Keloids are dermal tumors that occur in response to trauma. An hereditary predisposition to keloid formation occurs with high frequency in black populations. This disorder appears to involve abnormal regulation of wound healing such that the proliferative phase does not stop, resulting in massive accumulation of scar tissue. When compared to normal mature scar or dermis, keloid tissue shows a high rate of collagen synthesis. The goal of this study is to identify and characterize the abnormal regulatory mechanism causing this condition. Two types of dermal fibroblasts, distinguishable by their response to glucocorticoids, have been identified. One cell type has been isolated from normal dermis of people with and without keloids, from normal early wounds, from different layers of normal mature scars, and from the upper layer of keloids. In response to physiological levels of hydrocortisone these normal fibroblasts show marked inhibition of collagen synthesis, growth stimulation and 2-fold induction of System A amino acid transport. The other cell type has been isolated only from the nodule of keloids. With Keloid-derived fibroblasts, collagen synthesis is not turned off and growth is not stimulated by hydrocortisone while System A transport is induced 10-fold by this hormone. This in vitro phenotype resembles the in vivo disorder in that the cells fail to respond to a signal that normally causes reduction of collagen synthesis. System A transports proline, glycine and alanine which together comprise over 50% of the collagen molecule. Hyperactivity of System A may contribute to the high rate of collagen synthesis by increasing amino acid availability. Increased nutrient availability could also contribute to tumor growth. Preliminary evidence of differences between normal and keloid cells in production of and response to peptide growth factors suggests that keloid formation may result from abnormal production of an autocrine growth factor. Many studies have indicated interaction between glucocorticoids and growth factors in regulating cellular phenotype, but mechanisms responsible have not been identified. Work described here will attempt to answer questions in three areas: 1) production of and response to peptide growth factors by normal and keloid cells; 2) mechanisms of interaction between glucocorticoids and growth factors in regulation of growth, collagen synthesis and amino acid transport in the two cell types; 3) regulation of collagen synthesis at the molecular level in normal and keloid-derived fibroblasts.
