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Epigenetic regulator UHRF1 suppressively organize multiple pathogenesis in rheumatoid arthritis [MBD-seq]

ABSTRACT: Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, leading joint destruction. However, epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here we showed that Ubiquitin-like containing PHD and RING finger domains 1 (known as UHRF1) is a central epigenetic regulator to suppressively orchestrate the expression of multiple exacerbation factors in RA. We found remarkable up-regulation of Uhrf1, which is known as a key molecular for maintenance of DNA methylation during cell division 1-3, in murine arthritis tissue, especially synovial fibroblasts (SF). SF-specific Uhrf1 conditional knockout mice indicated more severe arthritic phenotypes with apoptosis resistant SF. Integrative analysis between transcriptome and methylome showed that expression of several cytokines including Ccl20 were up-regulated in Uhrf1-deficient SF. In RA patients, disease activity scores, CCL20 expression, Th17 accumulation, apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, stabilization of UHRF1 by administration of Ryuvidine improved pathogenesis of arthritis model mice. Our results demonstrated that UHRF1 expressed in SF contributes to suppressively orchestrate expression of genes of multiple exacerbating factors under RA progression. Targeting UHRF1 could provide a novel therapeutic strategy for RA.

ORGANISM(S): Mus musculus

PROVIDER: GSE166747 | GEO | 2021/02/16

REPOSITORIES: GEO

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Epigenetic regulator UHRF1 suppressively organize multiple pathogenesis in rheumatoid arthritis [RNA-seq]

Project description:Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, leading joint destruction. However, epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here we showed that Ubiquitin-like containing PHD and RING finger domains 1 (known as UHRF1) is a central epigenetic regulator to suppressively orchestrate the expression of multiple exacerbation factors in RA. We found remarkable up-regulation of Uhrf1, which is known as a key molecular for maintenance of DNA methylation during cell division 1-3, in murine arthritis tissue, especially synovial fibroblasts (SF). SF-specific Uhrf1 conditional knockout mice indicated more severe arthritic phenotypes with apoptosis resistant SF. Integrative analysis between transcriptome and methylome showed that expression of several cytokines including Ccl20 were up-regulated in Uhrf1-deficient SF. In RA patients, disease activity scores, CCL20 expression, Th17 accumulation, apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, stabilization of UHRF1 by administration of Ryuvidine improved pathogenesis of arthritis model mice. Our results demonstrated that UHRF1 expressed in SF contributes to suppressively orchestrate expression of genes of multiple exacerbating factors under RA progression. Targeting UHRF1 could provide a novel therapeutic strategy for RA.

2021-02-16 | GSE166746 | GEO

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Project description:Objective. To analyse the pathogenesis of the diseases rheumatoid arthritis (RA) and spondyloarthritis (SpA) we investigated the protein composition in synovial fluid from the patients. Methods. Fifty-six synovial fluid (SF) were analysed with non-gel based proteomics from patients with RA (32) and SpA (24). Rheumatoid factor was measured in plasma, and cell-free DNA was measured in SF. Results. Two hundred proteins were quantified in the samples. The inflammatory proteins were more abundant in the RA group, specially proteins from neutrophil granulocytes. Cell-free DNA (cfDNA) in the SF was statistically associated with proteins that are known to form neutrophil extracellular traps (NETs). Plasma C-reactive protein (CRP), was correlated to other acute phase proteins in the SF. Minimal correlation was seen between acute phase proteins and proteins in NETs. Conclusions. The results show that in the synovial cavity in vivo neutrophils form NETs. This result sustains that neutrophils from RA patients are activated and are likely to undergo NETosis resulting in SF cfDNA specific of arthritis pathology with NETosis.

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Project description:Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and cartilage/bone destruction. RA affects the synovial joints, the synovial lining and consequently the permeability of the synovium. As the latter is of central relevance for the distribution of systemically delivered therapeutics into synovial fluid (SF), we here assessed the protein composition of paired plasma and SF of patients diagnosed with RA at three distinct levels of depth using mass spectrometric approaches: the “total” proteome, the “total” IgG1 antibody repertoire and the RA-specific ACPA IgG1 autoantibody repertoire. The SF proteome was dominated by >150 plasma proteins, and we additionally detected several cartilage- and neutrophil-derived proteins of lower abundance. Strikingly, the plasma proteins were not only qualitatively reflected in SF but also quantitatively, independent of their size and/or other biochemical features. Also the synovial “total” IgG1 and autoreactive ACPA IgG1 repertoire highly resembled the IgG1 repertoires detected in plasma within the same patient. Our comprehensive multilayer data thus reveals that the proteome, including the dominant, most abundant (auto)antibody clones, present in SF of RA patients is a direct reflection of the proteome present in blood, spiked by the local (immune) processes within the RA joint. We thus conclude that proteins directly pass from blood into SF of these joints without substantial filtration bias. These findings thereby not only exemplify the use of in-depth multilayer proteome analyses to revisit basic concepts underlying RA pathology and to monitor the local (immune) processes destructive to cartilage, but also provide evidence indicating that (protein-based) therapeutics may equally enter SF of swollen joints and that pharmacokinetic analyses of such therapeutics in blood are directly relevant to the synovial compartment.

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