Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo.
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.
Axmann
Roland
R
Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, Germany.
Böhm
Christina
C
Krönke
Gerhard
G
Zwerina
Jochen
J
Smolen
Josef
J
Schett
Georg
G
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
D000888:Antibodies, Anti-Idiotypic; D007375:Interleukin-1; D015850:Interleukin-6; D053245:RANK Ligand; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha