Calcium pyrophosphate crystal deposition disease (CPPD) is a common arthritis of the elderly in which calcium pyrophosphate dihydrate (CPPD) crystals are deposited within articular joints. The pathogenesis of the disease is unknown, but altered alkaline phosphatase (ALP) activity could be a contributing factor. In this research, the hypothesis that some endogenous molecules can inhibit ALP's pyrophosphatase (PPiase) and CPPD crystal dissolution activities was tested. Using enzyme kinetic studies, arginine, lysine, histidine and cysteine, which are inhibitors of ALP's phosphatase (Piase) activity at alkaline pH, were examined for their effects on ALP's Piase, PPiase and CPPD crystal dissolution activities at physiologic pH. Specific activities and kinetic parameters V max, KM, KI and I50 indicated that these amino acids, especially cysteine, inhibited ALP under physiologic conditions. Theses results suggest that certain amino acids, by inhibiting ALP activity, contribute to the pathogenesis of CPPD if they accumulate within the articular cartilage.