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Open Access Highly Accessed Research article

14-3-3η is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage

Walter P Maksymowych1*, Désirée van der Heijde2, Cornelia F Allaart2, Robert Landewé3, Gilles Boire4, Paul P Tak56, Yuan Gui7, Aziz Ghahary8, Ruhangiz Kilani8 and Anthony Marotta7

Author Affiliations

1 Department of Medicine, University of Alberta, 562 Heritage Medical Research Building, Edmonton, AB T6G 2S2, Canada

2 Department of Rheumatology, C1R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands

3 Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam & Atrium Medical Center, Meibergdreef 9, Amsterdam 1105AZ, The Netherlands

4 Service de rhumatologie, Département de médecine, Faculté de médecine et des sciences de la santém, Université de Sherbrooke, 3001-12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada

5 Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam & Atrium Medical Center, Meibergdreef 9, Amsterdam 1105AZ, The Netherlands

6 GlaxoSmithKline, Stevenage, UK

7 Augurex Life Sciences Corp, 887 Great Northern Way, Vancouver, BC V5T 4T5, Canada

8 Department of Surgery, University of British Columbia, 818 West 10th Avenue, Vancouver, BC V5Z 1M9, Canada

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Arthritis Research & Therapy 2014, 16:R99  doi:10.1186/ar4547

Published: 21 April 2014

Abstract

Introduction

The aim of this study was to investigate whether 14-3-3η, a specific isoform of a family of proteins regulating processes such as cellular signalling, activates cell-signalling pathways and induces factors known to contribute to the pathophysiology of rheumatoid arthritis (RA). We also investigated whether 14-3-3η is associated with more severe disease in both early and established RA.

Methods

We investigated the effect of 14-3-3η on the activation of RA-relevant signalling cascades and induction of proinflammatory mediators that contribute to the joint damage process. 14-3-3η titres from 33 patients with early RA (mean RA duration = 1.8 months) and from 40 patients with established RA were measured in serum drawn at the 3-year time point of the Behandel Strategieën study. The relationship between 14-3-3η titres and standard clinical variables was investigated by correlation analysis. The association with radiographic damage and radiographic progression over at least a 2-year period was investigated using univariate and multivariate regression analyses.

Results

14-3-3η activated selected members of the mitogen-activated protein kinase (MAPK) family, mainly extracellular regulated kinase 1/2 and c-Jun kinase, but not p38MAPK. Activation by 14-3-3η, using levels spanning the concentration range found in RA patient serum, resulted in the induction of inflammatory transcripts such as interleukin 1 (IL-1) and IL-6 and factors linked to the joint damage process, such as receptor activator of nuclear factor κB ligand and matrix metalloproteinase 1. Serum 14-3-3η correlated significantly with rheumatoid factor (RF) (r = 0.43) and anticitrullinated protein antibodies (ACPAs) (r = 0.31) in the early RA cohort, but not with C-reactive protein (CRP) or the Disease Activity Score in 28 joints in either cohort. Serum 14-3-3η concentrations were significantly higher in patients with radiographically assessed joint damage and in those who had radiographic progression. By multivariate analysis, we show that 14-3-3η complemented markers such as CRP, RF and ACPA in informing RA radiographic status and/or progression.

Conclusions

Extracellular 14-3-3η activates key signalling cascades and induces factors associated with the pathogenesis of RA at concentrations found in patients with RA, and its expression is higher in patients with radiographic damage and RA progression.