Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis

Nikitopoulou, Ioanna; Oikonomou, Nikos; Karouzakis, Emmanuel; Sevastou, Ioanna; Nikolaidou-Katsaridou, Nefeli; Zhao, Zhenwen; Mersinias, Vassilis; Armaka, Marietta; Xu, Yan; Masu, Masayuki; Mills, Gordon B.; Aidinis, Vassilis

doi:10.1084/jem.20112012

Cited by 146 publications

(155 citation statements)

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“…Expression of ATX was analyzed by immunohistochemistry and ELISA. ATX was highly expressed in RA synovium compared with OA synovium ( Figure 1A), as well as in RA SF (mean Ϯ SEM 0.60 Ϯ 0.093 mg/liter; n ϭ 15) compared with OA SF (0.27 Ϯ 0.045 mg/liter; n ϭ 10) (P Ͻ 0.05), similar to previously reported findings (18). In RA ST, ATX was expressed on stromal cells, including CD68ϩ macrophages and vWF-positive endothelial cells ( Figure 1B).…”

Section: Resultssupporting

confidence: 90%

“…Recent studies demonstrated that ATX was expressed on FLS and in the ST and SF of patients with RA, and that conditional genetic ablation of ATX in mesenchymal cells resulted in disease attenuation in animal models of arthritis (18). It has been suggested that the ATX/LPA axis plays an important role in the development of arthritis.…”

Section: Discussionmentioning

confidence: 99%

“…Messenger RNA (mRNA) for ATX and LPA 1-3 is expressed on FLS from patients with RA, and LPA has been shown to induce cell motility and production of interleukin-6 (IL-6) and IL-8 in RA FLS (15)(16)(17). It was recently demonstrated that conditional genetic ablation of ATX in mesenchymal cells attenuates the development of arthritis in an animal model of RA (18).…”

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confidence: 99%

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Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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Objective. Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA 1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA 1 on the development of arthritis.Methods. Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. The effects of abrogation of LPA 1 on collageninduced arthritis (CIA) were evaluated using LPA 1 -deficient mice or LPA 1 antagonist. Migrating fluorescence-labeled CD11b؉ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4؉ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined.Results. LPA 1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA 1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA 1 antagonist also ameliorated murine CIA. Abrogation of LPA 1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b؉ macrophages from LPA 1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA 1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA 1 deficiency or LPA 1 inhibition in vitro.Conclusion. Collectively, these results indicate that LPA/LPA 1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA 1 may be a promising target molecule for RA therapy.Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by inflammatory cell infiltration and bone destruction at multiple joints. The inflammation process in RA leads to synovial hyperplasia with proliferation of fibroblast-like synoviocytes (FLS), angiogenesis, and infiltration of inflammatory cells, including lymphocytes and macrophages (1,2).

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Miyabe

Iwai

et al. 2013

Arthritis & Rheumatism

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“…The pannus formation is associated with inhibition of neutrophil infiltration. 25,26 Treatment with RC showed protective effect support its anti-arthritic effect. The inhibition of pannus formation and bone erosion may be associated with inhibition of neutrophil infiltration.…”

Section: Discussionmentioning

confidence: 92%

Evaluation of anti-inflammatory potential of ayurvedic formulation Rheumacure in animal model of rheumatoid arthritis

Patel¹,

Desai

Shah³

et al. 2016

Int J Basic Clin Pharmacol

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“…embryogenesis and basic cell functions including growth, migration, DNA repair etc. Several studies indicate a role for the ATX-LPA axis in inflammatory conditions of the lung such as asthma [2] and idiopathic lung fibrosis [3] , but also in wound healing [4] , rheumatoid arthritis [5,6] and in linking inflammation and carcinogenesis in e.g. mammary cancer [7] .…”

Section: Autotaxin (Atx) the Atx-lpa Axis Inflammation And Xenobioticsmentioning

confidence: 99%

Autotaxin signaling, purinergic receptors and lung damage

Högberg

2015

Inflamm Cell Signal

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ATX is a secreted enzyme that produces lysophosphatindic acid (LPA) in plasma. For several years investigators have characterized endogenous factors that regulate ATX expression and compartmentalization. However many questions remain unanswered and this article highlights our recent finding that autotaxin (ATX) is readily induced by toxic environmental chemicals. LPA binds G-protein coupled receptors that affect basic cell functions. The interest in the ATX-LPA axis stems from its role in embryogenesis and its association to diseases such as allergic asthma, idiopathic lung fibroses, rheumatoid arthritis, wound healing and several common types of cancer. In our study we used toluene diisocyanate (TDI) and other diisocyanates. Diisocyanates are low-molecular weight industrial chemicals notorious for being respiratory sensitizers and lung toxicants. Mechanisms behind these effects are not sufficiently characterized. We mainly used TDI and found that TDI in the nM range induced a rapid secretion of ATX from respiratory epithelial cells. Two purinergic receptors, P2X4 and P2X7, were implicated in this effect of TDI, suggesting that there is a "P2X-ATX axis" in bronchial epithelium that is sensitive to diisocyanates. We also showed associations between TDI exposures, LPA levels in plasma and symptoms reported by exposed individuals. Thus, our data support a role for the ATX-LPA axis in TDI toxicity. Furthermore, they suggest novel ways to study the regulation of ATX expression. Of particular interest is to understand how ATX expression is affected by purinergic receptors, and to investigate a possible involvement of ATX in asthma induced by diisocyanates and perhaps other low-molecular weight environmental chemicals. Our study also raises questions about current occupational exposure limits for diisocyanates.

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Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis

Abstract: Synovial fibroblasts from patients and mice with arthritis express autotaxin, and ablation of autotaxin in fibroblasts ameliorates disease.

Cited by 146 publications

References 32 publications

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Necessity of Lysophosphatidic Acid Receptor 1 for Development of Arthritis

Evaluation of anti-inflammatory potential of ayurvedic formulation Rheumacure in animal model of rheumatoid arthritis

Autotaxin signaling, purinergic receptors and lung damage

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