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


METHODS
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.
Lazarus
D D
DD
Department of Preclinical Research, PRAECIS Pharmaceuticals Incorporated, Waltham, MA 02451, USA.
Doyle
E G
EG
Bernier
S G
SG
Rogers
A B
AB
Labenski
M T
MT
Wakefield
J D
JD
Karp
R M
RM
Clark
E J
EJ
Lorusso
J
J
Hoyt
J G
JG
Thompson
C D
CD
Hannig
G
G
Westlin
W F
WF
D000626:Aminopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors*; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D001862:Bone Resorption / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007596:Joints / Q000473:pathology; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D004852:Epoxy Compounds; C488724:PPI 2458; D011480:Protease Inhibitors; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D014633:Valine