title: Tumor necrosis factor-inhibiting therapy preferentially targets bone destruction but not synovial inflammation in a tumor necrosis factor-driven model of rheumatoid arthritis.
abstract: OBJECTIVE
  To investigate how tumor necrosis factor (TNF)-inhibiting therapy affects bone destruction and inflammation in a TNF-driven mouse model of rheumatoid arthritis.
  
  
  METHODS
  In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell-derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNF-transgenic mice with different doses of adalimumab.
  
  
  RESULTS
  TNF stimulated osteoclastogenesis mainly by increasing the number of osteoclast precursor cells in vitro. This TNF effect was independent of the presence of RANKL. In the hTNF-transgenic mouse model of destructive arthritis, low-dose TNF-inhibiting therapy with adalimumab had no effect on synovial inflammation but significantly inhibited local bone destruction and the generation of osteoclasts. This inhibition was accompanied by a reduction in the number of c-Fms-positive osteoclast precursor cells in the bone marrow and a reduction of the osteoclast precursor pools in the blood and inflamed synovial membrane of hTNF-transgenic mice.
  
  
  CONCLUSIONS
  Low-dose TNF-inhibiting therapy significantly reduces bone erosions by reducing the number of circulating and joint-invading osteoclast precursors. This effect is uncoupled from its antiinflammatory action.
authors.affiliation: Medical University of Vienna, Vienna, Austria.
authors.forename: Nikolaus B
authors.initials: NB
authors.lastname: Binder
authors.forename: Antonia
authors.initials: A
authors.lastname: Puchner
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.forename: Silvia
authors.initials: S
authors.lastname: Hayer
authors.forename: Harald
authors.initials: H
authors.lastname: Leiss
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.forename: Roman
authors.initials: R
authors.lastname: Kreindl
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
mesh_terms: D000068879:Adalimumab; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D053245:RANK Ligand / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology; D013585:Synovitis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000068879:Adalimumab