Gold compounds are disease-modifying agents for the treatment of rheumatoid arthritis. They act on the immune system but the mechanism is not fully understood. Gold has been shown to affect antigen processing by T-cells and also reduces expression of cytokines in macrophages. Tartrate-resistant acid phosphatase (TRAP), expressed by osteoclasts, macrophages and dendritic cells is an enzyme with roles in skeletal metabolism and the immune response. TRAP is able to degrade skeletal phosphoproteins including osteopontin, identical to the T-cell cytokine, Eta-1; we thus propose that TRAP regulates the Eta-1 pathway common to the immune system and skeleton. We compared the distribution of osteopontin and TRAP in sections of 18-day-old embryonic mice by immunohistochemistry. Both proteins occurred in the same locations. To determine whether gold compounds exert their effects by modification of TRAP activity, we examined the action of gold chloride and the prodrugs, aurothioglucose and aurothiomalate on the dephosphorylation of osteopontin by TRAP. Aurothioglucose and aurothiomalate had little effect on phosphatase activity; gold chloride was a potent non-competitive inhibitor (Ki < 47 x 10(-9) M). These findings indicate a possible molecular mechanism for the action of therapeutic gold and further implicate TRAP in the control of immunity.