Abstract
IntroductionThe 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.MethodsWe 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.Results14-3-3η 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.ConclusionsExtracellular 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.
Highlights
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)
In a previous study of an early RA cohort, we reported that 60% of patients were positive for 14-3-3η, 32% for rheumatoid factor (RF), 44% for Anticitrullinated protein antibody (ACPA) and 72% for at least one of those three markers [8]
In 2007, we reported a strong correlation between the expression of 14-3-3η and matrix metalloproteinases (MMPs) and demonstrated that extracellular 14-3-3η possesses Matrix metalloproteinase (MMP)-1-inducing activity in vitro on the basis of 14-3-3η levels at the upper range of serum levels observed in a small subset of RA patients [5,6,7]
Summary
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). There is consensus amongst rheumatologists that the development of a risk stratification strategy to group patients into low-, medium- and high-risk categories for radiographic progression at presentation is a clinical imperative [4]. This remains a major limitation in patient management because risk factors such as rheumatoid factor (RF), anticitrullinated protein antibodies (ACPAs; often detected by performing an anti– cyclic citrullinated peptide antibody test) and C-reactive protein (CRP) together account for only 32% of the total variance in predicting joint destruction, leaving 68% of the variance unaccounted for [4]. In a previous study of an early RA cohort, we reported that 60% of patients were positive for 14-3-3η, 32% for RF, 44% for ACPA and 72% for at least one of those three markers [8]
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