Amelioration of collagen-induced arthritis by thrombin inhibition
Ingrid Marty, … , Alexander So, Nathalie Busso
Ingrid Marty, … , Alexander So, Nathalie Busso
Published March 1, 2001
Citation Information: J Clin Invest. 2001;107(5):631-640. https://doi.org/10.1172/JCI11064.
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Article

Amelioration of collagen-induced arthritis by thrombin inhibition

Abstract

The deleterious role of fibrin deposition in arthritic joints prompted us to explore the effect of the thrombin inhibition on the course of collagen-induced arthritis (CIA) in the mouse. CIA was induced in male DBA/1J mice using native chicken type II collagen. The thrombin inhibitor polyethyleneglycol-hirudin (PEG-hirudin) was given for 16 days, starting 20 days after the first immunization (preventive treatment) or at the onset of clinical signs of arthritis (curative treatment). All the mice treated with PEG-hirudin had a significantly prolonged clotting time compared with control mice. PEG-hirudin, administered in a preventive way, led to significantly reduced incidence and severity of CIA during most of the treatment period, as assessed by clinical scoring. Accordingly, histological features showed a significant diminution of synovial hyperplasia in PEG-hirudin–treated mice compared with untreated mice. There was also a significant downmodulation of the synovial proinflammatory IL-1β and IL-12p35 cytokine mRNAs in treated mice. Intra-articular fibrin, evaluated by immunohistochemistry, was significantly reduced in treated mice compared with control mice and correlated with both clinical and histological scorings. Most importantly, once arthritis was established, PEG-hirudin also showed a curative effect. In conclusion, PEG-hirudin can both prevent the onset of CIA in a dose-dependent manner and ameliorate established arthritis, suggesting that thrombin inhibition may offer a new therapeutic approach in arthritis.

Authors

Ingrid Marty, Veronique Péclat, Gailute Kirdaite, Roberto Salvi, Alexander So, Nathalie Busso

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Development of CIA in PEG-hirudin–treated mice. (a–c) From day 20 after ...
Development of CIA in PEG-hirudin–treated mice. (a–c) From day 20 after type II collagen immunization, test mice were treated daily with PEG-hirudin (subcutaneous injection at 1 mg/kg/day, n = 13). Placebo mice received PBS (n = 13). Mice were observed daily for development of arthritis. (a) Percentage of mice that developed arthritis. (b) Arthritis severity. Mean arthritic index + SEM is shown. (c) Number of arthritic paws (mean + SEM). Dose-response effect of PEG-hirudin on incidence (d) and severity (e). From day 20 after immunization, test mice were treated daily subcutaneously with PEG-hirudin (0.1 mg/kg or 1 mg/kg; n = 13 in each group). Placebo mice received PBS only (n = 13). Mice groups were compared by statistical analysis using the nonparametric Wilcoxon/Kruskal-Wallis tests (rank sums). (a) P < 0.05 from day 24 to day 36. (b) P < 0.01 from day 24–27 and P < 0.05 until day 36. (c) P < 0.05 from day 24 to day 36. (d) P < 0.02 from day 21 until day 27 for the dose of 0.1 mg/kg. P < 0.02 from day 21 until day 28 and P < 0.05 from day 28–31 for the dose of 1 mg/kg. (e) P < 0.02 from day 21 until day 27 for the dose of 0.1 mg/kg and until day 32 for the dose of 1 mg/kg.