title: Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice.
abstract: OBJECTIVE
  To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.
  
  
  METHODS
  We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.
  
  
  RESULTS
  Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (-37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (-85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF-mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1beta (IL-1beta), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.
  
  
  CONCLUSIONS
  OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.
authors.affiliation: Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. georg.schett@akh-wien.ac.at
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Brad
authors.initials: B
authors.lastname: Bolon
authors.forename: Colin
authors.initials: C
authors.lastname: Dunstan
authors.forename: Birgit
authors.initials: B
authors.lastname: Görtz
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulz
authors.forename: Helga
authors.initials: H
authors.lastname: Bergmeister
authors.forename: Giorgos
authors.initials: G
authors.lastname: Kollias
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000276:immunology; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D002908:Chronic Disease; D006023:Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D006023:Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D014409:Tumor Necrosis Factor-alpha