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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE217012 | GEO | 2023/09/27

REPOSITORIES: GEO

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Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naïve Rheumatoid Arthritis Patients

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

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

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Repurposing of a known antipsychotic drug to target arthritogenic synovial fibroblasts

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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.

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

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