The role of proinflammatory cytokines in the generation and maintenance of joint pain

Schaible, Hans‐Georg; Banchet, Gisela Segond von; Boettger, Michael Karl; Bräuer, Rolf; Gajda, Mieczysław; Richter, Frank; Hensellek, Susanne; Brenn, Daniel; Natura, Gabriel

doi:10.1111/j.1749-6632.2009.05301.x

Cited by 172 publications

(128 citation statements)

References 55 publications

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“…Proinflammatory cytokines like tumor necrosis factor (TNF) and interleukin 6 (IL‐6) are both of specific importance in RA pathogenesis, and specific cytokine blockade has been shown beneficial 22, 23. Both TNF and IL‐6 also affect pain thresholds in experimental arthritis 24, 25, as well as long‐term sensitization of joint nociceptors 26. In RA, general hyperalgesia to mechanical and thermal stimuli have been reported 27, and decreased pain thresholds over nonpainful areas were also shown in established RA, but not in early disease, suggesting the impact of long‐term inflammation in this context 28.…”

Section: Discussionmentioning

confidence: 99%

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

Altawil

Saevarsdóttir

Wedrén

et al. 2016

Arthritis Care & Research

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ObjectiveTo investigate the frequency of remaining pain in early rheumatoid arthritis (RA) after 3 months of treatment with methotrexate as the only disease modifying antirheumatic drug, with a special focus on patients with a good clinical response.MethodsThe study base was cases reported to a population‐based early RA cohort who had followup data from the Swedish Rheumatology Quality Register (n = 1,241). The Disease Activity Score in 28 joints European League Against Rheumatism (EULAR) response criteria were used to evaluate clinical response to treatment as good, moderate, and no response. The primary end point was remaining pain at the 3‐months followup visit, defined as pain >20 mm on a 100‐mm visual analog scale (VAS).ResultsRemaining pain in spite of a EULAR good response at followup was associated with higher baseline disability, using the Health Assessment Questionnaire (adjusted odds ratio [OR] 2.2 [95% confidence interval (95% CI) 1.4–3.4] per unit increase), and less baseline inflammation, using the erythrocyte sedimentation rate (adjusted OR 0.81 [95% CI 0.70–0.93] per 10‐mm increase). Similar associations were detected for remaining pain at followup in spite of low inflammatory activity, defined as a C‐reactive protein level <10. Increase in VAS pain during the treatment period was observed in 19% of the whole cohort, with frequencies in the EULAR response groups of 9% (good response), 15% (moderate response), and 45% (no response).ConclusionThese results are in line with the hypothesis that a subgroup of early RA patients exhibits pain that is not inflammatory mediated, where alternative treatment strategies to traditional antiinflammatory medications need to be considered.

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Section: Discussionmentioning

confidence: 99%

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

Altawil

Saevarsdóttir

Wedrén

et al. 2016

Arthritis Care & Research

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“…29 IL-6 not only promotes and maintains inflammation in arthritis but also contributes to the generation and maintenance of inflammatory pain by acting at nociceptive nerve cells. 30 In a clinical study, anti-IL-6R antibody (tocilizumab) has been shown to be a novel therapeutic strategy for certain inflammatory and autoimmune diseases, including RA and systemic onset juvenile idiopathic arthritis, with significant clinical improvement and amelioration of joint damage. 31 Some studies have demonstrated that uric acid crystals can induce human eosinophils and neutrophils to produce the neutrophil chemokine CXCL8.…”

Section: Discussionmentioning

confidence: 99%

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

et al. 2011

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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...

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“…Recent studies have also shown that macrophages produce a number of inflammatory cytokines, particularly interleukin (IL)-1b, IL-6 and tumour necrosis factor (TNF)-a, which contribute to pain and the progression of OA [8][9][10]. In addition, Hill et al [11] used magnetic resonance imaging (MRI) imaging to demonstrate that synovitis correlates with OA pain.…”

Section: Introductionmentioning

confidence: 99%

Synovial macrophage-derived IL-1βregulates the calcitonin receptor in osteoarthritic mice

Takano

Uchida

Miyagi

et al. 2015

Clinical and Experimental Immunology

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SummaryRecent studies have reported that calcitonin gene-related peptide (CGRP) contributes to joint pain. However, regulation of the CGRP/CGRP receptor signalling in osteoarthritis (OA) is not fully understood. To investigate the regulation of CGRP/CGRP receptor signalling by macrophages in the synovial tissue (ST) of OA joints, we characterized the gene expression profiles of CGRP and CGRP receptors in the ST of OA mice (STR/Ort). In addition, we examined whether macrophage depletion by the systemic injection of clodronate-laden liposomes affected the expression of CGRP and CGRP receptors in ST. of STR/Ort was higher than that in C57/BL6J mice. Notably, the F4/80 1 cell fraction expressed IL-1b highly, whereas the F4/80 2 cell fraction expressed CGRP, CLR, and RAMP1 highly. In addition, expression of the IL-1b and CLR genes was increased in ST, but was decreased upon macrophage depletion, and the IL-1b treatment of cultured synovial cells up-regulated CLR. Taken together, the present findings suggest that synovial macrophages are the major producers of IL-1b and regulators of CLR in OA mice. Therefore, macrophages and IL-1b may be suitable therapeutic targets for treating OA pain.

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The role of proinflammatory cytokines in the generation and maintenance of joint pain

Cited by 172 publications

References 55 publications

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

Remaining Pain in Early Rheumatoid Arthritis Patients Treated With Methotrexate

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

Synovial macrophage-derived IL-1βregulates the calcitonin receptor in osteoarthritic mice

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