title: Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo.
abstract: OBJECTIVE
  To investigate the efficacy of a murine anti-interleukin-6 receptor (anti-IL-6R) antibody in directly blocking tumor necrosis factor (TNF)- and RANKL-mediated osteoclastogenesis in vitro and in vivo.
  
  
  METHODS
  The efficacy of a murine antibody against IL-6R in blocking osteoclast differentiation of mononuclear cells stimulated with RANKL was tested. In addition, arthritic human TNFalpha-transgenic mice were treated with anti-IL-6R antibody, and osteoclast formation and bone erosion were assessed in arthritic paws.
  
  
  RESULTS
  Blockade of IL-6R dose dependently reduced osteoclast differentiation and bone resorption in monocyte cultures stimulated with RANKL or RANKL plus TNF. In human TNFalpha-transgenic mice, IL-6R blockade did not inhibit joint inflammation, but it strongly reduced osteoclast formation in inflamed joints as well as bone erosion in vivo. Neither the cell influx into joints nor the synovial expression of IL-6 and RANKL changed with IL-6R blockade, while the synovial expression of IL-1 was significantly reduced. In contrast, TNF-mediated systemic bone loss was not inhibited by IL-6R blockade.
  
  
  CONCLUSIONS
  These data suggest that blockade of IL-6R directly affects osteoclast formation in vitro and in vivo, suggesting a direct and specific effect of anti-IL-6R therapy on osteoclasts independently of its antiinflammatory effects. This effect adds significantly to the structure-sparing potential of pharmacologic blockade of IL-6R in arthritis.
authors.affiliation: Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Axmann
authors.forename: Christina
authors.initials: C
authors.lastname: Böhm
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Josef
authors.initials: J
authors.lastname: Smolen
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D001862:Bone Resorption / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007375:Interleukin-1; D015850:Interleukin-6; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha