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

Wei-Shan Hsieh,Shir-Ly Huang,Shih-Chang Lin,Chia-Chi Kung,Wei-Hsin Sun

doi:10.1038/s41598-017-09200-6

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.

Highlights

Rheumatoid arthritis (RA) affects approximately 1% of the global population, for one of the most prevalent chronic health problems
Because a local acidosis signal is mediated by proton-sensing receptors, we examined gene expression in arthritic mice and found upregulated expression of the proton-sensing genes acid-sensing ion channel 3 (ASIC3) and T-cell death-associated gene 8 (TDAG8) in ipsilateral Dorsal root ganglia (DRG)
Because ASIC3 gene expression was upregulated after intra-articular complete Freund’s adjuvant (CFA) injection, we investigated whether loss of ASIC3 gene reduced CFA-induced arthritis

Summary

Introduction

Rheumatoid arthritis (RA) affects approximately 1% of the global population, for one of the most prevalent chronic health problems. In an arthritis model induced by complete Freund’s adjuvant (CFA) injection in C57BL/6 mice, deletion of transient receptor potential/vanilloid receptor subtype 1 (TRPV1) attenuated joint and paw swelling, mechanical hyperalgesia, synovial inflammation, bone erosion, and cartilage damage in the early disease phase (≤5 weeks)[11,12,13]. Deletion of T-cell death-associated gene 8 (TDAG8), a proton-sensing GPCR, increased the severity of anti-collagen antibody/lipopolysaccharide-induced arthritis, but arthritis-induced pain was not assessed in this study[15] All these previous studies focused on the acute phase of arthritis (

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