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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 in the collagen-induced arthritis model. Clinical scoring was carried out as described in the ‘Material and methods’ section. Non-immunised and non-treated animals were used as negative control (‘normal’; n=2). Immunised and lipopolysaccharide (LPS)-treated animals served as positive controls (‘vehicle’, n=10). (A) Immunised and LPS-treated animals given orally the highly specific MMP-13 inhibitor (n=10 each group) showed a dose-dependent and significant reduction of clinical signs of arthritis. A mean erosion score was evaluated by analysing toluidine blue stained slides. (B) The highly selective MMP-13 inhibitor decreased dose dependently the destruction process of the joints by 21–38%. *p≤ 0.05; **p=0.01.
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Figure 4: Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor in the collagen-induced arthritis model. Clinical scoring was carried out as described in the ‘Material and methods’ section. Non-immunised and non-treated animals were used as negative control (‘normal’; n=2). Immunised and lipopolysaccharide (LPS)-treated animals served as positive controls (‘vehicle’, n=10). (A) Immunised and LPS-treated animals given orally the highly specific MMP-13 inhibitor (n=10 each group) showed a dose-dependent and significant reduction of clinical signs of arthritis. A mean erosion score was evaluated by analysing toluidine blue stained slides. (B) The highly selective MMP-13 inhibitor decreased dose dependently the destruction process of the joints by 21–38%. *p≤ 0.05; **p=0.01.

Mentions: For CIA in mice the specific MMP-13 inhibitor was administered orally at 3, 10 and 30 mg/kg without any toxic side effects. By analysing each limb, a clinical score was obtained for the treated and control animals. Non-immunised and non-treated animals did not develop any clinical signs of arthritis (normal, figure 4A). Immunised and lipopolysaccharide-treated animals served as positive controls and developed severe clinical signs of arthritis (vehicle, figure 4A). Immunised and lipopolysaccharide-treated animals treated with the specific MMP-13 inhibitor showed a dose-dependent and significant decrease of clinical signs of arthritis (30 mg/kg: p=0.01; 10 mg/kg: p=0.05). The lowest dosage of 3 mg/kg showed no significant effects (figure 4A). By evaluation of the mean erosion score the MMP-13 inhibitor decreased dose dependently the destruction process of the joints (figure 4B). Clear effects were seen even with the lowest dose of 3 mg/kg, resulting in 21% decrease of destruction, and with 10 mg/kg resulting in 28% reduction of destruction. A significant inhibition of joint erosion by 38% could be observed with 30 mg/kg, p<0.05 (figures 4B and 5). In conclusion, the selective MMP-13 inhibitor decreased clinical signs of arthritis and cartilage erosions in CIA.


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 in the collagen-induced arthritis model. Clinical scoring was carried out as described in the ‘Material and methods’ section. Non-immunised and non-treated animals were used as negative control (‘normal’; n=2). Immunised and lipopolysaccharide (LPS)-treated animals served as positive controls (‘vehicle’, n=10). (A) Immunised and LPS-treated animals given orally the highly specific MMP-13 inhibitor (n=10 each group) showed a dose-dependent and significant reduction of clinical signs of arthritis. A mean erosion score was evaluated by analysing toluidine blue stained slides. (B) The highly selective MMP-13 inhibitor decreased dose dependently the destruction process of the joints by 21–38%. *p≤ 0.05; **p=0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effects of the specific matrix metalloproteinase 13 (MMP-13) inhibitor in the collagen-induced arthritis model. Clinical scoring was carried out as described in the ‘Material and methods’ section. Non-immunised and non-treated animals were used as negative control (‘normal’; n=2). Immunised and lipopolysaccharide (LPS)-treated animals served as positive controls (‘vehicle’, n=10). (A) Immunised and LPS-treated animals given orally the highly specific MMP-13 inhibitor (n=10 each group) showed a dose-dependent and significant reduction of clinical signs of arthritis. A mean erosion score was evaluated by analysing toluidine blue stained slides. (B) The highly selective MMP-13 inhibitor decreased dose dependently the destruction process of the joints by 21–38%. *p≤ 0.05; **p=0.01.
Mentions: For CIA in mice the specific MMP-13 inhibitor was administered orally at 3, 10 and 30 mg/kg without any toxic side effects. By analysing each limb, a clinical score was obtained for the treated and control animals. Non-immunised and non-treated animals did not develop any clinical signs of arthritis (normal, figure 4A). Immunised and lipopolysaccharide-treated animals served as positive controls and developed severe clinical signs of arthritis (vehicle, figure 4A). Immunised and lipopolysaccharide-treated animals treated with the specific MMP-13 inhibitor showed a dose-dependent and significant decrease of clinical signs of arthritis (30 mg/kg: p=0.01; 10 mg/kg: p=0.05). The lowest dosage of 3 mg/kg showed no significant effects (figure 4A). By evaluation of the mean erosion score the MMP-13 inhibitor decreased dose dependently the destruction process of the joints (figure 4B). Clear effects were seen even with the lowest dose of 3 mg/kg, resulting in 21% decrease of destruction, and with 10 mg/kg resulting in 28% reduction of destruction. A significant inhibition of joint erosion by 38% could be observed with 30 mg/kg, p<0.05 (figures 4B and 5). In conclusion, the selective MMP-13 inhibitor decreased clinical signs of arthritis and cartilage erosions in CIA.

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