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.
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.
Authors: John L Hamilton; Masashi Nagao; Brett R Levine; Di Chen; Bjorn R Olsen; Hee-Jeong Im Journal: J Bone Miner Res Date: 2016-04-08 Impact factor: 6.741
Authors: Christopher C Arico-Muendel; Heather Blanchette; Dennis R Benjamin; Teresa M Caiazzo; Paolo A Centrella; Jennifer DeLorey; Elisabeth G Doyle; Steven R Johnson; Matthew T Labenski; Barry A Morgan; Gary O'Donovan; Amy A Sarjeant; Steven Skinner; Charles D Thompson; Sarah T Griffin; William Westlin; Kerry F White Journal: ACS Med Chem Lett Date: 2013-02-22 Impact factor: 4.345