MODULATION OF COLLAGEN-SYNTHESIS BY GROWTH-FACTORS - THE ROLE OF ASCORBATE-STIMULATED LIPID-PEROXIDATION

Ascorbic acid has been shown to stimulate collagen synthesis through induction of lipid peroxidation leading to increased transcription of the collagen genes. The mechanism by which lipid peroxidation stimulates collagen transcription is unknown; however, an alteration of cell membranes may affect the activity of serum growth factors leading to a change in gene expression. To test this hypothesis, we treated dermal fibroblasts with transforming growth factor-beta (TGF-β),4 4 Abbreviations used: TGF-β, transforming growth factor-beta; EGF, epidermal growth factor; IL-1, interleukin-1; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; DMEM, Dulbecco's modified Eagle's medium; HIDCS, heat-inactivated dialyzed calf serum; PBS, phosphate-buffered saline; NF-1, Nuclear Factor 1. epidermal growth factor (EGF), interleukin-1 (IL-1), platelet-derived growth factor (PDGF), or fibroblast growth factor (FGF) in the presence of lipid peroxidation stimulating (200 μm) and nonstimulating (1 μm) concentrations of ascorbic acid. EGF and IL-1 had no effect on collagen synthesis at either concentration of ascorbic acid. FGF affected collagen synthesis only in the presence of 200 μm ascorbic acid, producing both a stimulation (0.4-2 ng/ml) and an inhibition (>50 ng/ml). PDGF and TGF-β stimulated collagen synthesis in the presence of both concentrations of ascorbic acid, with TGF-β producing an 11-fold increase in collagen synthesis in the presence of ascorbate. This synergism produced by the combination of ascorbic acid and TGF-β was inhibitable by the lipid peroxidation inhibitor, propyl gallate. These results indicate that regulation of collagen synthesis by ascorbic acid does not occur through altering the response to EGF or Il-1. Ascorbate has no effect on PDGF but the effects of TGF-β and FGF on collagen synthesis appear to be sensitive to lipid peroxidation. © 1991.