Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arthritic joint

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2015-05, Vol.67 (8), p.2071-2075
• Main Authors: Yeremenko, Nataliya, Zwerina, Karin, Rigter, Gemma, Pots, Desiree, Fonseca, Joao E, Zwerina, Jochen, Schett, Georg, Baeten, Dominique
• Format: Article
• Language: English
• Subjects: Adult; Arthritis, Rheumatoid; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Male; Middle Aged; RNA, Messenger - metabolism; Spondylarthropathies; Synovial Fluid - metabolism; Synovial Membrane - cytology; Synovial Membrane - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 2326-5205
• DOI: 10.1002/art.39183

Tumor necrosis factor (TNF) drives bone destruction, but it also inhibits new bone formation by inducing Dkk-1, an inhibitor of the Wnt pathway. Accordingly, blocking of Dkk-1 reverses the phenotype in experimental arthritis from a pattern of bone destruction to a pattern of bone formation. To delineate the potential role of Dkk-1 in the structural phenotype of human arthritis, we analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA). Expression of Dkk-1 and proinflammatory cytokines was determined by enzyme-linked immunosorbent assay and microarray analysis in synovial fluid (SF) and synovial tissue, respectively. Regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures. TNF and interleukin-1β (IL-1β) levels, were higher in RA SF than in SpA SF (P < 0.001 for both), whereas levels of IL-6 were not. Levels of Dkk-1 were similar in SpA SF and RA SF and were not correlated with TNF and IL-1β levels. However, Dkk-1 levels showed an inverse correlation with IL-6 levels in both SpA SF (r = -0.31, P = 0.04) and RA SF (r = -0.39, P = 0.01); this result was reproduced at the messenger RNA level in synovial tissue. In vitro experiments with FLS confirmed that Dkk-1 production was strongly induced by TNF but clearly suppressed by IL-6. Moreover, IL-6 was able to suppress the TNF-induced up-regulation of Dkk-1 production by FLS. The inverse correlation of Dkk-1 levels with IL-6 levels observed in vivo in the inflamed joints was mirrored by the differential regulation of Dkk-1 production by TNF and IL-6 in vitro. The relative balance between these and other factors in the arthritic joints may determine functional Wnt signaling and tissue remodeling.