Tube formation in collagen gel was induced in human omental microvascular endothelial (HOME) cells in the presence of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha). TGF-alpha enhanced the expression of the tissue type plasminogen activator (t-PA) gene, whereas TGF-beta increased the expression of the PA inhibitor-1 (PAI-1) gene and inhibited that of the t-PA gene. TGF-beta inhibited the tube formation of HOME cells in type I collagen gel that was enhanced in response to TGF-alpha. We have recently established an angiogenesis model in vitro in which vascular endothelial cells on type I collagen gel in an inner chamber are co-cultured with other types of cells in an outer chamber. Here we examined whether the EGF/TGF-alpha-induced tube formation in HOME cells was modulated by human chondrocytes co-culture in the outer chamber. TGF-alpha-dependent tube formation of HOME cells was inhibited when human chondrocytes were co-cultured in the outer chamber. This chondrocyte-induced inhibition of tube formation was partly abrogated by co-administration of anti-TGF-beta antibody. These findings suggest that TGF-beta is partly involved in the human chondrocyte-dependent inhibition of tube formation by human microvascular endothelial cells. This is the first model system demonstrating that avascularity of human chondrocytes is partly due to TGF-beta family produced from them.