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Vanadate, an Inhibitor of Stromelysin and Collagenase Expression, Suppresses Collagen Induced Arthritis

STEPHEN J. OLIVER, GARY S. FIRESTEIN, LARRY ARSENAULT, TONY F. CRUZ, TAMMY P. CHENG, MONA L. BANQUERIGO, DAVID L. BOYLE, and ERNEST BRAHN

ABSTRACT.

Objective. Collagen induced arthritis (CIA) is a model of chronic inflammatory synovitis with pannus, neovascularization, and joint destruction similar to rheumatoid arthritis (RA). Matrix metalloproteinases (MMP) are involved in degradation of the extracellular matrix and joint destruction in RA. c-fos and c-jun are protooncogenes whose products combine to form activating protein (AP-1), a regulatory protein that is required for cell proliferation and the transcription of a variety of genes, including MMP such as collagenase and stromelysin. Administration of vanadium compounds suppresses c-fos/c-jun expression and AP-1 activity, resulting in inhibition of MMP expression in response to factors such as interleukin 1 (IL-1). We evaluated whether a vanadium AP-1 inhibitor could reduce MMP expression and subsequent joint damage in CIA.

Methods. Vanadate [bis (maltolato) oxovanadium (IV) (BMOV; 10 mg/kg/day)] and the reducing agent N-acetyl cysteine (NAC; 100 mg/kg/day) were given subcutaneously daily in an attempt to suppress established CIA in rats. NAC in combination with vanadate appeared to increase the efficacy of c-fos/c-jun inhibition, while decreasing toxicity. Controls were given NAC alone. Clinical, radiographic, and histologic measures were evaluated as well as synovial MMP and IL-1a expression.

Results. BMOV therapy, initiated on the day of onset of clinical arthritis, significantly reduced clinical arthritis within 2 days (p < 0.05) compared to controls. Significance was maintained to the termination of the study on Day 18 post-arthritis onset (p < 0.005), with a maximum difference seen on Day 5 (p < 0.00001). Blinded radiographic scores at the completion of the protocols indicated less joint destruction in the experimental group compared to the control group (p < 0.005). Scanning and transmission electron microscopy confirmed the preservation of articular cartilage with therapy. In BMOV-treated rats, synovial mRNA expression of collagenase, stromelysin, and IL-la were reduced by 78%, 58%, and 85%, respectively, compared to controls.

Conclusion. This is the first study of vanadate as a potential antirheumatic agent. Further study of this AP-1 and MMP inhibitor may lead to new treatment options in RA. (First Release August 1 2007; J Rheumatol 2007;34:1802-9)

Key Indexing Terms:

ANIMAL DISEASE MODELS
MATRIX METALLOPROTEINASES
VANADATE
COLLAGEN-INDUCED ARTHRITIS
AP-1

From the Division of Rheumatology, UCLA School of Medicine, Los Angeles, California; UCSD School of Medicine, San Diego, California; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario; and Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Supported in part by NIH Grant AR-42200 and Angiotech Pharmaceuticals, Vancouver, British Columbia, Canada.

S.J. Oliver, MD (current affiliation New York University School of Medicine, New York, NY); T. Cheng, MD (current affiliation Washington University School of Medicine); M.L. Banquerigo, MD; E. Brahn, MD, Division of Rheumatology, UCLA School of Medicine; G.S. Firestein, MD; D.L. Boyle, BA, UCSD School of Medicine; L. Arsenault, PhD, Department of Pathology and Molecular Medicine, McMaster University; T.F. Cruz, PhD, Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto (current affiliation Transition Therapeutics, Toronto, Canada).

Address reprint requests to Dr. E. Brahn, UCLA School of Medicine, Division of Rheumatology, 1000 Veteran Avenue, Los Angeles, CA 90095-1670. E-mail: ebrahn@mednet.ucla.edu

Accepted for publication June 6, 2007.