PT  - JOURNAL ARTICLE
AU  - Gisela Ruiz Heiland
AU  - Karin Zwerina
AU  - Wolfgang Baum
AU  - Trayana Kireva
AU  - Jörg H Distler
AU  - Mario Grisanti
AU  - Frank Asuncion
AU  - Xiadong Li
AU  - Michael Ominsky
AU  - William Richards
AU  - Georg Schett
AU  - Jochen Zwerina
TI  - Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression
AID  - 10.1136/ard.2010.132852
DP  - 2010 Dec 01
TA  - Annals of the Rheumatic Diseases
PG  - 2152--2159
VI  - 69
IP  - 12
4099  - http://ard.bmj.com/content/69/12/2152.short
4100  - http://ard.bmj.com/content/69/12/2152.full
SO  - Ann Rheum Dis2010 Dec 01; 69
AB  - 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.