Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study

Abstract

IntroductionAntibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruction. Our objective was to investigate the potential of survivin and Flt3L as predictors of RA in samples from patients prior to onset of symptoms.MethodsThis study included 47 individuals sampled before onset of RA (median 2.5 years (IQR 4.5) and 155 matched controls, all were donors to the Medical Biobank of Northern Sweden, and 36 RA patients. Levels of anti-CCP, survivin and Flt3L were measured using ELISAs and 29 cytokines/chemokines by multiplex detection.ResultsLevels of survivin were increased in pre-symptomatic individuals compared with controls (P = 0.003), whilst the levels of Flt3L were similar. The frequency of survivin positivity in the pre-symptomatic individuals was increased compared with the controls (36.2 vs.14.2%, P = 0.001) and predicted disease development (odds ratio (OR) =3.4 (95% confidence interval (CI) 1.6-7.2)). The frequency of survivin and Flt3L in RA patients was increased compared with the controls (both, P <0.0001, OR = 12.1 (95% CI, 5.3-27.6) and OR = 11.0 (95% CI, 3.9-30.9), respectively). Anti-CCP positive pre-symptomatic individuals and patients had significantly higher levels of survivin compared with anti-CCP2 negative individuals. In pre-symptomatic individuals, survivin correlated with IL-12, IL-1β and IL-9 whereas Flt3L correlated to a significantly broader spectrum of cytokines in RA patients.ConclusionProto-oncogene survivin was increased in individuals prior to onset of symptoms of RA and was correlated to cytokines suggesting its role at pre-clinical stages of the disease.

Impaired signaling through the Fms-like tyrosine kinase 3 receptor increases osteoclast formation and bone damage in arthritis

“…Like others, we have previously shown that Flt3L is enriched in the serum of patients with RA and that this protein accumulates in the synovial fluid of arthritic joints [30][31][32]. In addition, Flt3L has been suggested as a useful serological marker at early stages of RA [33].…”

“…The presence of Flt3 + cells in the synovial tissue of patients with RA and the potential involvement for Flt3L in OC differentiation suggest that Flt3L may contribute to the severe bone damage that occurs during RA [31]. This hypothesis is further supported by the increased levels of Flt3L in the serum and synovial fluid of patients with RA showing high correlation to TNF-a, IL-1b, and IL-6, cytokines known to potentiate OC differentiation [32]. Accordingly, local knee exposure to Flt3L aggravates arthritis in mice [30].…”

Down-regulation of survivin alleviates experimental arthritis

“…A pilot study on the Medical Biobank of Northern Sweden showed that survivin was increased in individuals before clinical onset of RA. Importantly, survivin correlated with the cytokines driving formation of Th1 and Th17 proinflammatory effector T cells at the initial stages of RA [2]. In the experimental setting, survivin is shown critical for the process of antigen presentation; the break point of immune responses in RA, as it is required for the fms-related tyrosine kinase 3-dependent maturation of dendritic cells; and expression of the MHCII receptor [14,15].…”

“…Survivin, the smallest member of the inhibitor of apoptosis protein family, has emerged recently as a biomarker of RA [2]. It is a multifunctional protein that plays biologic roles in apoptosis and the cell cycle.…”

microRNA involvement in the regulation of survivin in peripheral blood mononuclear cells from rheumatoid arthritis patients

“…Studies have reported high expression of total survivin in RA synovial fibroblast cells, peripheral blood mononuclear cells (PBMCs), serum, and synovial fluid which correlated with disease activity and joint destruction . Increased serum levels of survivin correlated with expression of Th1 and Th17 pathogenic cytokines in RA patients . Serum survivin led to increased expression of α‐chains of β2‐integrins on leukocytes, suggesting contribution of survivin to the enhanced infiltration of pathogenic immune cells to the sites of inflammation in RA patients.…”