%0 Journal Article %A Gisela Ruiz Heiland %A Karin Zwerina %A Wolfgang Baum %A Trayana Kireva %A Jörg H Distler %A Mario Grisanti %A Frank Asuncion %A Xiadong Li %A Michael Ominsky %A William Richards %A Georg Schett %A Jochen Zwerina %T Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression %D 2010 %R 10.1136/ard.2010.132852 %J Annals of the Rheumatic Diseases %P 2152-2159 %V 69 %N 12 %X Introduction Inflammation is a major risk factor for systemic bone loss. Proinflammatory cytokines like tumour necrosis factor (TNF) affect bone homeostasis and induce bone loss. It was hypothesised that impaired bone formation is a key component in inflammatory bone loss and that Dkk-1, a Wnt antagonist, is a strong inhibitor of osteoblast-mediated bone formation. Methods TNF transgenic (hTNFtg) mice were treated with neutralising antibodies against TNF, Dkk-1 or a combination of both agents. Systemic bone architecture was analysed by bone histomorphometry. The expression of β-catenin, osteoprotegerin and osteocalcin was analysed. In vitro, primary osteoblasts were stimulated with TNF and analysed for their metabolic activity and expression of Dkk-1 and sclerostin. Sclerostin expression and osteocyte death upon Dkk-1 blockade were analysed in vivo. Results Neutralisation of Dkk-1 completely protected hTNFtg mice from inflammatory bone loss by preventing TNF-mediated impaired osteoblast function and enhanced osteoclast activity. These findings were accompanied by enhanced skeletal expression of β-catenin, osteocalcin and osteoprotegerin. In vitro, TNF rapidly increased Dkk-1 expression in primary osteoblasts and effectively blocked osteoblast differentiation. Moreover, blockade of Dkk-1 not only rescued impaired osteoblastogenesis but also neutralised TNF-mediated sclerostin expression in fully differentiated osteoblasts in vitro and in vivo. Conclusions These findings indicate that low bone formation and expression of Dkk-1 trigger inflammatory bone loss. Dkk-1 blocks osteoblast differentiation, induces sclerostin expression and leads to osteocyte death. Inhibition of Dkk-1 may thus be considered as a potent strategy to protect bone from inflammatory damage. %U https://ard.bmj.com/content/annrheumdis/69/12/2152.full.pdf