Session Title: Rheumatoid Arthritis - Animal Models I
Session Type: Abstract Submissions (ACR)
Background/Purpose: Matrix metalloproteinase 13 (MMP-13) is expressed by chondrocytes and synovial cells in human osteoarthritis and rheumatoid arthritis (RA) (Takaishi et al., 2008). Serum MMP-13 is increased in stages III and IV in RA and treatment with methotrexate (MTX) reduced serum concentrations of MMP-13 in RA patients (Takemura et al., 2005; Fiedorczyk et al., 2006). The aim of the study was to evaluate translational potential of serum MMP-13 as a biomarker for treatment efficacy. Therefore, we investigated effects of different anti-arthritic treatments on serum MMP-13 concentrations in correlation with severity of bone destruction in rat collagen induced arthritis (CIA). Serum MMP-13 was also used as a systemic marker of bone destruction in a mouse LPS-induced bone resorption model.
Methods: CIA was induced in male Dark Agouti rats by immunization with bovine type II collagen (days 0 and 7) and the animals were treated intraperitoneally with etanercept (10 mg/kg, 3 times per week) or orally with MTX (0.1 mg/kg once daily) starting from day 17 to day 31. Histological evaluation was performed on hind paws by scoring bone and cartilage lesion, cell infiltrate and pannus severity (scoring system ranged from 1 to 4 for all parameters). In the LPS induced bone resorption model, mice were subcutaneously injected by a single dose of 20 mg/kg LPS (E.coli) and treated subcutaneously with MTX (5, 0.5 and 0.05 mg/kg once daily) for 4 days. Serum MMP-13 concentration was determined in both models by ELISA (USCNK Life Science Inc., China). Serum MMP-13 concentrations were correlated with histological data on individual level.
Results: Treatment with both etanercept and MTX significantly reduced the mean serum MMP-13 concentration in rat CIA (63% and 33%, respectively). On the level of individual values, serum MMP-13 concentration correlated with individual total histological scores with R2=0.74 for MTX and R2= 0.67 for etanercept. The correlation with individual bone and cartilage lesion scores showed to be even better for etanercept (R2=0.72 and R2=0.68, respectively) while for MTX the correlations were comparable with the one obtained for individual total histological scores (R2=0.71 for both). In LPS induced bone resorption model, treatment with MTX dose dependently reduced the mean serum MMP-13 concentrations: a 100% reduction at 5 mg/kg, 84% at 0.5 mg/kg and no inhibition at 0.05 mg/kg.
Conclusion: Our data showed that serum MMP-13 concentration measurement is an useful tool to assess effects of anti-arthritic therapy since it correlates with severity of bone and cartilage destruction. Furthermore, serum MMP-13 concentrations can be effectively used as marker of compound potency in a short, simple model of LPS-induced bone resorption in mice to predict efficacy of treatment in CIA. Since MMP-13 was shown to be a marker of disease activity in humans, these results strongly support its usefulness as a translational marker.
V. Ivetic Tkalcevic,
M. Dominis Kramaric,
V. Erakovic Haber,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/serum-matrix-metalloproteinase-13-as-a-translational-marker-for-efficacy-of-anti-arthritic-treatments-in-rat-collagen-induced-arthritis-and-mouse-model-of-lipopolysaccharide-induced-bone-resorption/