Net loss of the cartilage extracellular matrix occurs in all forms of arthritis, and it is important to identify the factors that initiate and maintain this process. Extracellular ATP can elicit biological responses via P2-purinoceptors, and we have obtained evidence for the presence of these receptors at the surface of cultured human articular chondrocytes. We have extended this work by examining whether exogenous ATP also promotes cartilage resorption. Cultured explants of bovine nasal cartilage were used, and breakdown of proteoglycans was monitored by measuring the release of glycosaminoglycans. ATP, GTP, CTP, UTP, ITP, 2-methylthioadenosine 5'-triphosphate, and adenosine 5'-O-(3-thiotriphosphate) all promoted release of glycosaminoglycans, whereas ADP, AMP, adenosine, and adenosine 5'-(alpha,beta-methylene)triphosphate were inactive. On lowering the concentration of foetal calf serum in the tissue culture medium from 10% (v/v) to 2.5% (v/v), the response to ATP was enhanced and the minimum effective concentration was reduced. The ATP-elicited release of glycosaminoglycans was also enhanced by interleukin 1 beta, tumour necrosis factor alpha, and transforming growth factor-beta, although only high concentrations of the latter were effective. These data provide further evidence for the presence of P2-purinoceptors in cartilage, and indicate that if ATP arises extracellularly, it could have potentially deleterious effects. The enhancement of the response to ATP by interleukin 1 beta and tumour necrosis factor alpha suggests an additional mechanism whereby these cytokines can promote cartilage resorption.