Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis

Antonia Boman,Ewa Berglin,Heidi Kokkonen,Lisbeth Ärlestig,Solbritt Rantapää-Dahlqvist

doi:10.1007/s10067-017-3570-4

Abstract

The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47–0.65) ng/mL compared with female controls 0.49 (0.4–0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.

Highlights

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation that eventually leads to the destruction of cartilage and bone [1]
We aimed to investigate the relationships between gene polymorphisms of the two proteins, sclerostin and Receptor activator of NF kappa B Ligand (RANKL), extracted from the Immunochip data, and plasma concentrations for radiological progression
Data on gene polymorphisms were extracted from Immunochip analysis (SNP&SEQ Technology Platform, Uppsala, Sweden) covering three single nucleotide polymorphisms (SNPs) for SOST gene and 539 for the tumor necrosis factor ligand superfamily member 11 (TNFSF11) gene [20]

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation that eventually leads to the destruction of cartilage and bone [1]. The destructive process is related to the presence of autoantibodies, genetic polymorphism involving proteins in the Wingless (Wnt)-β-catenin pathway, and markers of inflammation, cartilage and bone metabolism [2, 3]. The protein plays a central role in osteoclast differentiation and activation and the RANKL/osteoprotegerin pathway (RANKL/OPG) is strongly upregulated by pro-inflammatory cytokines [4]. This is an important pathway for inflammatory bone loss in patients with RA [5]. Synovial cells expressing RANKL are responsible for the formation of osteoclasts and bone loss in an experimental model of RA directly linking the immune system to bone [6].

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