SFEBES2009 Oral Communications Young Endocrinologists prize session (8 abstracts)
Effects of glucocorticoids on Wnt gene expression in synovial fibroblasts: potential role in inflammatory bone loss
Rowan Hardy 1 , Pushpa Patel 1 , Mohammad Ahasan 1 , Elizabeth Rabbitt 1 , Andrew Filer 2 , Karim Raza 2 , Chris Buckley 2 , Paul Stewart 1 & Mark Cooper 1
1School of Clincal and Experimental Medicine, University of Birmingham, Birmingham, UK; 2School of Immunity and Infection, University of Birmingham, Birmingham, UK.
Synovial fibroblasts (SFs) form a substantial component of inflamed rheumatoid synovium and generate endogenous glucocorticoids (GCs) during inflammation. Recently, production of DKK-1 (a Wnt signalling inhibitor that reduces bone formation) by SFs in response to TNFα has been proposed to be the master regulator of inflammatory osteoporosis. We have identified that in addition to TNFα, GCs potently induce DKK-1 secretion. This may provide a novel mechanism whereby locally generated GCs contribute to bone loss in inflammatory disease, however DKK-1 is one component of a multitude of secreted Wnt signalling factors. Consequently, we have now assessed the affects of GCs and TNFα on a range of Wnt agonists and antagonists.
Primary SFs were isolated from synovial biopsies from three patients with RA undergoing orthopaedic surgery. Fibroblasts were treated with vehicle, dexamethasone (Dex) (100 nmol/l) or TNFα (10 ng/ml) for 24 h. Gene expression of Wnt signalling components (95 in total) was determined using TaqMan gene expression plates.
As previously reported, treatment with Dex in SFs significantly increased DKK-1 mRNA expression (3.1-fold, vehicle versus Dex; P<0.05). In addition to DKK-1, treatment with Dex resulted in a significant increase in expression of the Wnt antagonist FRZB (10.7-fold, vehicle versus Dex; P<0.05). We did not identify a significant increase in DKK-1 or FRZB gene expression with TNFα treatments. Treatment with Dex also resulted in a significant decrease in expression of the Wnt agonist Wnt2 (7.3-fold, vehicle versus Dex; P<0.05).
This study supports our previous finding that GCs increase expression of the Wnt antagonist DKK-1 to a greater degree than the inflammatory cytokine TNFα. In addition, this study has identified that several other factors involved in Wnt signalling are regulated by GCs and may contribute to the imbalance in bone metabolism observed in inflammatory disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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