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-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.


CONCLUSIONS
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.
Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Nataliya
N
Yeremenko
University of Erlangen-Nurnberg, Erlangen, Germany.
Karin
K
Zwerina
Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Gemma
G
Rigter
Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Desiree
D
Pots
Hospital de Santa Maria, Lisbon Academic Medical Center, and Instituto de Medicina Molecular, Lisbon, Portugal.
Joao E
JE
Fonseca
University of Erlangen-Nurnberg, Erlangen, Germany.
Jochen
J
Zwerina
University of Erlangen-Nurnberg, Erlangen, Germany.
Georg
G
Schett
Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.
Dominique
D
Baeten
D000328:Adult; D001172:Arthritis, Rheumatoid; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism*; D025242:Spondylarthropathies; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
C501126:DKK1 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha