Brief Report: Tumor Necrosis Factor and Interleukin‐6 Differentially Regulate Dkk‐1 in the Inflamed Arthritic Joint

Abstract

ObjectiveTumor 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).MethodsExpression 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.ResultsTNF 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.ConclusionThe 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.