Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis.
It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and semiquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.
De Bandt
Michel
M
Institut Nationale de la Santé et de la Recherche Médicale, Unité 479, Faculté Xavier Bichat, Paris, France. debandt@bichat.inserm.fr
Ben Mahdi
Meriem H
MH
Ollivier
Véronique
V
Grossin
Maggy
M
Dupuis
Magali
M
Gaudry
Murielle
M
Bohlen
Peter
P
Lipson
Kenneth E
KE
Rice
Audie
A
Wu
Yan
Y
Gougerot-Pocidalo
Marie-Anne
MA
Pasquier
Catherine
C
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009930:Organic Chemicals / Q000008:administration & dosage; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology*
D007106:Immune Sera; D009930:Organic Chemicals; D012333:RNA, Messenger; C474557:SU 11657; D020794:Receptor Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2