Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

Akahoshi, Tohru; Namai, Rie; Murakami, Yousuke; Watanabe, Megumi; Matsui, Toshimichi; Nishimura, Akito; Kitasato, Hidero; Kameya, Toru; Kondo, Hirobumi

doi:10.1002/art.10709

Cited by 74 publications

(59 citation statements)

References 37 publications

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“…Monosodium urate crystals were prepared according to a previously published method. 21 Briefly, 800 mg uric acid was dissolved in 155 ml boiling distilled water containing 5 ml of 1 mol/l NaOH. After the pH of the solution was adjusted to 7.2 by the addition of 1 mol/l HCl, the solution was cooled gradually with stirring at room temperature and then stored overnight at 4 uC.…”

Section: Reagentsmentioning

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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Section: Reagentsmentioning

confidence: 99%

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

et al. 2011

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“…Importantly, activation of PPAR␥ by naturally occurring ligands also appears to have antiinflammatory effects. In the joint, for example, monosodium urate monohydrate crystals have been shown to activate PPAR␥ on monocytes, presumably via endogenous 15d-PGJ 2 , and crystal-induced PPAR␥ activation was implicated as a potential mechanism to explain the spontaneous resolution of acute inflammation associated with gouty arthritis (21). In light of its potent antiinflammatory effects, PPAR␥ ligands hold substantial promise as novel immunomodulatory and antiinflammatory agents.…”

mentioning

confidence: 99%

Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator–activated receptor γ

Ghosh¹,

Bhattacharyya²,

Lakos³

et al. 2004

Arthritis & Rheumatism

189

168

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Objective. In fibroblasts, transforming growth factor ␤ (TGF␤) stimulates collagen synthesis and myofibroblast transdifferentiation through the Smad intracellular signal transduction pathway. TGF␤-mediated fibroblast activation is the hallmark of scleroderma and related fibrotic conditions, and disrupting the intracellular TGF␤/Smad signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, we examined the expression of the nuclear hormone receptor peroxisome proliferator-activated receptor ␥ (PPAR␥) in normal skin fibroblasts and its effect on TGF␤-induced cellular responses.Methods. The expression and activity of PPAR␥ in normal dermal fibroblasts were examined by Northern and Western blot analyses, immunocytochemistry, flow cytometry, and transient transfections with reporter constructs. The same approaches were used to evaluate the effects of PPAR␥ activation by naturally occurring and synthetic ligands on collagen synthesis and ␣-smooth muscle actin (␣-SMA) expression. Modulation of Smad-mediated transcriptional responses was examined by transient transfection assays using wild-type and dominant-negative PPAR␥ expression constructs. Abnormal synthesis and tissue accumulation of collagen are hallmarks of scleroderma and are responsible for the damage and failure of affected organs. Lesional scleroderma fibroblasts display an activated phenotype characterized by accelerated transcription of genes coding for collagen and other extracellular matrix proteins, increased expression of cell surface receptors for transforming growth factor ␤ (TGF␤), and sustained production of TGF␤, connective tissue growth factor, Supported by grants from the NIH (AR-46390 and AR-42309) and the Scleroderma Foundation. Results

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“…Treatment with PKA stimulators markedly increased PPARg activity (Akahoshi et al 2003). Interestingly, Liu et al (2009) also found cAMP/PKA signals could induce TR4 expression by triggering C/EBPa and b binding to the selective cAMP response elements located on the TR4 promoter that leads to the modulation of gluconeogenesis.…”

Section: Phosphorylationmentioning

confidence: 94%

Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases

Liu

Lin

et al. 2014

Endocrine-Related Cancer

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Peroxisome proliferator-activated receptor g (PPARg, NR1C3) and testicular receptor 4 nuclear receptor (TR4, NR2C2) are two members of the nuclear receptor (NR) superfamily that can be activated by several similar ligands/activators including polyunsaturated fatty acid metabolites, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, as well as some anti-diabetic drugs such as thiazolidinediones (TZDs). However, the consequences of the transactivation of these ligands/activators via these two NRs are different, with at least three distinct phenotypes. First, activation of PPARg increases insulin sensitivity yet activation of TR4 decreases insulin sensitivity. Second, PPARg attenuates atherosclerosis but TR4 might increase the risk of atherosclerosis. Third, PPARg suppresses prostate cancer (PCa) development and TR4 suppresses prostate carcinogenesis yet promotes PCa metastasis. Importantly, the deregulation of either PPARg or TR4 in PCa alone might then alter the other receptor's influences on PCa progression. Knocking out PPARg altered the ability of TR4 to promote prostate carcinogenesis and knocking down TR4 also resulted in TZD treatment promoting PCa development, indicating that both PPARg and TR4 might coordinate with each other to regulate PCa initiation, and the loss of either one of them might switch the other one from a tumor suppressor to a tumor promoter. These results indicate that further and detailed studies of both receptors at the same time in the same cells/organs may help us to better dissect their distinct physiological roles and develop better drug(s) with fewer side effects to battle PPARg-and TR4-related diseases including tumor and cardiovascular diseases as well as metabolic disorders.

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Rapid induction of peroxisome proliferator–activated receptor γ expression in human monocytes by monosodium urate monohydrate crystals

Cited by 74 publications

References 37 publications

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

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

Disruption of transforming growth factor β signaling and profibrotic responses in normal skin fibroblasts by peroxisome proliferator–activated receptor γ

Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases

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