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TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis.

ABSTRACT: Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. High hydrogen ion concentration (acidosis) found in synovial fluid in RA patients is associated with disease severity. Acidosis signaling acting on proton-sensing receptors may contribute to inflammation and pain. Previous studies focused on the early phase of arthritis (<5 weeks) and used different arthritis models, so elucidating the roles of different proton-sensing receptors in the chronic phase of arthritis is difficult. We intra-articularly injected complete Freund's adjuvant into mice once a week for 4 weeks to establish chronic RA pain. Mice with knockout of acid-sensing ion channel 3 (ASIC3) or transient receptor potential/vanilloid receptor subtype 1 (TRPV1) showed attenuated chronic phase (>6 weeks) of RA pain. Mice with T-cell death-associated gene 8 (TDAG8) knockout showed attenuated acute and chronic phases of RA pain. TDAG8 likely participates in the initiation of RA pain, but all three genes, TDAG8, TRPV1, and ASIC3, are essential to establish hyperalgesic priming to regulate the chronic phase of RA pain.

SUBMITTER: Hsieh WS

PROVIDER: S-EPMC5566336 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis.

Hsieh Wei-Shan WS Kung Chia-Chi CC Huang Shir-Ly SL Lin Shih-Chang SC Sun Wei-Hsin WH

Scientific reports 20170821 1

Rheumatoid arthritis (RA), characterized by chronic inflammation of synovial joints, is often associated with ongoing pain and increased pain sensitivity. High hydrogen ion concentration (acidosis) found in synovial fluid in RA patients is associated with disease severity. Acidosis signaling acting on proton-sensing receptors may contribute to inflammation and pain. Previous studies focused on the early phase of arthritis (<5 weeks) and used different arthritis models, so elucidating the roles o ...[more]

PMID: 28827659

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Project description:BackgroundThe pathogenesis of rheumatoid arthritis (RA) is complex. This study aimed to identify diagnostic biomarkers and transcriptional regulators that underlie RA based on bioinformatics analysis and experimental verification.Material and methodsWe applied weighted gene co-expression network analysis (WGCNA) to analyze dataset GSE55457 and obtained the key module most relevant to the RA phenotype. We then conducted gene function annotation, gene set enrichment analysis (GSEA) and immunocytes quantitative analysis (CIBERSORT). Moreover, the intersection of differentially expressed genes (DEGs) and genes within the key module were entered into the STRING database to construct an interaction network and to mine hub genes. We predicted microRNA (miRNA) using a web-based tool (miRDB). Finally, hub genes and vital miRNAs were validated with independent GEO datasets, RT-qPCR and Western blot.ResultsA total of 367 DEGs were characterized by differential expression analysis. The WGCNA method divided genes into 14 modules, and we focused on the turquoise module containing 845 genes. Gene function annotation and GSEA suggested that immune response and inflammatory signaling pathways are the molecular mechanisms behind RA. Nine hub genes were screened from the network and seven vital regulators were obtained using miRNA prediction. CIBERSORT analysis identified five cell types enriched in RA samples, which were closely related to the expression of hub genes. Through ROC curve and RT-qPCR validation, we confirmed five genes that were specific for RA, including CCL25, CXCL9, CXCL10, CXCL11, and CXCL13. Moreover, we selected a representative gene (CXCL10) for Western blot validation. Vital miRNAs verification showed that only the differences in has-miR-573 and has-miR-34a were statistically significant.ConclusionOur study reveals diagnostic genes and vital microRNAs highly related to RA, which could help improve our understanding of the molecular mechanisms underlying the disorder and provide theoretical support for the future exploration of innovative therapeutic approaches.

Dataset Information

TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis.

Publications

TDAG8, TRPV1, and ASIC3 involved in establishing hyperalgesic priming in experimental rheumatoid arthritis.

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