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Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis (MethylCap-Seq).

ABSTRACT: We used deep sequencing to probe the transcriptome, the methylome and the chromatin landscape of cultured mouse arthritogenic SFs at three stages of disease, as well as SFs stimulated with human TNF. We performed bioinformatics analyses at the gene, pathway and network levels, compared mouse and human data, and validated selected genes in both species.

ORGANISM(S): Mus musculus

PROVIDER: GSE95252 | GEO | 2017/04/19

SECONDARY ACCESSION(S): PRJNA376647

REPOSITORIES: GEO

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Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis (RNA-Seq).

Project description:We used deep sequencing to probe the transcriptome, the methylome and the chromatin landscape of cultured mouse arthritogenic SFs at three stages of disease, as well as SFs stimulated with human TNF. We performed bioinformatics analyses at the gene, pathway and network levels, compared mouse and human data, and validated selected genes in both species.

2017-04-19 | GSE95251 | GEO

Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis (H3K4me3-Seq).

2017-04-19 | GSE95254 | GEO

Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-04-19 | GSE95256 | GEO

Identification of microRNAs association with Rheumatoid Arthritis Synovial Fibroblasts using the Human TNF Transgenic Mouse Model

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

miR-221/222 drive synovial fibroblast expansion and pathogenesis of TNF-mediated arthritis

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

Identification of microRNAs association with Rheumatoid Arthritis Synovial Fibroblasts using the Human TNF Transgenic Mouse Model

2012-05-14 | GSE31667 | GEO

Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis

Project description:Genomic responses of mouse synovial fibroblasts during TNF-driven arthritogenesis greatly mimic those of human rheumatoid arthritis

| PRJNA376508 | ENA

Repurposing of Amisulpride, a known antipsychotic drug, to target synovial fibroblasts activation in arthritis.

Project description:Synovial Fibroblasts (SFs) are key pathogenic drivers in arthritis and their in vivo activation by TNF is sufficient to orchestrate full arthritic pathogenesis in animal models. TNF blockade has been efficacious for a large percentage of Rheumatoid Arthritis (RA) patients, although characterized by a plethora of side effects. Novel therapeutic discoveries remain however challenging, especially in optimizing drug safety, side effects, longer-term responses, costs and administration routes. Aiming to find new potent therapeutics, we applied the L1000CDS2 search engine, in order to identify compounds that could potentially reverse the pathogenic expression signature of arthritogenic SFs, derived from the human TNF transgenic mouse model (hTNFtg). We identified a neuroleptic drug, namely Amisulpride, which was validated to reduce SFs’ inflammatory potential while decreasing the clinical score of hTNFtg polyarthritis. Notably, we found that Amisulpride did not exert its biological activities through its known targets Dopamine receptors 2 and 3 and Serotonin Receptor 7, nor through TNFTNFRI binding inhibition. By applying a click chemistry approach, novel potential targets of Amisulpride were identified, which were further validated to repress hTNFtg SFs’ inflammatory potential in vitro (Ascc3 and Sec62), while phosphoproteomics analysis revealed important fibroblast activation pathways, such as adhesion, to be altered upon treatment. Our data support that Amisulpride could provide an additive beneficial effect to patients suffering from RA and comorbid dysthymia, as it may reduce SFs pathogenicity in parallel with its antidepressive activity. Importantly, Amisulpride may also serve as a “lead” compound for the development of novel, more potent therapeutics against chronic inflammatory diseases

2023-04-06 | PXD036283 | Pride

Repurposing of a known antipsychotic drug to target arthritogenic synovial fibroblasts

Project description:We applied quantitative mass spectrometry (MS)-based proteomics to investigate the phosphoproteome of hTNF-stimulated and Amisulpride-treated synovial fibroblasts (SFs), as part of a study aiming to find new potent orally-administered therapeutics to reverse the pathogenic expression signature of arthritogenic SFs. Phosphoproteomics analysis were done by DIA-based phosphoproteomic profiling of synovial fibroblasts. Samples consisted of hTNF-induced WT SFs. Three different time points (5’, 15’, 30’) of hTNF induction were used and compared to cells pretreated with Amisulpride for 1h before being stimulated at similar time points with hTNF (5’, 15’, 30’).

2023-04-11 | PXD035230 | Pride

MYD88 dimerization controls the proliferative, invasive, and pro-inflammatory responses of synovial fibroblasts from rheumatoid arthritis patients

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

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