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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, Sunyer T, Schorr O, Michel BA, Gay RE, Kolling C, Flory C, Gay S, Neidhart M - Ann. Rheum. Dis. (2009)

Bottom Line: 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.These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.

View Article: PubMed Central - PubMed

Affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland. Astrid.Juengel@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.

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Related in: MedlinePlus

Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor (30 mg/kg/day) in the antigen-induced arthritis (AIA) model in rabbits (normal rabbits n=2, arthritic animals (=vehicle) n=6, MMP-13 inhibitor treated n=7). The induction of AIA in untreated animals served as a positive control. (A) Treatment with the MMP-13 inhibitor did not significantly decrease the loss off proteoglycan. (B) The histological analysis of the cartilage erosions showed a non-significant downregulation of erosions by 14% in animals treated with the MMP-13 inhibitor.
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Figure 6: Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor (30 mg/kg/day) in the antigen-induced arthritis (AIA) model in rabbits (normal rabbits n=2, arthritic animals (=vehicle) n=6, MMP-13 inhibitor treated n=7). The induction of AIA in untreated animals served as a positive control. (A) Treatment with the MMP-13 inhibitor did not significantly decrease the loss off proteoglycan. (B) The histological analysis of the cartilage erosions showed a non-significant downregulation of erosions by 14% in animals treated with the MMP-13 inhibitor.

Mentions: To examine the inhibition of cartilage erosion by the MMP-13 inhibitor we developed AIA in rabbits. The oral application of the MMP-13 inhibitor (30 mg/kg/day) did not induce any side effects in the animals. To evaluate the break down of the cartilage, the concentration of proteoglycan of the joints was evaluated. The induction of AIA in untreated animals resulted in a significant loss of proteoglycans of the joints (positive control, proteoglycan ng/mg cartilage ± SEM: 112.4±6.6 to 82.2±4.8). However, the specific MMP-13 inhibitor did not significantly decrease the loss of proteoglycans (91.2±6.2; figure 6A). The histological analysis of the cartilage erosions showed an inhibition by 14%, but not significant, in animals treated with the specific MMP-13 inhibitor (figure 6B). In conclusion, in contrast to the other two animal models of arthritis, the MMP-13 inhibitor did not show significant effects in the AIA model.


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, Sunyer T, Schorr O, Michel BA, Gay RE, Kolling C, Flory C, Gay S, Neidhart M - Ann. Rheum. Dis. (2009)

Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor (30 mg/kg/day) in the antigen-induced arthritis (AIA) model in rabbits (normal rabbits n=2, arthritic animals (=vehicle) n=6, MMP-13 inhibitor treated n=7). The induction of AIA in untreated animals served as a positive control. (A) Treatment with the MMP-13 inhibitor did not significantly decrease the loss off proteoglycan. (B) The histological analysis of the cartilage erosions showed a non-significant downregulation of erosions by 14% in animals treated with the MMP-13 inhibitor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2925150&req=5

Figure 6: Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor (30 mg/kg/day) in the antigen-induced arthritis (AIA) model in rabbits (normal rabbits n=2, arthritic animals (=vehicle) n=6, MMP-13 inhibitor treated n=7). The induction of AIA in untreated animals served as a positive control. (A) Treatment with the MMP-13 inhibitor did not significantly decrease the loss off proteoglycan. (B) The histological analysis of the cartilage erosions showed a non-significant downregulation of erosions by 14% in animals treated with the MMP-13 inhibitor.
Mentions: To examine the inhibition of cartilage erosion by the MMP-13 inhibitor we developed AIA in rabbits. The oral application of the MMP-13 inhibitor (30 mg/kg/day) did not induce any side effects in the animals. To evaluate the break down of the cartilage, the concentration of proteoglycan of the joints was evaluated. The induction of AIA in untreated animals resulted in a significant loss of proteoglycans of the joints (positive control, proteoglycan ng/mg cartilage ± SEM: 112.4±6.6 to 82.2±4.8). However, the specific MMP-13 inhibitor did not significantly decrease the loss of proteoglycans (91.2±6.2; figure 6A). The histological analysis of the cartilage erosions showed an inhibition by 14%, but not significant, in animals treated with the specific MMP-13 inhibitor (figure 6B). In conclusion, in contrast to the other two animal models of arthritis, the MMP-13 inhibitor did not show significant effects in the AIA model.

Bottom Line: 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.These results strongly support the development of this class of drugs to reduce or halt joint destruction in patients with RA.

View Article: PubMed Central - PubMed

Affiliation: Centre of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH 8091 Zurich, Switzerland. Astrid.Juengel@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.

Show MeSH
Related in: MedlinePlus