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TNF and IL-6 differentially regulate the production of DKK-1, a master regulator of bone remodelling, by fibroblast-like synoviocytes

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Background

Different inflammatory joint diseases have distinct patterns of bone damage with pronounced erosions in rheumatoid arthritis (RA), a combination of bone destruction and formation in psoriatic arthritis (PsA), and new bone formation in spondyloarthritis (SpA). Although the underlying mechanisms remain elusive, blocking of DKK-1 reverses the bone-destructive pattern to a bone-forming pattern in experimental arthritis.

Aim

In order to delineate the role of DKK-1 in arthritis, we analyzed the regulation of DKK-1 expression in the inflamed peripheral joint of different types of inflammatory arthritis ex-vivo and in fibroblast-like synoviocyte (FLS) cultures in vitro.

Patients and methods

IL-6, DKK-1, TNF, and IL-1 beta levels in synovial fluid (SF) and synovial FLS lines were determined by ELISA. DKK-1 serum levels were assessed before and after IL-6R blockade in RA patients.

Results

SF DKK-1 levels were similar between 4 disease groups with a striking variability within each cohort. As DKK-1 production is strongly upregulated by TNF, we explored this inter-individual variability by correlating DKK-1 levels with pro-inflammatory cytokines levels. TNF and IL-1 beta levels were significantly higher in RA than SpA SF and did not correlate with DKK-1. In contrast, there was a striking inverse correlation between DKK-1 and IL-6 in both RA and SpA. Consistent with these data, in vitro DKK-1 production by FLS was strongly induced by TNF but clearly suppressed by IL-6 in dose-dependent manner. Preliminary data suggest that this regulation of DKK-1 by IL-6 is also relevant in vivo as treatment with the anti-IL-6 R antibody, tocilizumab, induced a transient upregulation of DKK-1 serum levels in RA patients.

Conclusions

DKK-1 is abundantly expressed in the inflamed joint of both destructive and remodelling forms of arthritis. However, DKK-1 production by FLS is differentially regulated by TNF and IL-6. The relative balance between these factors in the arthritic joints may determine the pattern of inflammation-induced tissue remodelling.

Author information

Correspondence to N Yeremenko.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yeremenko, N., Bisoendial, R., Zwerina, J. et al. TNF and IL-6 differentially regulate the production of DKK-1, a master regulator of bone remodelling, by fibroblast-like synoviocytes. J Transl Med 8, P43 (2010) doi:10.1186/1479-5876-8-S1-P43

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Keywords

  • Rheumatoid Arthritis
  • Rheumatoid Arthritis Patient
  • Synovial Fluid
  • Psoriatic Arthritis
  • Tocilizumab