An inhibitor of methionine aminopeptidase type-2, PPI-2458, ameliorates the pathophysiological disease processes of rheumatoid arthritis

• Published in: Inflammation research 2008, Vol.57 (1), p.18-27
• Main Authors: Lazarus, D. D., Doyle, E. G., Bernier, S. G., Rogers, A. B., Labenski, M. T., Wakefield, J. D., Karp, R. M., Clark, E. J., Lorusso, J., Hoyt, J. G., Thompson, C. D., Hannig, G., Westlin, W. F.
• Format: Article
• Language: English
• Subjects: Allergology; Aminopeptidases - analysis; Aminopeptidases - antagonists & inhibitors; Animals; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - pathology; Biomedical and Life Sciences; Biomedicine; Body Weight - drug effects; Bone Resorption - prevention & control; Cell Differentiation - drug effects; Cells, Cultured; Dermatology; Epoxy Compounds - pharmacology; Epoxy Compounds - therapeutic use; Female; Immunology; Joints - pathology; Metalloendopeptidases - analysis; Metalloendopeptidases - antagonists & inhibitors; Mice; Neurology; Osteoclasts - cytology; Osteoclasts - drug effects; Pharmacology/Toxicology; Protease Inhibitors - therapeutic use; Rats; Rats, Inbred Lew; Rheumatology; Valine - analogs & derivatives; Valine - pharmacology; Valine - therapeutic use
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-007-7075-5

. Objective: To elucidate the role of methionine aminopeptidase type-2 (MetAP-2) in the clinical pathology of rheumatoid arthritis, arthritis was induced in rats by administration of peptidoglycan-polysaccharide (PG-PS). Design: The inhibitor of MetAP-2, PPI-2458, was administered orally at 5 mg/kg every other day during 3 distinct phases of the disease. In vitro studies were performed to clarify in vivo findings. Results: Ankle swelling was completely alleviated by MetAP-2 inhibition. Inhibition of MetAP-2 in blood and tissues correlated with protection against PG-PS-induced arthritis. Histopathology of the tarsal joints improved following PPI-2458 administration, including a significant improvement of bone structure. In in vitro studies, osteoclast formation and activity were inhibited by PPI-2458, a mechanism not previously attributed to MetAP-2 inhibition. Conclusions: The important role that MetAP-2 has in the pathophysiological disease processes of PG-PS arthritis provides a strong rationale for evaluating PPI-2458 as a disease modifying antirheumatic treatment for rheumatoid arthritis.