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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE31667 | GEO | 2012/05/14

SECONDARY ACCESSION(S): PRJNA145387

REPOSITORIES: GEO

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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

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

Transcriptomic analysis of synovial cells derived from collagen-induced arthritis mice

Project description:The destruction of bone and cartilage results in a loss of joint functionality, critically impairing the quality of life in arthritis patients. Synovial fibroblasts (SFs) 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 pathogenic fibroblast phenotype in arthritis, we performed single-cell RNA sequencing (scRNA-seq) on the synovial cells which were isolated from collagen-induced arthritis (CIA) mice.

2022-07-06 | GSE192504 | GEO

Mass Spectometry of rat synovial fibroblasts immunoprecipitated with anti-HIP1

Project description:Identify HIP1 binding proteins implicated in regulation of invasive property of Rheumatoid Arthritis (RA) fibroblast-like synoviocytes (FLS) by using FLS cell line from arthritic DA (highly invasive) and R6 (minimally invasive) arthritis-protected congenic rats, which differ in amino-acid changing HIP1 SNPs.

2024-04-18 | PXD051384 | 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

The role of extracellular vesicle miRNAs and tRNAs in synovial fibroblast senescence

Project description:We studied extracellular vesicles (EVs) from synovial fibroblast (SF). EVs were isolated from the secretome of non-senescent and irradiation-induced senescent SFs using size exclusion chromatography. EV RNA was extracted and subject to small RNA sequencing on an Illumina NovaSeq SP using 100bp, single end reads. After mapping against GRCh38.p12 and miRBase v22.1 differential expression analysis was undertaken with edgeRv3.28 using a quasi-likelihood negative binomial generalized log-linear model. We identified a panel of differentially expressed small non-coding RNAs.

2022-08-31 | GSE200330 | GEO

DNA methylation analysis of synovial fibroblasts from mice undergoing collagen-induced arthritis (CIA) treated, or not, with the the helminth-derived immunomodulator, ES-62

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

Patel2023 - miRNA-199a/b-5p regionation of chondrogenesis - enchanced

Project description:From a previous microarray study we developed a small chondrogenesis model. We performed qPCR and measured how knockdown of miR-199a-5p or miR-199b-5p could modulate chondrogenesis. Several experiments were used to determine the parameters of this model. We utilised parameter scan and manual sliding to refine the model. Within are two models - an initial model which only comprises of genes which we have data for, and an enhanced model which expands of the initial model to make more predictions - e.g. how miR-140-5p is indirectly regulated by miR-199a-5p and miR-199b-5p.

2023-06-06 | MODEL2305010001 | BioModels

microRNA-218 modulates gene expression in fibroblast-like synovial cells in rheumatoid arthritis

Project description:Objective: Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS. Methods: MicroRNA(miRNA) array analysis was performed to investigate the differentially expressed miRNAs during the osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfection with miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyse the ability of miR-218 to induce osteogenic differentiation. Results: The miRNA array revealed that 12 miRNAs were up-regulated and 24 miRNAs were down-regulated after osteogenic differentiation. We observed that miR-218 rose in the early phase of osteogenic differentiation and then decreased. Micro array analysis revealed the mir-218 modulate the expression of ROBO1 in RA-FLS. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation.

2018-03-26 | GSE111946 | GEO

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