Modulation of procollagen gene expression by retinoids. Inhibition of collagen production by retinoic acid accompanied by reduced type I procollagen messenger ribonucleic acid levels in human skin fibroblast cultures.

Abstract

Recent clinical observations have suggested that retinoids, which are in frequent use in dermatology, can affect the connective tissue metabolism in skin and other tissues. In this study, we examined the effects of several retinoids on the metabolism of collagen by human skin fibroblasts in culture. Incubation of cultured fibroblasts with all-trans-retinoic acid or 13-cis-retinoic acid, in 10-5 M or higher concentrations, markedly reduced the procollagen production, as measured by synthesis of radioactive hydroxyproline. The effect was selective in that little, if any, inhibition was noted in the incorporation of [Hjleucine into the noncollagenous proteins, when the cells were incubated with the retinoids in 10-5 M concentration. Similar reduction in procollagen production was noted with retinol and retinal, whereas an aromatic analogue of retinoic acid ethyl ester (RO-10-9359) resulted in a slight increase in procollagen production in these cultures. The reduction in procollagen production by all-trans-retinoic acid was accompanied by a similar reduction in proa2(I) of type I procollagen specific messenger RNA (mRNA), as detected by dot blot and Northern blot hybridizations. Hybridizations with human fibronectin and fl-actin specific DNA probes indicated that the levels of the corresponding mRNAs were not affected by the retinoids, further suggesting selectivity in the inhibition of procollagen gene expression. Further control experiments indicated that all-trans-retinoic acid, under the culture conditions employed, did not affect the posttranslational hydroxylation of prolyl residues, the mannosylation of newly synthesized procollagen, the specific radioactivity of the intracellular prolyltransfer RNA pool, or DNA replication. All-trans-retinoic acid also elicited a reduction in trypsin-activatable collagenase, but not in the activity of prolyl hydroxylase or an elastaselike neutral protease in the fibroblast cultures. Incubation of three fibroblast lines established from human keloids with all-transretinoic acid or 13-cis-retinoic acid also resulted in a marked reduction in procollagen production. The results, therefore, suggest that further development of retinoids might provide a novel means of modulating collagen gene expression in patients with various diseases affecting the connective tissues.

Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production.

“…The marked difference in the potency of retinol versus retinoic acid has been previously noted and parallels the observed differences in their serum concentrations (retinol 10-6 M versus retinoic acid < 10-9 M) as well as the intracellular Ito cell concentrations of the respective cytosolic binding proteins (22,24,42). The medically used and related 13-cis-retinoic acid caused similar inhibition of cell proliferation at the 10-6-lo-8 M range.…”

“…lOOX lower molar concentrations than used in previous studies with retinol ( 19,20). This difference in sensitivity to retinol versus retinoic acid has been previously noted in other cell systems and may be especially important in any potential applications in vivo (24,42). In other cell systems, however, the response to retinoic acid may differ considerably.…”

“…For example, some work suggests that retinoic acid actually augments cell growth (24). Previous in vitro work with 10-fold higher concentrations of retinoic acid had found, similar to Ito cells, that collagen over production by human keloid skin fibroblast cultures was inhibited, but the effect appeared to be at a pretranslational level (42).…”

Regulation of a Novel Gene Encoding a Lysyl Oxidase-related Protein in Cellular Adhesion and Senescence

“…We felt it was relevant, therefore, to compare levels of expression of these two genes by fibroblasts in culture in the presence of TGF-␤1 or indomethacin, which increase procollagen-I transcripts (25,26), and in the presence of phorbol ester or retinoic acid, which inhibit procollagen-I gene expression (27,28). As shown in Fig.…”

Light- and Electron-Microscopic Findings in Lichen sclerosus of the Vulva during Etretinate Treatment

“…This suggests that the therapeutic effect of etretinate in LS could be at least partly due to its effect on the epidermis. The adaptation of epidermal cells to etretinate and the subsequent modu lation of their differentiation lead to the restoration of normal structure and func tion [7], Previous studies have shown that etretinate has also anti-inflammatory properties and that it can stimulate collagen production [7,21]. In patients receiving etretinate, we observed a decrease in the number of inflammatory cells but an in crease in the number of invading fibroblasts.…”