Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritisReport as inadecuate




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Arthritis Research and Therapy

, 14:R226

First Online: 18 October 2012Received: 05 April 2012Revised: 23 August 2012Accepted: 19 September 2012

Abstract

IntroductionInflammatory arthritis is associated with increased bone resorption and suppressed bone formation. The Wnt antagonist dickkopf-1 DKK1 is secreted by synovial fibroblasts in response to inflammation and this protein has been proposed to be a master regulator of bone remodelling in inflammatory arthritis. Local glucocorticoid production is also significantly increased during joint inflammation. Therefore, we investigated how locally derived glucocorticoids and inflammatory cytokines regulate DKK1 synthesis in synovial fibroblasts during inflammatory arthritis.

MethodsWe examined expression and regulation of DKK1 in primary cultures of human synovial fibroblasts isolated from patients with inflammatory arthritis. The effect of TNFα, IL-1β and glucocorticoids on DKK1 mRNA and protein expression was examined by real-time PCR and ELISA. The ability of inflammatory cytokine-induced expression of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 11β-HSD1 to sensitise fibroblasts to endogenous glucocorticoids was explored. Global expression of Wnt signalling and target genes in response to TNFα and glucocorticoids was assessed using a custom array.

ResultsDKK1 expression in human synovial fibroblasts was directly regulated by glucocorticoids but not proinflammatory cytokines. Glucocorticoids, but not TNFα, regulated expression of multiple Wnt agonists and antagonists in favour of inhibition of Wnt signalling. However, TNFα and IL-1β indirectly stimulated DKK1 production through increased expression of 11β-HSD1.

ConclusionsThese results demonstrate that in rheumatoid arthritis synovial fibroblasts, DKK1 expression is directly regulated by glucocorticoids rather than TNFα. Consequently, the links between synovial inflammation, altered Wnt signalling and bone remodelling are not direct but are dependent on local activation of endogenous glucocorticoids.

AbbreviationsASankylosing spondylitis

DKK1dickkopf-1

ELISAenzyme-linked immunosorbent assay

GRαglucocorticoid receptor alpha

11β-HSD11beta-hydroxysteroid dehydrogenase

IL-1interleukin 1

OAosteoarthritis

PCRpolymerase chain reaction

RArheumatoid arthritis

TNFαtumor necrosis factor alpha.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4065 contains supplementary material, which is available to authorized users.

Karim Raza and Mark S Cooper contributed equally to this work.

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Author: Rowan Hardy - Maria Juarez - Amy Naylor - Jinwen Tu - Elizabeth H Rabbitt - Andrew Filer - Paul M Stewart - Christopher 

Source: https://link.springer.com/







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