Effects of dehydroepiandrosterone on collagen and collagenase gene expression by skin fibroblasts in culture

Abstract

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are the most abundant steroids in humans whose low levels are related to aging, greater incidence of various cancers, immune dysfunction, atherosclerosis, and osteoporosis. It has been shown that collagen and collagenase gene expression decreases in fibroblasts taken from more aged donors. In this paper, to investigate the relationship between DHEA and skin aging, we examined the effects of DHEA on the regulation of collagen, collegians and stromelysin-1 genes in cultured human skin fibroblasts. In collagen assay, DHEA slightly increased collagen production in a dose-related fashion, its maximal effect occurred at 10−5 M DHEA (P>0.05). In the presence of DHEA, steady-state levels of α1 (I) procollagen mRNA increased to 1.6-fold of the non-treated group, while those of fibronectin were not. Interestingly, DHEA differently regulated collagenase and stromelysin-1 gene expression. The steady-state levels of collagenase mRNA decreased in response to DHEA by 40%, whereas those of stromelysin-1 mRNA increased up to 2.4-fold, compared to controls. Similar results were obtained for chloramphenicol acetyltransferase assay (CAT); maximal promoter activation of stromelysin-1 gene occurred at 10−6 M DHEA, 4.5-fold higher than control. CAT assay revealed that treatment with 10−5 M DHEA resulted in a strong (≈70%) inhibition of the collagenase promoter activity. In our experiments, the effects of DHEA on these gene expressions were higher at pharmacologic concentration (≥10−5 M) than those at physiologic concentration (10−8–10−6 M). This study suggests that the level of DHEA may be related to the process of skin aging through the regulation of production and degradation in extracellular matrix.