Tumor Necrosis Factor and Interleukin-6 Differentially Regulate Dkk-1 in the Inflamed Arthritic Joint

Objective. 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). Methods. 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. Results. TNF and interleukin-1 beta (IL-1 beta) 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-1 beta 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. Conclusion. 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.