Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis.
OBJECTIVE
We assessed the clinical and histologic features of angiogenesis inhibition in a transgenic mouse model of arthritis that closely resembles rheumatoid arthritis (RA) in humans.


METHODS
KRN/NOD mice, which spontaneously develop arthritis, were treated with TNP-470, an angiogenesis inhibitor. Disease was monitored by use of clinical indices and histologic examinations; circulating blood levels of vascular endothelial growth factor were determined by enzyme-linked immunosorbent assay.


RESULTS
In the preventive protocol, with TNP-470 administration at a dosage of 60 mg/kg of body weight, the onset of arthritis was delayed and its clinical intensity was rather mild; 100% of placebo-treated transgenic mice developed arthritis that led to severe articular destruction. At a dosage of 90 mg/kg of TNP-470, the appearance of clinical signs was delayed for a longer period of time and disease was almost abolished. The therapeutic regimen alleviated clinical signs only when given during the very early stage of disease. Reductions in cartilage and bone destruction by TNP-470 treatment were observed histologically, a feature that was still evident at 30 and 80 days after injections were withdrawn.


CONCLUSIONS
Our demonstration that in vivo administration of an angiogenesis inhibitor suppresses arthritis and protects from bone destruction provides new insight into the pathogenesis of the disease and opens new possibilities in the treatment of RA in humans.
de Bandt
M
M
INSERM U479, Centre Hospitalo-Universitaire Xavier Bichat, Paris, France.
Grossin
M
M
Weber
A J
AJ
Chopin
M
M
Elbim
C
C
Pla
M
M
Gougerot-Pocidalo
M A
MA
Gaudry
M
M
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D001862:Bone Resorption / Q000517:prevention & control*; D003510:Cyclohexanes; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000097:blood; D008222:Lymphokines / Q000097:blood; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077609:O-(Chloroacetylcarbamoyl)fumagillol