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CTLA-4 directly inhibits osteoclast formation
  1. R Axmann1,
  2. S Herman1,
  3. M Zaiss1,
  4. S Franz1,
  5. K Polzer1,
  6. J Zwerina1,
  7. M Herrmann1,
  8. J Smolen2,
  9. G Schett1,2
  1. 1
    Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nurnberg, Erlangen, Germany
  2. 2
    Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria
  1. Georg Schett, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuernberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany; georg.schett{at}uk-erlangen.de

Abstract

CTLA-4 is a regulator of co-stimulation and inhibits the activation of T cells through interfering with the interaction of CD80/86 on antigen-presenting cells with CD28 on T cells. CTLA-4 binds to the surface of antigen-presenting cells, such as dendritic cells and monocytes through CD80/86. Monocytes can differentiate in osteoclasts, the primary bone resorbing cells. Herein, we investigated whether the binding of CTLA-4 affects the differentiation of monocytes into osteoclasts in vitro and vivo. We show that CTLA-4 dose-dependently inhibits RANKL- as well as tumour necrosis factor (TNF)-mediated osteoclastogenesis in vitro without the presence of T cells. Furthermore, CTLA-4 was effective in inhibiting TNF-induced osteoclast formation in a non-T cell dependent TNF-induced model of arthritis as well as the formation of inflammatory bone erosion in vivo. These data suggest that CTLA-4 is an anti-osteoclastogenic molecule that directly binds osteoclast precursor cells and inhibits their differentiation. These findings are an attractive explanation for the anti-erosive effect of abatacept, a CTLA-4 immunoglobulin fusion protein used for the treatment of rheumatoid arthritis.

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Footnotes

  • Competing interests: None.

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