Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesisReport as inadecuate




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Arthritis Research and Therapy

, 14:R14

First Online: 20 January 2012Received: 13 July 2011Revised: 21 November 2011Accepted: 20 January 2012

Abstract

IntroductionInterleukin-34 IL-34 is a recently defined cytokine, showing a functional overlap with macrophage colony stimulating factor M-CSF. This study was undertaken to address the expression of IL-34 in rheumatoid arthritis RA patients and to investigate its regulation and pathogenic role in RA.

MethodsIL-34 levels were determined in the RA synovium, synovial fluid SF and fibroblast-like synovial cells FLS by immunohistochemistry, real-time PCR, enzyme-linked immunosorbent assay and immunoblotting. RA activity was assessed using Disease Activity Score 28 DAS28 activity in the plasma collected at baseline and one year after treatment. Conditioned media CM were prepared from RA FLS culture with tumor necrosis factor alpha TNFα for 24 hours and used for functional assay.

ResultsIL-34 was expressed in the synovium, SF, and FLS from RA patients. The production of IL-34 in FLS was up-regulated by TNFα in RA samples compared with osteoarthritis OA patients. Importantly, the preferential induction of IL-34 rather than M-CSF by TNFα in RAFLS was mediated by the transcription factor nuclear factor kappa B NF-κB and activation of c-Jun N-terminal kinase JNK. IL-34 elevation in plasma from RA patients was decreased after the administration of disease-modifying anti-rheumatic drugs DMARDs in accordance with a decrease in DAS28. CM from RAFLS cultured with TNFα promoted chemotactic migration of human peripheral blood mononuclear cells PBMCs and subsequent osteoclast OC formation, effects that were attenuated by an anti-IL-34 antibody.

ConclusionsThese data provide novel information about the production of IL-34 in RA FLS and indicate that IL-34 is an additional osteoclastogenic factor regulated by TNFα in RA, suggesting a discrete role of IL-34 in inflammatory RA diseases.

AbbreviationsAbantibody

BSAbovine serum albumin

CMconditioned media

DAS28disease activity score 28

DMARDsdisease-modifying antirheumatic drugs

ERKextracellular signal-regulated protein kinase

FLSfibroblast-like synovial cells

HRPhorseradish peroxidase

IL-34interleukin-34

JNKc-Jun N-terminal kinase

MAPKmitogen-activated protein kinase

M-CSFmacrophage colony-stimulating factor

NF-κBnuclear factor kappa B

OAosteoarthritis

OCosteoclast

OCPsosteoclast precursors

PBSphosphate-buffered saline

PDTCpyrrolidine dithiocarbamate

PsApsoriatic arthritis

PBMCsperipheral blood mononuclear cells

qRT-PCRquantitative reverse transcriptase -polymerase chain reaction

RArheumatoid arthritis

RANKLreceptor activator of NF-κB ligand

RT-PCRreverse transcriptase-polymerase chain reaction

SFsynovial fluid

TNFαtumor necrosis factor alpha

TRAPtartrate-resistant acid phosphatase.

Electronic supplementary materialThe online version of this article doi:10.1186-ar3693 contains supplementary material, which is available to authorized users.

Seung-Jun Hwang, Bongkun Choi contributed equally to this work.

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