatoid arthritis (RA) joint. Dysregulation of microRNAs (miRNAs) contributes to FLS activation in the context of chronic inflammation. However, functional association of the miRNAs-targets relationships characterizing FLS phenotypes in RA has not been fully elucidated yet. Thus, we uncovered the novel miRNA-target interactions characterizing pathologic phenotypes of RA-FLS. We performed microarray analyses of miRNA in RA- and osteoarthritis (OA) FLS with or without interleukin-1β (IL-1β) stimulation. The miRNA-target prediction and network model-ing were performed using TargetScan and Cytoscape. Identified miRNA-target relationships and their cellular functions were validated in vitro.
2017-10-31 | GSE91026 | GEO
Project description:Objectives: TNF-induced activation of fibroblast-like synoviocytes (FLS) is a critical determinant for synovial inflammation and joint destruction in rheumatoid arthritis (RA). The detrimental role of TNF-receptor 1 (TNFR1) has thoroughly been characterized. The contributions of TNFR2, however, are largely unknown. This study was performed to delineate the role of TNFR2 in human FLS activation. Methods: TNFR2 expression in synovial tissue samples was determined by immunohistochemistry. Expression of TNFR2 was silenced using RNAi or CRISPR/Cas9 technologies. Global transcriptional changes were determined by RNA-seq. QPCR, ELISA and immunoblotting were used to validate RNA-seq results and to uncover pathways operating downstream of TNFR2 in FLS. Results. TNFR2 expression was increased in RA when compared to OA synovial tissues. In particular, RA-FLS demonstrated higher levels of TNFR2 when compared to OA-FLS. TNFR2 expression in RA-FLS correlated with RA disease activity, synovial T- and B-cell infiltration. TNF and IL1 were identified as inflammatory mediators that upregulate TNFR2 in RA-FLS. Silencing of TNFR2 in RA-FLS markedly diminished the TNF-induced expression of inflammatory cytokines and chemokines, including CXCR3-binding chemokines and the B-cell activating factor TNFSF13B. Immunobiochemical analyses revealed that TNFR2-mediated expression of inflammatory mediators critically depends on STAT1. Conclusion: Our results define a critical role for TNFR2 in FLS-driven inflammation and unfold its participation in the unresolved course of synovial inflammation in RA.
2022-04-26 | GSE195557 | GEO
Project description:Invasive pannus, mainly composed of fibroblast-like synoviocytes (FLSs), is a hallmark of rheumatoid arthritis (RA) pathology. Secreted proteins from RA-FLS play key roles in RA invasive pannus. However, RA-FLS-derived secretome associated with invasive pannus has not been systematically investigated. Here, we first identified 843 secreted proteins from RA-FLSs treated with TNFα and IL-1β using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Functional enrichment analysis revealed that 58.5% (493 proteins) of the secretome were associated with pannus-driven RA pathologies. Among them, parallel reaction monitoring (PRM) analysis then identified 16 secreted proteins that were increased in RA SFs (117 samples) than in OA SFs (45 samples). Of them, MYH9 further showed significant positive correlations with RA pathological parameters, such as synovial hyperplasia, increased articular vascularity, and inflammation severity. Molecular and cellular experiments confirmed that MYH9 was expressed in RA-FLSs and more highly under disease-aggravating conditions, and MYH9 depletion significantly defected migration and invasion of RA-FLS in RA pannus. Our study provides a comprehensive resource of RA-FLS-derived secretome, and our results suggest MYH9 that was increased in RA SF and strongly correlated with disease severity as a potential therapeutic target for invasive pannus.
2023-06-30 | PXD041077 | Pride