Limits...
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.

Show MeSH

Related in: MedlinePlus

Expression of matrix metalloproteinase 13 (MMP-13) in human rheumatoid arthritis (RA) (A) synovial tissue (magnification ×200) and (B) the isotype control (magnification ×200). Arrows indicate the expression of MMP-13 at sites of cartilage destruction. Expression of MMP-13 in the explants of the SCID-mouse co-implantation model of (C) RA (magnification ×400) and (D) the isotype control staining (magnification ×400). Expression of (E) MMP-1 (magnification ×400) and (F) the isotype control staining (magnification ×400).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Expression of matrix metalloproteinase 13 (MMP-13) in human rheumatoid arthritis (RA) (A) synovial tissue (magnification ×200) and (B) the isotype control (magnification ×200). Arrows indicate the expression of MMP-13 at sites of cartilage destruction. Expression of MMP-13 in the explants of the SCID-mouse co-implantation model of (C) RA (magnification ×400) and (D) the isotype control staining (magnification ×400). Expression of (E) MMP-1 (magnification ×400) and (F) the isotype control staining (magnification ×400).

Mentions: MMP-13 was highly expressed in human RA synovium at sites of cartilage invasion. In addition, all explants from the SCID-mouse co-implantation model showed expression of MMP-13 in fibroblasts around the explants as well as in chondrocytes of the implanted cartilage. In addition, MMP-1 was highly expressed in the explants from the SCID-mouse co-implantation model (figure 1A–F).


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)

Expression of matrix metalloproteinase 13 (MMP-13) in human rheumatoid arthritis (RA) (A) synovial tissue (magnification ×200) and (B) the isotype control (magnification ×200). Arrows indicate the expression of MMP-13 at sites of cartilage destruction. Expression of MMP-13 in the explants of the SCID-mouse co-implantation model of (C) RA (magnification ×400) and (D) the isotype control staining (magnification ×400). Expression of (E) MMP-1 (magnification ×400) and (F) the isotype control staining (magnification ×400).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Expression of matrix metalloproteinase 13 (MMP-13) in human rheumatoid arthritis (RA) (A) synovial tissue (magnification ×200) and (B) the isotype control (magnification ×200). Arrows indicate the expression of MMP-13 at sites of cartilage destruction. Expression of MMP-13 in the explants of the SCID-mouse co-implantation model of (C) RA (magnification ×400) and (D) the isotype control staining (magnification ×400). Expression of (E) MMP-1 (magnification ×400) and (F) the isotype control staining (magnification ×400).
Mentions: MMP-13 was highly expressed in human RA synovium at sites of cartilage invasion. In addition, all explants from the SCID-mouse co-implantation model showed expression of MMP-13 in fibroblasts around the explants as well as in chondrocytes of the implanted cartilage. In addition, MMP-1 was highly expressed in the explants from the SCID-mouse co-implantation model (figure 1A–F).

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