Inhibition of interleukin-6 receptor directly blocks osteoclast formation in vitro and in vivo

Arthritis Rheum. 2009 Sep;60(9):2747-56. doi: 10.1002/art.24781.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / pharmacology*
  • Bone Resorption / metabolism
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • In Vitro Techniques
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Mice
  • Mice, Transgenic
  • Osteoclasts / cytology*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • RANK Ligand / metabolism
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction / physiology
  • Synovial Membrane / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies, Anti-Idiotypic
  • Interleukin-1
  • Interleukin-6
  • RANK Ligand
  • Receptors, Interleukin-6
  • Tumor Necrosis Factor-alpha