TGF-BETA INDUCES BIMODAL PROLIFERATION OF CONNECTIVE-TISSUE CELLS VIA COMPLEX CONTROL OF AN AUTOCRINE PDGF LOOP

Transforming growth factor-β (TGF-β) acts as a growth inhibitor, yet it can stimulate proliferation; 1-2 fg/cell of TGF-β1 elicits maximal proliferation of dense and sparse cultured smooth muscle cells (SMCs), whereas higher amounts are less stimulatory. This bimodal response is not limited to SMCs, as TGF-β induces a similar response in human fibroblasts and chondrocytes. The amount of TGF-β1 per cell that induces maximal proliferation is identical for dense and sparse SMCs. At low concentrations of TGF-β, there is a 10-12 hr delay in DNA synthesis compared with that elicited by PDGF. PDGF-AA is detected in the culture medium at 24 hr, and anti-PDGF IgG blocks DNA synthesis. At higher concentrations, TGF-β1 decreases transcripts and expression of PDGF receptor α subunits. Hence, TGF-β induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF-β, is decreased by down-regulation of PDGF receptor α subunits and perhaps by direct growth inhibition. © 1990.