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

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.

Serum 14-3-3η is a Novel Marker that Complements Current Serological Measurements to Enhance Detection of Patients with Rheumatoid Arthritis

“…However, 14-3-3η levels are lower in PsA compared to RA, and detectable only in those patients with erosive PsA. Serum 14-3-3η is a constituent of exosomes, and following extracellular release has been shown to participate in a positive feedback interactive loop with TNF in promoting inflammation 13 . Thus, TNF stimulates expression of 14-3-3η while 14-3-3η stimulates expression of TNF, and this may be relevant to the finding that 14-3-3η is elevated in both patients with RA and patients with PsA with more severe radiographic changes.…”

“…In vitro data show that the soluble extracellular form of 14-3-3η activates several proinflammatory signaling cascades relevant to RA 13 . A notable exception contrasting Table 3A.…”

“…Serum 14-3-3η has also been described as a potent inducer of MMP in vitro, and levels of 14-3-3η correlate with MMP expression in serum and synovial fluid of patients with RA, suggesting that it may play a role in the joint damage cascade 10,13 . We have also reported data suggesting an association between serum 14-3-3η levels and radiographic damage in patients with PsA, also described herein.…”

“…In the extracellular environment, at concentrations present in the serum of patients with RA, soluble 14-3-3η possesses ligand activity, preferentially activating cells of the innate immune system 10 . Soluble 14-3-3η acts through signaling cascades such as the extracellular signal-regulated kinase and p38 pathway to upregulate proinflammatory cytokines, including interleukin 1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and factors that are involved in joint degradation such as MMP-9 and receptor activator of nuclear factor-κB ligand (RANKL) 13 .…”

14-3-3η in “Seronegative” Rheumatoid Arthritis

“…To the Editor: Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA) 1 . Unlike rheumatoid factor (RF) or anticitrullinated protein antibody (ACPA), which can arise as a consequence of disease in sites distinct from inflamed joints, 14-3-3η hyperexpression in RA is restricted to synovial joints with a significantly higher expression in synovial fluid than matched serum 2 .…”