title: Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression.
abstract: 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.
authors.affiliation: Department of Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gisela Ruiz
authors.initials: GR
authors.lastname: Heiland
authors.forename: Karin
authors.initials: K
authors.lastname: Zwerina
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baum
authors.forename: Trayana
authors.initials: T
authors.lastname: Kireva
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Distler
authors.forename: Mario
authors.initials: M
authors.lastname: Grisanti
authors.forename: Frank
authors.initials: F
authors.lastname: Asuncion
authors.forename: Xiadong
authors.initials: X
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Ominsky
authors.forename: William
authors.initials: W
authors.lastname: Richards
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001862:Bone Resorption / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010011:Osteocytes / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; C501127:Dkk1 protein, mouse; D005819:Genetic Markers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C486030:Sost protein, mouse; D014409:Tumor Necrosis Factor-alpha