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Abstract

ABSTRACT. Objective. To explore the potential role of Dickkopf-1 (DKK-1) in rheumatoid arthritis (RA) and to evaluate the effect of a tumor necrosis factor-a (TNF-a) inhibitor (infliximab) and an interleukin 1 receptor antagonist (IL-1Ra; anakinra) on DKK-1 secretion in patients with RA. Methods. Serum samples were collected from 100 patients with RA, 100 patients with other rheumatic diseases (e.g., osteoarthritis and ankylosing spondylitis), and 40 healthy controls. DKK-1 and osteoprotegerin (OPG) levels in serum were detected by ELISA. Serum C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), rheumatoid factor (RF) titers, and anti-cyclic citrullinated peptide antibody were also measured in patients with RA. Results. The serum level of DKK-1 was significantly higher in patients with RA than in healthy controls and those with other rheumatic diseases (p < 0.01); the serum DKK-1 level was correlated with levels of CRP (r = 0.488, p = 0.003) and ESR (r = 0.458, p = 2.4 x 10 -4 ) and the Sharp score of radiologic change (r = 0.449, p = 0.001) in RA. In contrast to the increasing level of OPG, DKK-1 was significantly decreased in RA patients treated with TNF-a inhibitor (p < 0.01). DKK-1 was significantly decreased in RA patients treated with IL-1Ra (p < 0.01). Conclusion. DKK-1, as an important mediator, was correlated with bone erosion and inflammation in RA. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that primarily attacks synovial joints, leading to articular destruction and functional disability. It typically presents as symmetric peripheral polyarthritis and most commonly involves the small joints of the hands and feet 1,2 . One of the hallmarks of RA is progressive bone erosion. Research on the mechanisms by which RA induces osteolysis has focused on the osteoclast's roles in shifting the normal balance between bone formation and resorption. This imbalance is generated by key molecules that regulate osteoclast differentiation, such as cross-talk between receptor activators of nuclear factor-kB ligand (RANKL) and Wingless (Wnt) signaling pathway, which is important for the growth and differentiation of osteoblasts 3,4 . Dickkopf-1 (DKK-1) is an endogenous, secreted inhibitory factor in the canonical Wnt signaling by binding the Wnt coreceptor LRP5/6 5 . Studies have demonstrated that activation of the Wnt signaling pathway in mature osteoblasts upregulates osteoprotegerin (OPG), which blocks RANKL-induced osteoclastogenesis and results in the inhibition of bone resorption Cytokines play a pivotal role in RA pathogenesis. Tumor necrosis factor-a (TNF-a) contributes substantially to the pathology of RA. Interestingly, studies have shown that upregulation of DKK-1 could activate TNF receptor-1 (TNFR1) in cultivated articular mesenchymal cells 11 . TNF-a inhibitor could downregulate DKK-1 in ankylosing spondylitis (AS) 12 . Moreover, interleukin 1 (IL-1) can modulate the RANKL/OPG pathway, and may also affect the ability of the osteoblast to repair bone at sites of articular erosio