CTLA-4 directly inhibits osteoclast formation.
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.
Axmann
R
R
Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuernberg, Erlangen, Germany.
Herman
S
S
Zaiss
M
M
Franz
S
S
Polzer
K
K
Zwerina
J
J
Herrmann
M
M
Smolen
J
J
Schett
G
G
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001862:Bone Resorption / Q000276:immunology / Q000473:pathology; D060908:CTLA-4 Antigen; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D010010:Osteoclasts / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D014409:Tumor Necrosis Factor-alpha