Article Text

other Versions

PDF
Extended report
Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis
  1. Astrid Jüngel1,
  2. Caroline Ospelt1,
  3. Mark Lesch2,
  4. Melissa Thiel2,
  5. Teresa Sunyer2,
  6. Olivier Schorr1,
  7. Beat A Michel1,
  8. Renate E Gay1,
  9. Christoph Kolling3,
  10. Craig Flory2,
  11. Steffen Gay1,
  12. Michel Neidhart1
  1. 1Centre of Experimental Rheumatology, University Hospital of Zurich and Zurich Centre of Integrative Human Physiology (ZIHP), Switzerland
  2. 2Pfizer Inc, La Jolla, California, USA
  3. 3Schulthess Clinic, Zurich, Switzerland
  1. Correspondence to Dr Astrid Jüngel, Centre of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland; Astrid.Juengel{at}usz.ch

Abstract

Objective To evaluate the decrease of cartilage destruction by a novel orally active and specific matrix metalloproteinase 13 (MMP-13) inhibitor in three different animal models of rheumatoid arthritis (RA).

Materials and methods The SCID mouse co-implantation model of RA, the collagen-induced arthritis (CIA) model in mice and the antigen-induced arthritis model (AIA) in rabbits were used.

Results In the SCID mouse co-implantation model, the MMP-13 inhibitor reduced cartilage destruction by 75%. In the CIA model of RA, the MMP-13 inhibitor resulted in a significant and dose-dependent decrease in clinical symptoms as well as of cartilage erosion by 38% (30 mg/kg), 28% (10 mg/kg) and 21% (3 mg/kg). No significant effects were seen in the AIA model. No toxic effects were seen in all three animal models.

Conclusion Although several MMPs in concert with other proteinases have a role in the process of cartilage destruction, there is a need for highly selective MMP inhibitors to reduce severe side effects that occur with non-specific inhibitors. Significant inhibition of MMP-13 reduced cartilage erosions in two of three tested animal models of RA. These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.

Statistics from Altmetric.com

Footnotes

  • Funding This study was supported by a grant from Pfizer Inc. AJ: Autocure FP6, Masterswich FP7; CK: Schwyzer Stiftung; SG: SNF 32000-116842, Autocure FP6 and Masterswitch FP7.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Swiss ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.