Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
TNF and IL-6 Differentially Regulate the Production of DKK-1, a Master Regulator of Bone Remodelling, by Fibroblast-Like Synoviocytes.
Yeremenko2, Nataliya, Polzer3, Karin, Righter2, Gemma, Bisoendial2, Radjesh, Zwerina3, Jochen, Schett3, Georg, Tak1, Paul P.
Academic Med Ctr/Univ of Amsterdam, Amsterdam, The Netherlands
Division of Clinical Immunology and Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, The Netherlands
Internal Medicine 3, Erlangen, Germany
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 dominant new bone formation in spondyloarthritis (SpA). Although the underlying molecular mechanisms remain poorly understood, blocking of Dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, reverses the bone-destructive pattern to a bone-forming pattern in experimental arthritis. In order to delineate the role of DKK-1 in the structural phenotype of SpA versus RA, we analyzed here 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.
Synovial fluid (SF) was obtained from actively inflamed knee joints of RA (n=45), non-psoriatic SpA (n=38), PsA (n=33), and gout (n=17) patients. The concentrations of IL-6, DKK-1, TNF, and IL-1 beta were determined by ELISA. Synovial FLS lines were established from tissue samples obtained from patients with inflammatory synovitis including RA (n=5), SpA (n=6), PsA (n=6). Expression of DKK-1 was determined by ELISA in FLS cultures following stimulation with TNF, IL-1 beta, IL-6, LPS and oncostatin M (OSM). DKK-1 serum levels were assessed before and after IL-6R blockade in RA patients.
SF DKK-1 levels were similar between the 4 disease groups with, however, a striking inter-individual variability within each cohort. As we previously demonstrated that DKK-1 production is strongly upregulated by TNF, we explored this inter-individual variability by correlating DKK-1 levels with pro-inflammatory cytokines levels in the inflamed joint. TNF and IL-1 beta levels were significantly higher in RA than SpA SF and did not correlate with SF DKK-1 levels, suggesting that other factors contribute to the regulation of DKK-1 in vivo. In contrast, there was a striking inverse correlation between DKK-1 and IL-6 in both RA and SpA. Exploring the functional impact of IL-6 on DKK-1 in vitro, DKK-1 production by RA, SpA, and PsA FLS was strongly induced by TNF (but not IL-1 beta) but clearly suppressed by IL-6 and OSM. This suppression was confirmed in dose-response experiments, although lower doses of IL-6 (10 ng/ml) have a stimulatory rather than inhibitory effect. Higher doses of IL-6 (50 ng/ml) were also able to reverse the TNF-induced upregulation of DKK-1 production by FLS. Preliminary data suggest that this regulation of DKK-1 production 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.
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 in vitro and in vivo. The relative balance between these factors in the arthritic joints may determine the pattern of inflammation-induced tissue remodelling.
To cite this abstract, please use the following information:
Yeremenko, Nataliya, Polzer, Karin, Righter, Gemma, Bisoendial, Radjesh, Zwerina, Jochen, Schett, Georg, et al; TNF and IL-6 Differentially Regulate the Production of DKK-1, a Master Regulator of Bone Remodelling, by Fibroblast-Like Synoviocytes. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :629