Endocrine Abstracts (2009) 19 OC6

Locally generated glucocorticoids, rather than pro-inflammatory cytokines, directly regulate synovial DKK-1 expression in inflammatory arthritis

R Hardy1, M Ahasan1, P Patel1, A Filer2, E Rabbitt1, K Raza2, P Stewart1, C Buckley2 & M Cooper1


1School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, West Midlands, UK; 2School of Immunity and Infection, University of Birmingham, Birmingham, West Midlands, UK.


We have previously proposed a central role for locally generated glucocorticoids in the periarticular and systemic osteoporosis seen in rheumatoid arthritis (RA). Synovial fibroblasts (SFs) express the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme and this expression increases dramatically with inflammation. Recently, production of DKK-1 (a Wnt signalling inhibitor known to inhibit bone formation) by SFs in response to inflammation has been proposed to explain this effect. We tested the hypothesis that DKK-1 production in inflamed synovium was primarily mediated by glucocorticoids and indirectly by inflammatory cytokines.

Primary SFs were isolated from synovial biopsies from 4 patients with RA undergoing orthopaedic surgery. Glucocorticoid metabolism by 11β-HSD1 was measured in assays using tritiated tracers and TLC analysis. DKK-1 expression was measured by real-time RT-PCR and ELISA on cell culture supernatant.

High basal DKK-1 mRNA and protein expression were found in SFs. TNFα treatment resulted in a small increase in expression (2.3 fold in mRNA; 1.4 fold in protein) whereas IL-1 had no effect. Glucocorticoids (cortisol, DEX) caused a substantially greater increase in mRNA and protein expression (2.3 and 2.8 fold in protein respectively, P<0.05). Importantly, the inactive glucocorticoid cortisone also increased DKK-1 expression in SFs (2.7 fold, P<0.05) to a much greater degree than TNFα/IL1, an effect blocked by an 11β-HSD1 inhibitor. When glucocorticoids and TNFα/IL1 were combined the effect on DKK-1 expression was similar to that of glucocorticoids alone. Even though the direct effects of TNFα/IL-1 on DKK1 were modest/absent both cytokines were able to substantially increase 11β-HSD1 expression and glucocorticoid production in these cells.

These results show that the effect of TNFα/IL-1 on SF DKK-1 expression, and any consequences on bone remodelling, are unlikely to be direct but instead are mediated through induction of 11β-HSD1 expression and the consequent increased level of glucocorticoids.

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