EFFECT OF RETINOIC ACID IN COMBINATION WITH PLATELET-DERIVED GROWTH FACTOR-BB OR TRANSFORMING GROWTH-FACTOR-BETA ON TISSUE INHIBITOR OF METALLOPROTEINASES AND COLLAGENASE SECRETION FROM HUMAN SKIN AND SYNOVIALFIBROBLASTS

This report shows for the first time that platelet-derived growth fact or-BE (PDGF-BB) and transforming growth factor-beta (TGF-beta) can int eract in a synergistic manner with retinoic acid to stimulate the prod uction of tissue inhibitor of metalloproteinases (TIMP) from human ski n and synovial fibroblasts. When cells are treated with 1, 10, and 100 ng/ml of either of these growth factors in combination with 10(-5) M retinoic acid, this results in a dose-dependent synergistic induction of TIMP protein secretion which is greater than the additive effect of the agents by up to fourfold. These responses can be inhibited by the presence of specific neutralising antibodies to the growth factors, d emonstrating that they are not the result of an experimental artefact such as contamination with bacterial endotoxin. The mechanisms of thes e synergistic responses may involve the induction of receptors for ret inoic acid, PDGF, or TGF-beta or may result from synergistic effects o n TIMP gene transcription. We have also found that retinoic acid poten tly down-regulates PDGF-BB-stimulated collagenase in both types of fib roblast and that the effect of PDGF-BB alone on collagenase secretion from skin fibroblasts is biphasic. Finally, this study reports that re tinoic acid and TGF-P do not act in an additive fashion to inhibit the production of collagenase from skin fibroblasts. (C) 1996 Wiley-Liss, Inc.