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Tetrathiomolybdate Is Effective in a Mouse Model of Arthritis
MARK D. McCUBBIN, GUOQING HOU, GERALD D. ABRAMS, ROBERT DICK, ZHAN ZHANG, and GEORGE J. BREWER ABSTRACT. Objective. To test for protective effects of therapy with tetrathiomolybdate, a copper-lowering drug, against collagen-induced arthritis in mice. Methods. Mice were injected with bovine collagen II, and limb joint swelling and erythema were scored. Tetrathiomolybdate treated mice received drug by oral gavage or in drinking water. Plasma ceruloplasmin was followed as a measure of body copper status, and maintained between 20 and 60% of baseline. Urine for isoprostane studies was collected in metabolic cages. At sacrifice, blood was collected for cytokine assays, and hind limbs fixed in formalin. Results. Tetrathiomolybdate strongly protected against the collagen-induced arthritis as reflected in scores of swelling and erythema, and as seen histologically. Further, tetrathiomolybdate strongly protected against the increase in urine isoprostanes (a marker of oxidant damage) seen in collagen treated controls. The drug also protected against the increase in interleukin 2, interleukin 1ß, and tumor necrosis factor-a levels seen in collagen treated controls. Conclusion. Based on the positive results reported here, and the good safety profile of tetrathiomolybdate in human studies so far, a trial of tetrathiomolybdate in arthritis syndromes seems warranted. (First Release Oct 15 2006; J Rheumatol 2006;33:2501–6) Key Indexing Terms:
TETRATHIOMOLYBDATE From the Departments of Human Genetics, Pathology, and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA. Supported in part by grants FD-R-002153 and FD-R-002132 from the US Food and Drug Administration and by miscellaneous gifts. The University of Michigan has recently licensed the antifibrotic and antiinflammatory uses of tetrathiomolybdate to Pipex Therapeutic Inc., Miami, FL. Dr. Brewer has equity in and is a paid consultant to Pipex Inc. M.D. McCubbin, BS, Research Assistant; G. Hou, PhD, Research Scholar; R. Dick, BS, Research Associate; Z. Zhang, PhD, Research Assistant, Department of Human Genetics; G.D. Abrams, PhD, Emeritus Professor, Department of Pathology; G.J. Brewer, MD, Emeritus Professor, Departments of Human Genetics and Internal Medicine, University of Michigan Medical School. Address reprint requests to Dr. G.J. Brewer, University of Michigan Medical School, 5024 Kresge Bldg. II, Ann Arbor, MI 48109-0534, USA. E-mail: brewergj@umich.edu Accepted for publication July 7, 2006. |
