All-trans retinoic acid stimulates growth and extracellular matrix production in growth-inhibited cultured human skin fibroblasts.

All-trans retinoic acid was examined for effects on human dermal fibroblast proliferation and for effects on fibroblast production and expression of non-collagenous and collagenous components of the extracellular matrix in vitro. Fibroblast proliferation was blocked when the cells were cultured in the presence of a serum-free culture medium containing epidermal growth factor, hydrocortisone, insulin, ethanolamine, phosphoethanolamine, and bovine pituitary extract as growth supplements and 0.15 mM Ca++. This level of extracellular Ca++ is lower than that needed to support fibroblast growth. Under these conditions, growth was stimulated by all-trans retinoic acid. Proliferation was also stimulated in the same basal medium without the growth supplements. Growth-promoting concentrations of all-trans retinoic acid ranged from 0.5-2.0 micrograms/ml (1.7-6.6 X 10(-6) M). Stimulation of proliferation was not seen at higher or lower concentrations. Concentrations of all-trans retinoic acid that stimulated proliferation also induced increased production of fibronectin as indicated by biosynthetic labeling/immunoprecipitation and by enzyme-linked immunosorbent assay. Increased production was associated with increased staining for fibronectin in the extracellular matrix. Increased production of two other non-collagenous extracellular matrix component, i.e., thrombospondin and laminin, also occurred in all-trans retinoic acid-treated cells. At 0.5 micrograms/ml, all-trans retinoic acid also stimulated production of type I collagen by the dermal fibroblasts, but at higher concentrations (2.5 micrograms/ml) production of type I collagen was inhibited. These data indicate that all-trans retinoic acid can induce changes in dermal fibroblasts in vitro (i.e., increased proliferation and extracellular matrix production) that mimic the major changes seen in the dermis after topical treatment with this agent.