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

Abstract

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‐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. 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.

Antagonists of Wnt/β‐catenin signalling in the periodontitis associated with type 2 diabetes and smoking

“…tis. An inverse correlation of DKK1 with IL-6 levels was also demonstrated in inflamed arthritic joints (Yeremenko et al, 2015). Previous studies have shown that DKK1 and SOST upregulated the expression of RANKL and downregulated that of OPG (Fujita & Janz, 2007;Wijenayaka et al, 2011).…”

“…These findings suggest that TNF‐α, IL‐1ß and IL‐6 might interact differently with the Wnt/β‐catenin antagonists in periodontitis. An inverse correlation of DKK1 with IL‐6 levels was also demonstrated in inflamed arthritic joints (Yeremenko et al., ). Previous studies have shown that DKK1 and SOST upregulated the expression of RANKL and downregulated that of OPG (Fujita & Janz, ; Wijenayaka et al., ).…”

“…The secondary aims were to assess the relationships between DKK1 and SOST with each other and with RANKL, OPG, interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)α and key periodontal pathogens. The osteoclastogenesis-related factors and pro-inflammatory cytokines evaluated are supposed to be related to periodontitis and Wnt/β-catenin pathway and its antagonists (Baek et al, 2014;Choe, Hun Kim, Park, Choi, & Kim, 2016;Fujita & Janz, 2007;Heiland et al, 2010;Kim et al, 2012;Wang et al, 2011;Wijenayaka et al, 2011;Yeremenko et al, 2015).…”

Mediators of inflammation and bone remodeling in rheumatic disease

“…These data implicate DKK-1 in inhibiting osteoblast-mediated bone formation in RA. Recently, IL-6 was shown to decrease DKK-1 levels in cultured fibroblast-like synoviocytes isolated from inflamed peripheral joints [80]. Thus, regulation of Wnt signaling may be a therapeutic approach to protection from bone loss in RA.…”

Dkk1: A key molecule in joint remodelling and fibrosis

“…In an effort to explore the strong link between Dkk-1 expression and the joint remodeling phenotype, Yeremenko and coworkers analyzed the expression of Dkk-1 and its regulation by proinflammatory cytokines in the inflamed peripheral joints of patients with SpA and RA. 28 178 Expression of Dkk-1 and proinflammatory cytokines were assessed in synovial fluid (SF) and synovial tissue while regulation of Dkk-1 production by proinflammatory cytokines was assessed in fibroblast-like synoviocyte (FLS) cultures. Dkk-1 circulating levels and DKK1 mRNA levels showed an inverse correlation with IL-6 levels in both SpA SF and RA SF.…”