Transforming growth factor beta (TGF-beta) increases up to 20-fold the expression of various forms of chondroitin/dermatan sulfate proteoglycan, the major type of sulfated proteoglycan present in the extracellular matrix and culture medium of various human, rodent, and mink cell types including kidney and lung fibroblasts, lung epithelial cells, preadipocytes, and skeletal muscle myoblasts. TGF-beta regulates the level and molecular size of these proteoglycans by acting simultaneously at two levels: it elevates the biosynthetic rate of the 45-kDa proteoglycan core protein in a cycloheximide- and actinomycin D-sensitive manner, and it induces an increase in the molecular mass of the glycosaminoglycan chains. These cellular responses correlate with occupancy of type III TGF-beta receptors by TGF-beta 1 and TGF-beta 2 and are not induced by other growth factors tested. The parameters of this effect of TGF-beta in kidney fibroblasts and myoblasts are ED50 = 5-10 pM TGF-beta 1 or TGF-beta 2, and t 1/2 = 6-8 h. These results identify the chondroitin/dermatan sulfate proteoglycans as a major component of mammalian mesenchymal and epithelial extracellular matrices whose expression and structure are regulated by TGF-beta.