ALL-TRANS-RETINOIC ACID INTERACTS SYNERGISTICALLY WITH BASIC FIBROBLAST GROWTH-FACTOR AND EPIDERMAL GROWTH-FACTOR TO STIMULATE THE PRODUCTION OF TISSUE INHIBITOR OF METALLOPROTEINASES FROM FIBROBLASTS

This report examines the effect of all-trans-retinoic acid in combinat ion with basic fibroblast growth factor (bFGF) or epidermal growth fac tor (EGF) on collagenase and tissue inhibitor of metalloproteinases (T IMP) production from human foreskin and synovial fibroblasts. When 10( -5) M retinoic acid is applied in combination with 1, 10, and 100 ng/m l of either FGF or EGF to foreskin or synovial fibroblasts, this resul ts in a dose-dependent synergistic increase in TIMP protein production which is greater than the additive effect of the agents by up to four fold. These responses can be inhibited by the presence of specific neu tralizing antibodies to bFGF and EGF, demonstrating that they result f rom the presence of the growth factors and not from an experimental ar tifact such as bacterial endotoxin. We have also found that retinoic a cid potently inhibits bFGF- and EGF-stimulated collagenase protein pro duction in both skin and synovial fibroblasts. (C) 1995 Academic Press , Inc.