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

Abstract

Objective To evaluate the decrease of cartilage destruction by a novel orally active and specifi c 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 signifi cant 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 signifi cant 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-specifi c inhibitors. Signifi cant 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.

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…The employment of an highly selective non-competitive inhibitor of MMP-13 (Johnson et al, 2007) significantly reduced the cartilage erosion in animal models of RA (Jüngel et al, 2010). The chondroprotective effects of micro-RNA inhibition of the MMP-13 expression was proved in human cartilage explants in vitro and through the development of inflammatory arthritis in mouse model in vivo (Akhtar et al, 2010).…”

DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts

“…51 In particular, MMP-1 and MMP-13 were reported to have a crucial role in the invasive properties of RASFs as shown in the severe combined immunodeficiency mouse co-implantation model. 52,53 Expression of MMPs is regulated by multiple pathways. DNA hypomethylation modulates expression of different MMPs in cancer cells.…”

Novel selective MMP-13 inhibitors reduce collagen degradation in bovine articular and human osteoarthritis cartilage explants

“…An MMP inhibitor that preferentially inhibits MMP-13 has been shown to block the degradation of explanted human osteoarthritic cartilage [11]. Recently published results showed the efficacy of a selective MMP-13 inhibitor to reduce cartilage degradation in the rabbit ACL model [12] and in some models of rheumatoid arthritis [13]. The selective MMP-13 inhibitor investigated in this study showed chondroprotective effects in the rat model of monoiodoacetate (MIA)-induced OA and in a surgical medial meniscus tear model [14].…”