Details

Autor(en) / Beteiligte

• Heiland, Gisela Ruiz
• Zwerina, Karin
• Baum, Wolfgang
• Kireva, Trayana
• Distler, Jörg H
• Grisanti, Mario
• Asuncion, Frank
• Li, Xiadong
• Ominsky, Michael
• Richards, William
• Schett, Georg
• Zwerina, Jochen

Titel

Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression

Ist Teil von

• Annals of the rheumatic diseases, 2010-12, Vol.69 (12), p.2152-2159

Ort / Verlag

London: BMJ Publishing Group Ltd and European League Against Rheumatism

Erscheinungsjahr

2010

Quelle

BMJ Journals Archiv - DFG Nationallizenzen

Beschreibungen/Notizen

• 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.