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)-a or interleukin (IL)-1b, 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-a or IL-1b. 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. Keywords: cytokines; fibroblast-like synoviocytes; rheumatoid arthritis; signal transduction; uric acid INTRODUCTION Arthritis is the most common cause of joint pain and physical disability in developed countries and worldwide. 1 Gout is an acute inflammatory arthritis whose incidence has increased over the past decade, which is characterized by elevated serum urate concentrations and recurrent attacks by intra-articular uric acid crystal deposition. 2 Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis with 1% prevalence in industrialized countries, which is characterized by cytokinemediated inflammation of the synovium and destruction of cartilage and bone. 3 Uric acid crystal-mediated gouty attacks have also been observed in patients with RA. 4,5 Fibroblast-like synoviocytes (FLS) are resident mesenchymal cells in synovial joints that play crucial roles in both joint damage and the propagation of inflammation in arthritic diseases. 6 The ability of FLS to erode cartilage is a multistep process that includes the attachment of FLS onto cartilage and the synthesis of matrix metalloproteinases (MMPs) such as MMP-1. 7 Additionally, FLS secrete receptor activator of nuclear factor-kB ligand, which can attract macrophages from the vasculature, stimulate the differentiation of vascular-and tiss...

Serum uric acid levels correlate with benign paroxysmal positional vertigo

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ERK2 and JNK1 contribute to TNF-α-induced IL-8 expression in synovial fibroblasts

“…When we used canine synovial fibroblasts as a model for the study, the involvement of ERK and JNK MAPK pathways, but not of p38, on TNF-α-induced IL-8 expression was observed. In normal human synovial fibroblasts, TNF-α was demonstrated to induce IL-8 secretion and to activate ERK and JNK, but not p38 MAPK [ 53 ]. Therefore, TNF-α-induced activation of p38 MAPK related to IL-8 expression may occur in synovial fibroblasts of RA patients.…”

Characterization of human PDGFR-β-positive pericytes from IPF and non-IPF lungs

“…DAMP molecules included high mobility group box 1 protein (HMGB1; R&D Systems, Minneapolis, MN), heat shock protein-60 (HSP-60; Enzo Life Sciences, Farmingdale, NY), and ATP (Sigma-Aldrich, St. Louis, MO). Uric acid (Sigma-Aldrich) crystals were prepared as described (9). Necrotic cell lysate was prepared from normal human lung PDGFR-␤-negative cells by subjecting 10 7 cells/ml to five successive freeze/thaw cycles.…”