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.
Institut Nationale de la Santé et de la Recherche Médicale, Unité 479, Faculté Xavier Bichat, Paris, France. debandt@bichat.inserm.fr
Michel
M
De Bandt
Meriem H
MH
Ben Mahdi
Véronique
V
Ollivier
Maggy
M
Grossin
Magali
M
Dupuis
Murielle
M
Gaudry
Peter
P
Bohlen
Kenneth E
KE
Lipson
Audie
A
Rice
Yan
Y
Wu
Marie-Anne
MA
Gougerot-Pocidalo
Catherine
C
Pasquier
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