Several lines of evidence indicate that polypeptide growth factors are important in articular cartilage homeostasis and repair. It is not yet clear how these growth factors are regulated. We tested the hypothesis that the growth factors responsible for regulating cartilage are themselves regulated by growth factors. We delivered insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), and/or transforming growth factor-beta1 (TGF-beta1) to adult bovine articular chondrocytes in primary culture and measured the resulting changes in IGF-I, FGF-2, and TGF-beta1 gene expression and protein production. These growth factors differentially regulated their own and each others gene expression and protein production. In concert, they regulated each other in an interactive fashion. Their interactions ranged from inhibitory to synergistic. The time course of the regulatory effects differed among the individual growth factors and combinations. Growth factor-induced changes in growth factor protein production by articular chondrocytes generally corresponded to the changes in gene expression patterns. These studies suggest that interactions among IGF-I, FGF-2, and TGF-beta1 substantially modulate their regulatory functions. The results may help guide the application of growth factors to articular cartilage repair.