The serum level of Dickkopf-1 in patients with rheumatoid arthritis: A systematic review and meta-analysis

Highlights

• Serum levels of Dickkopf-1 are associated with the pathogenesis of Rheumatoid arthritis.

• Study application region and ELISA kit platform may be the source of heterogeneity.

• Dickkopf-1 may be a potential therapeutic target for pathological bone erosion.

Abstract

Objective

Dickkopf-1 (DKK-1) is an endogenous inhibitor of canonical Wnt pathway that was implicated in the pathogenesis of rheumatoid arthritis (RA), but the serum levels of DKK-1 in RA were inconsistent among studies. Therefore, we conducted a meta-analysis to systematically evaluate the relationship between serum DKK-1 levels and RA.

Methods

PubMed, Web of Science and Cochrane Library were comprehensively retrieved till 1 January 2018 for pertinent studies. The pooled standard mean differences (SMDs) of serum DKK-1 levels were calculated according to the random effects model.

Results

Nine original studies containing 1305 RA patients and 504 healthy controls were included in the meta-analysis. The pooled SMD of serum DKK-1 between RA patients and healthy controls was 0.79 (95% CI = 0.11 to 1.48, Z = 2.28 and P = 0.023), indicating a significantly higher serum level of DKK-1 in RA patients.

Conclusion

Serum level of DKK-1 is elevated in patients with RA compared to healthy controls, suggesting an important role of DKK-1 in the pathogenesis and treatment of RA.

Introduction

Dickkopf-1 (DKK-1), a member of the Dickkopf family, is a secreted protein consisted of two cysteine-rich domains and a signal peptide sequence [1]. DKK-1 is an endogenous soluble inhibitor of the Wnt/β-catenin signaling pathway (canonical Wnt pathway). The canonical Wnt pathway regulates bone remodeling by simulating the proliferation, maturation and differentiation of osteoblast and the producing of osteogenesis-associated proteins, and by suppressing osteoclastic bone resorption [[2], [3], [4], [5]]. DKK-1 was demonstrated to mediate bone metabolism through the canonical Wnt pathway and enhance target gene expression, including vascular endothelial growth factor, Runt-related transcription factor 2 and several other genes associated with an enhanced cell growth and ossification [6,7]. Moreover, DKK-1 has been suggested to play a pivotal role in the etiology and progression of various autoimmune articular diseases, such as osteoarthritis (OA), ankylosing spondylitis (AS) and rheumatoid arthritis (RA) [[8], [9], [10], [11], [12]].

RA is a chronic inflammatory autoimmune arthropathy that predominantly affects the synovial joints, and is characterized by the degradation, erosion and destruction of cartilage and bone. RA usually leads to a progressive joint destruction, early unemployment, reduced life expectancy and considerable disability [13]. Recently, increasing evidence suggested that the pathogenesis of RA was influenced by multifactor [14,15]. Dysfunction of bone metabolism due to the aberrant expression of DKK-1 was involved in the pathogenesis of pathological bone erosion [16,17]. However, results concerning the relationship between serum levels of DKK-1 and RA were inconsistent. Daoussis et al. firstly reported in 2010 that the serum levels of DKK-1 were slightly higher, without reaching a statistical significance, in RA patients compared to healthy controls, but another study found that serum level of DKK-1 was significantly higher in RA patients [9,18]. A previous meta-analysis synthesized four studies including 136 RA patients and 232 healthy controls before December 2014, and drew the conclusion that there was no difference of the serum DKK-1 levels between RA patients and healthy controls [19]. Since then, several new studies consistently reported that the serum DKK-1 levels were elevated in RA patients [[20], [21], [22], [23]]. Therefore, we conducted the present meta-analysis to evaluate the role of serum DKK-1 in the development of RA.