title: Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis.
abstract: Hyperuricemia-mediated uric acid crystal formation may cause joint inflammation and provoke the destruction of joints through the activation of inflammasome-mediated innate immune responses. However, the immunopathological effects and underlying intracellular regulatory mechanisms of uric acid crystal-mediated activation of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) have not been elucidated. Therefore, we investigated the in vitro effects of monosodium urate crystals, alone or in combination with the inflammatory cytokines tumor-necrosis factor (TNF)-α or interleukin (IL)-1β, on the activation of human FLS from RA patients and normal control subjects and the underlying intracellular signaling mechanisms of treatment with these crystals. Monosodium urate crystals were able to significantly increase the release of the inflammatory cytokine IL-6, the chemokine CXCL8 and the matrix metalloproteinase (MMP)-1 from both normal and RA-FLS (all P<0.05). Moreover, the additive or synergistic effect on the release of IL-6, CXCL8 and MMP-1 from both normal and RA-FLS was observed following the combined treatment with monosodium urate crystals and TNF-α or IL-1β. Further experiments showed that the release of the measured inflammatory cytokine, chemokine and MMP-1 stimulated by monosodium urate crystals were differentially regulated by the intracellular activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways but not the p38 mitogen-activated protein kinase pathway. Our results therefore provide a new insight into the uric acid crystal-activated immunopathological mechanisms mediated by distinct intracellular signal transduction pathways leading to joint inflammation in RA.
authors.affiliation: Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China.
authors.forename: Da P
authors.initials: DP
authors.lastname: Chen
authors.forename: Chun K
authors.initials: CK
authors.lastname: Wong
authors.forename: Lai S
authors.initials: LS
authors.lastname: Tam
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Li
authors.forename: Christopher W K
authors.initials: CW
authors.lastname: Lam
mesh_terms: D001172:Arthritis, Rheumatoid / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D033461:Hyperuricemia / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053583:Interleukin-1beta / Q000009:adverse effects / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013582:Synovial Fluid / Q000166:cytology* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology; D014527:Uric Acid / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1