Suppression of arthritis and protection from bone destruction by treatmentwith 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 cl inical indices and histologic examinations; circulating blood levels of vas cular endothelial growth factor were determined by enzyme-linked immunosorb ent assay. Results. In the preventive protocol, with TNP-470 administration at a dosag e of 60 mg/kg of body weight, the onset of arthritis was delayed and its cl inical intensity was rather mild; 100% of placebo-treated transgenic mice d eveloped 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 lo nger period of time and disease was almost abolished. The therapeutic regim en 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treatment were observed histologically, a feature that was still evident at 30 and 8 0 days after injections were withdrawn. Conclusion. Our demonstration that in vivo administration of an angiogenesi s inhibitor suppresses arthritis and protects from bone destruction provide s new insight into the pathogenesis of the disease and opens new possibilit ies in the treatment of RA in humans.