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Inflammation Research

, Volume 57, Issue 1, pp 18–27 | Cite as

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

  • D. D. Lazarus
  • E. G. Doyle
  • S. G. Bernier
  • A. B. Rogers
  • M. T. Labenski
  • J. D. Wakefield
  • R. M. Karp
  • E. J. Clark
  • J. Lorusso
  • J. G. Hoyt
  • C. D. Thompson
  • G. Hannig
  • W. F. Westlin
Article

Abstract.

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.

Keywords:

Arthritis Aminopeptidase Osteoclast 

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Copyright information

© Birkhaueser 2008

Authors and Affiliations

  • D. D. Lazarus
    • 7
    • 1
  • E. G. Doyle
    • 7
  • S. G. Bernier
    • 7
  • A. B. Rogers
    • 8
  • M. T. Labenski
    • 9
    • 2
  • J. D. Wakefield
    • 3
    • 9
  • R. M. Karp
    • 7
  • E. J. Clark
    • 7
  • J. Lorusso
    • 7
  • J. G. Hoyt
    • 4
    • 9
  • C. D. Thompson
    • 9
    • 5
  • G. Hannig
    • 7
  • W. F. Westlin
    • 6
    • 7
  1. 1.GPC Biotech, Inc.WalthamUSA
  2. 2.State University of ArizonaTempeUSA
  3. 3.Microbia, Inc.CambridgeUSA
  4. 4.Infinity Pharmaceuticals, Inc.CambridgeUSA
  5. 5.Merck Pharmaceuticals, Inc.West PointUSA
  6. 6.Avila TherapeuticsWalthamUSA
  7. 7.Department of Preclinical ResearchPRAECIS Pharmaceuticals IncorporatedWalthamUSA
  8. 8.Division of Comparative MedicineMassachusetts Institute of TechnologyCambridgeUSA
  9. 9.Department of Analytical PharmacologyPRAECIS Pharmaceuticals IncorporatedWalthamUSA

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