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Open Access Highly Accessed Research article

Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis

Anthony J Milici1*, Elizabeth M Kudlacz2, Laurent Audoly3, Samuel Zwillich2 and Paul Changelian4

Author Affiliations

1 Pfizer Global Research and Development, MS#8220-2235, Groton, CT 06340, USA

2 Pfizer Global Research and Development, 50 Pequot Ave, New London, CT 06320, USA

3 Merck Research Laboratories, West Point, PA 19486, USA

4 1009 Glenhill Drive, Northville, MI 48167, USA

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Arthritis Research & Therapy 2008, 10:R14  doi:10.1186/ar2365

Published: 30 January 2008

Abstract

Introduction

CP-690550 is a small molecule inhibitor of Janus kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA).

Methods

CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5–15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically.

Results

CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease.

Conclusion

The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.