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.
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Funding This work was supported by the Interdisziplinäres Zentrum für Klinische Forschung Erlangen Project A34 (to GS and JZ), Deutsche Forschungsgemeinschaft Grant FOR 661 (to GS) and SFB 423 (to JZ and GS) and the European Union projects Masterswitch, Adipoa and Kinacept. This study was also supported by the Focus Programm SPP 1468 ‘Osteoimmunology - IMMUNOBONE – a program to unravel the mutual interactions between the immune system and bone’ of the Deutsche Forschungsgesellschaft.
Competing interests GS and JZ received speaker's fees from Amgen Incorporated. MG, FA, XL, MO and WR are employees of Amgen Incorporated.
Provenance and peer review Not commissioned; externally peer reviewed.