Transcriptomic analysis of synovial cells derived from collagen-induced arthritis mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192504 | GEO | 2022/07/06
REPOSITORIES: GEO
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Project description:Aim: Synovial fibroblasts (SFs) undergo a rewiring of their DNA methylation landscape that is associated with their development of an aggressive pathogenic phenotype during Rheumatoid Arthritis (RA), both in humans and in CIA, a mouse model of this chronic inflammatory disease. The helminth-derived immunomodulator, ES-62 acts to prevent joint destruction in CIA by suppressing pathogenic SF responses. We therefore investigated whether ES-62 suppressed the changes in DNA methylation observed in SFs from CIA, relative to those from healthy, mice. Methods: The DNA methylation status of SFs from naïve (no induction of CIA), CIA and ES-62-treated mice undergoing CIA (CIA_ES-62) was compared by Reduced Representation Bilsulphite Sequencing (RRBS) analysis performed by the Active Motif service. Results: Synovial fibroblasts from naive, CIA and CIA_ES-62 mice exhibit differential genomic methylation profiles. Conclusion: ES-62 protection against joint protection in CIA is not associated with prevention of the changes in DNA methylation occurring during rewiring of naive SFs to aggressively pathogenic CIA SFs but rather, reflects generation of a distinct ES-62 phenotype of SF genomic methylation.
2021-03-01 | GSE158185 | GEO
Project description:Synovial fibroblasts critically contribute to the pathogenesis of rheumatoid arthritis (RA) by acquiring either a pro-inflammatory or tissue-destructive phenotype. To explore the molecular mechanisms underlying the tissue-destructive fibroblast phenotype in arthritis, we performed bulk RNA-sequencing analysis on the synovial fibroblasts which were isolated from Col6a1-Cre-Ets1-flox/flox (Ets1ΔFib) and Ets1-flox/flox (Ets1flox) mice.
2022-07-06 | GSE201310 | GEO
Project description:In arthritis, synovial fibroblast (SF) senescence is linked to the activation of a pro-inflammatory phenotype contributing to chronic arthritis pathogenesis. Additionally, senescent cells accumulate in ageing tissues further promoting ageing and inflammation. These cells have dysregulated mitochondrial function and metabolism, limited tissue regeneration, produce reactive oxygen species (ROS) and secrete bioactive molecules, including pro-inflammatory cytokines, chemokines and matrix-remodelling enzymes known as SASP (senescence-associated secretory phenotype). In vitro, senescent cells can induce a senescent phenotype in surrounding bystander cells. Interestingly, extracellular vesicles (EVs) have critical roles in cellular senescence and ageing and are mediators in intercellular communication. We hypothesize that senescent cells in osteoarthritic SFs induce senescence and/or a proinflammatory phenotype in non-senescent osteoarthritic SFs, mediated through EV cargo.
2022-10-15 | PXD032757 | Pride
Project description:OBJECTIVE: MicroRNAs (miRNAs, miRs), a class of small non-coding RNA molecules, are posttranscriptional regulators involved in a plethora of cellular functions and have been proposed as potential therapeutic targets in various diseases, including rheumatoid arthritis (RA). In this study, we sought to discover novel miR associations in synovial fibroblasts (SFs), a key cell type mediating RA pathogenesis, by performing miR expression profiling on cells isolated from the human TNF transgenic mouse model (TghuTNF or Tg197). METHODS: miR expression in SFs isolated from 8-week-old, fully diseased TghuTNF and WT littermate control mice were determined by deep sequencing of small RNAs and the arthritic profile was established by pairwise comparisons of the two groups. qRT-PCR analysis was utilised for profile validation purposes and miR quantitation in patient SFs. Dysregulated miR target genes and pathways were predicted via bioinformatic algorithms. Synovial Fibroblasts isolated from TghuTNF mice (2 x biological replicates) and control WT littermate mice (2 x biological replicates)
2012-05-13 | E-GEOD-31667 | biostudies-arrayexpress
Project description:We observed resolution of inflammatory response in collagen-induced arthritis (CIA) mice. To identify molecular signatures defining resolution of the CIA, we applied microarray analysis for synovial tissues in the CIA mice in 6 (induction), 9 (peak) and 15 weeks (resolution) after immunization. To identify genes related to CIA resolution, we performed the following comparisons of gene expression profiles: peak versus induction phase and resolution versus peak phase. We identified that three genes, Itgb1, Ywhaz and Rps3, are the key regulators for the resolution by measuring degree, betweenness and closeness centrality in reconstructed network based on protein-protein interaction data. To confirm this result, we compared the gene and protein expression level of the three regulators between the two phases of inflammation. Furthermore, we showed that the gene and protein expression level of the three regulators are up-regulated in regulatory T cells and type 2 macrophages than other subtypes of CD4+ T cells and macrophages, and also we examined that recombinant peritoneal macrophages of the three regulators can modulate the expression of pro-inflammatory and anti-inflammatory cytokines. Thus, our findings suggest that those regulators can be employed as therapeutic uses for resolving inflammation
2020-05-19 | GSE99087 | GEO
Project description:To determine te lncRNA expression profile in collagen-induced arthritis rats and normal rats, we uesed lncRNA microArray analysis form Arraystar to examine the expression of lncRNAs in CIA and normal rats' synovial tissues.
2022-11-16 | GSE206097 | GEO
Project description:MicroRNAs (miRNAs) constitute fine tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA), however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. We have shown in the past that the expression of the miR-221/222 cluster is upregulated in RA SFs. Here, we demonstrate that miR-221/222 activation is downstream of major inflammatory cytokines, such as TNF and IL-1β, which promote miR-221/222 expression independently. miR-221/222 expression in SFs from the huTNFtg mouse model of arthritis correlates with disease progression. Targeted transgenic overexpression of miR-221/222 in SFs of the huTNFtg mouse model led to further expansion of synovial fibroblasts and disease exacerbation. miR-221/222 overexpression altered the transcriptional profile of SFs igniting pathways involved in cell cycle progression and ECM regulation. Validated targets of miR-221/222 included p27 and p57 cell cycle inhibitors, as well as Smarca1 (a chromatin remodeling component). In contrast, complete genetic ablation of miR-221/222 in arthritic mice led to decreased proliferation of fibroblasts, reduced synovial expansion and attenuated disease. scATAC-seq data analysis revealed increased miR-221/222 gene activity in the pathogenic and activated clusters of the intermediate and lining compartment. Taken together, our results establish an SF-specific pathogenic role of the miR-221/222 cluster in arthritis and suggest that its therapeutic targeting in specific subpopulations should inform the design of novel fibroblast-targeted therapies for human disease.
2022-12-16 | GSE210887 | GEO
Project description:The goal of this study is to define the pathophysiology of synovial fibroblasts in chroninc joint inflammation using NGS-derived synovial transcriptome profiling (RNA-seq) Methods: Synovial fibroblasts were isolated by FACs sorting [CD45-CD31-Popdoplanin+] from the synovium of healthy mice and mice undergoing experimental Collagen-Induced Arthritis (12 weeks old)(CIA). Methods: Whole Transcriptome Profiling of healthy and CIA synovial fibroblasts were generated by deep sequencing, in triplicate, using Illumina NextSeq™ 500 platform. Libraries were prepared using polyA selection (TruSeq stranded mRNA kit). Methods: The sequence reads that passed quality filters were aligned to mouse reference genome (GRCM38) using Hisat2 version 2.1.0. we mapped about 30 million sequence reads per sample (75 bp, paired-end) Methods: Featurecounts version 1.4.6 was used to quantify reads counts. Data quality control, non-expressed gene filtering, median ratio normalization (MRN) implemented in DESeq2 package and identification of differentially expressed (DE) genes were done using the R bioconductor project DEbrowser. Results: Results: We detected several differentially expressed (DE) genes in CIA synovial fibroblasts compared to naïve cells. These included 298 up-regulated genes and 88 down-regulated (>2 fold, adjp <0.05). DE genes reflected the reflecting the hyperplasia and activation observed during chronic joint disease. Pathways associated to DE genes were cell cycle and cell division and inflammatory response. Conclusions: our study shows pathophysiological changes associated to inflammatory synovial fibroblasts in a model of rheumatoid arthritis. Cells were directly isolated from fresh tissue, providing a valuable tool to study stromal inflammation.
2020-11-30 | GSE162306 | GEO
Project description:Purpose: We analyzed RNA-seq from rheumatoid arthritis synovial fibroblats and osteoarthritis syniovial fibroblast patients. Our goal was to evaluate the gene expression signatures after treatment with the MyD88 dimerization onhibitor ST2825 and identify its therapeutic potential. Methods: We analyzed bulk RNA-seq from RA synovial fibroblasts in diferent conditions: Untreated, ST2825-treated, LPS-treated, LPS+ST2825-treated. Aditionally, we analyzed bulk RNA-seq from OA synovial fibroblatss as a control. Collection of RNA was performed after 24 h of treatment and samples were sequenced to determine transcriptional changes and regulated processes. Results: paired-end reads were mapped to the homo sapiens GRCh37 genome assembly. RNA levels were normalized by RPKM and student's t-test. Conclusion: The aggressiveness of the RA SFs, in terms of their proliferation, invasiveness, and increased expression of pain and inflammation mediators was decreased by ST2825. Our data strongly suggest that targeting MyD88 dimerization could mitigate joint inflammation in RA SFs.
2023-09-27 | GSE217012 | GEO
Project description:The variant rs26232, in the first intron of the C5orf30 locus, has recently been associated with both risk of developing rheumatoid arthritis (RA) and severity of tissue damage. The biological activities of human C5orf30 are unknown, and neither the gene nor protein show significant homology to any other characterized human sequences. The C5orf30 gene is present only in vertebrate genomes with a high degree of conservation implying a central function in these organisms. Here we report that C5orf30 is highly expressed in the synovium of RA patients compared with control synovial tissue, and that it is predominately expressed by synovial fibroblast (RASF) and macrophages in the lining and sublining layer of the tissue. These cells play a central role in the initiation and perpetuation of RA and are implicated in cartilage destruction. RASFs lacking C5orf30 exhibit increased cell migration and invasion in vitro and gene-profiling following C5orf30 inhibition confirmed upregulation of genes involved in cell migration, adhesion, angiogenesis, and immune and inflammatory pathways. Importantly, loss of C5orf30 contributes to the pathology of inflammatory arthritis in vivo, since inhibition of C5orf30 in the collagen-induced arthritis model markedly accentuated joint inflammation and tissue damage. Our study reveal C5orf30 to be a novel negative regulator of tissue damage in RA and this may act by modulating the autoaggressive phenotype that is characteristic of RASFs. Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that affects synovial joints. A key characteristic of RA is hyperplasia of fibroblast-like synoviocytes (FLS) which develop a stable, auto-aggressive phenotype that augments tissue destruction. It is unknown how this phenotype is stably maintained; however, epigenetic changes have been implicated. Histone deacetylation is one proposed method; a process controlled by histone deacetylases (HDACs). However, there have recently been reports publishing conflicting data regarding the expression of HDACs in RA synovium and FLS. The objective of this thesis is to determine the role of HDACs in regulating the auto-aggressive phenotype of RA through studies in FLS and in mice. Real time-quantitative PCR was used to assess the levels of HDAC1-11 in RA compared to osteoarthritis (OA) FLS. Immunohistochemistry and western blotting were used to assess protein expression of HDAC1 in RA and OA synovial tissue and FLS. HDAC1 was found to be overexpressed in RA compared to OA. HDAC1 was knocked down in RA FLS, then cell proliferation, migration and invasion were assessed by using tritiated thymidine, a scratch assay and a Matrigel invasion assay respectively. All three functions were significantly reduced following HDAC1 knockdown. An Illumina BeadChip (47,000 transcripts) was used to analyse global gene expression changes after knockdown. This revealed significant gene changes in important functional clusters, such as proliferation and migration. HDAC1 knockout is embryonic lethal in mice, so the in vivo role of HDAC1 was investigated in a mouse model of collagen-induced arthritis (CIA) using in vivo siRNAs. Clinical scores of CIA were measured daily and HDAC1 knockdown mice showed a significantly reduced clinical score compared to controls, comparable to dexamethasone-treated mice. The bones were analysed using a microCT scanner and histology. Knocking down HDAC1 showed reduced bone erosion, joint inflammation and cartilage degradation compared to controls. Overall, this study shows that HDAC1 is dysregulated in RA and it has a significant role in the autoaggressive phenotype shown in RA FLS and collagen-induced arthritis. The novel data shown in this thesis demonstrates that inhibiting HDAC1 may provide a powerful new target for treating RA. Three independent patient RASF samples were analysed in this study for each siRNA gene knockdown. Also a non targerting control siRNA was also used for each of the patient RASFs
2015-08-22 | E-GEOD-72258 | biostudies-arrayexpress