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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 1beta, 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.