ADENOSINE 5'-TRIPHOSPHATE, URIDINE 5'-TRIPHOSPHATE, BRADYKININ, AND LYSOPHOSPHATIDIC ACID INDUCE DIFFERENT PATTERNS OF CALCIUM RESPONSES BYHUMAN ARTICULAR CHONDROCYTES

Small calcium-mobilizing inflammatory mediators have been implicated i n joint pathology. Here we demonstrate that bradykinin, adenosine 5'-t riphosphate, uridine 5'-triphosphate, and lysophosphatidic acid raise the intracellular calcium concentration ([Ca2+](i)) in human articular chondrocytes. Heterologous cross-desensitization experiments showed t hat the uridine 5'-triphosphate response was abolished by prior treatm ent with adenosine 5'-triphosphate and, conversely, that the adenosine 5'-triphosphate response was abolished by prior treatment with uridin e 5'-triphosphate; this indicated competition for the same receptor si te, whereas bradykinin and lysophasphatidic acid did not compete with other ligands. Pretreatment with thapsigargin abolished ligand-mediate d Ca2+ responses but not vice versa; this confirmed that Ca2+ release occurred from intracellular stores. Single-cell analysis of Fura-2 ace toxymethyl ester loaded chondrocytes showed mediator-dependent pattern s of oscillatory Ca2+ changes in a subset of cells when challenged wit h submaximal concentrations of bradykinin, adenosine 5'-triphosphate, or uridine 5'-triphosphate in the presence of extracellular Ca2+. Howe ver, no oscillatory responses were seen after a challenge with lysopho sphatidic acid. Therefore, although a number of different Ca2+-mobiliz ing ligands activate chondrocytes, the differences that occur in the t emporal patterning of Ca2+ responses may result in unique mediator-dep endent changes in cellular activity.