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Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis


Jüngel, A; Ospelt, C; Lesch, M; Thiel, M A; Sunyer, T; Schorr, O; Michel, B A; Gay, R E; Kolling, C; Flory, C; Gay, S; Neidhart, M (2010). Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis. Annals of the Rheumatic Diseases, 69(5):898-902.

Abstract

OBJECTIVE: In the present study we evaluated the decrease of cartilage destruction by a novel orally active and specific MMP-13 inhibitor in three different animal models of rheumatoid arthritis (RA). MATERIALS AND METHODS: The SCID mouse co-implantation model of RA, 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 this inhibitor resulted in 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 observed in the AIA model. No toxic effects were observed in all three animal models. CONCLUSION: Although several MMPs in concert with other proteinases play 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 out 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.

OBJECTIVE: In the present study we evaluated the decrease of cartilage destruction by a novel orally active and specific MMP-13 inhibitor in three different animal models of rheumatoid arthritis (RA). MATERIALS AND METHODS: The SCID mouse co-implantation model of RA, 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 this inhibitor resulted in 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 observed in the AIA model. No toxic effects were observed in all three animal models. CONCLUSION: Although several MMPs in concert with other proteinases play 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 out 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:May 2010
Deposited On:17 Jun 2009 15:17
Last Modified:05 Apr 2016 13:16
Publisher:BMJ Publishing Group
ISSN:0003-4967
Publisher DOI:10.1136/ard.2008.106021
PubMed ID:19497915
Permanent URL: http://doi.org/10.5167/uzh-19303

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