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


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.


CONCLUSIONS
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.
Jüngel
Astrid
A
Centre of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland. Astrid.Juengel@usz.ch
Ospelt
Caroline
C
Lesch
Mark
M
Thiel
Melissa
M
Sunyer
Teresa
T
Schorr
Olivier
O
Michel
Beat A
BA
Gay
Renate E
RE
Kolling
Christoph
C
Flory
Craig
C
Gay
Steffen
S
Neidhart
Michel
M
D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002358:Cartilage, Articular / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016513:Mice, SCID; D011817:Rabbits; D013583:Synovial Membrane / Q000201:enzymology
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1