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.
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.
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类维生素A调节原胶原基因表达。
DOI：
10.1172/jci111859
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发表时间：
1985
期刊：
影响因子：
--
通讯作者：
Uitto,J
中科院分区：
文献类型：
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作者：
Oikarinen,H;Oikarinen,AI;Tan,EM;Abergel,RP;Meeker,CA;Chu,ML;Prockop,DJ;Uitto,J
最近的临床观察表明，在皮肤病学中经常使用的类维生素a可以影响皮肤和其他组织的结缔组织代谢。在这项研究中，我们研究了几种类维生素a对培养的人皮肤成纤维细胞胶原代谢的影响。用10(-5)M或更高浓度的全反式维甲酸或13-顺式维甲酸孵育培养成纤维细胞，通过放射性羟脯氨酸的合成测量，显着减少了前胶原的产生。当细胞与10(-5)M浓度的类维生素a一起孵育时，这种作用是选择性的，因为[3H]亮氨酸与非胶原蛋白的结合很少（如果有的话）受到抑制。视黄醇和视网膜的前胶原蛋白产量也有类似的减少，而视黄酸乙酯的芳香类似物（RO-10-9359）在这些培养物中导致前胶原蛋白产量略有增加。斑点杂交和Northern杂交检测发现，全反式维甲酸减少了前胶原蛋白的产生，同时也减少了I型前胶原特异性信使RNA （mRNA）的前α 2(I)。与人纤维连接蛋白和β -肌动蛋白特异性DNA探针的杂交表明，相应mrna的水平不受类维生素a的影响，进一步表明抑制前胶原基因表达的选择性。进一步的对照实验表明，在所采用的培养条件下，全反式维甲酸不影响翻译后脯氨酸残基的羟基化，新合成的前胶原的甘露糖基化，细胞内脯氨酸转移RNA池的特定放射性或DNA复制。全反式维甲酸也引起胰蛋白酶活化胶原酶的减少，但在成纤维细胞培养中脯氨酸羟化酶或弹性蛋白酶样中性蛋白酶的活性没有减少。用全反式维甲酸或13-顺式维甲酸培养人瘢痕疙瘩形成的三种成纤维细胞系，也导致前胶原蛋白的产生显著减少。因此，这些结果表明，进一步开发类维生素a可能为调节各种影响结缔组织疾病患者胶原基因表达提供一种新的手段。图片
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 [3H]leucine 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 pro alpha 2(I) of type I procollagen specific messenger RNA (mRNA), as detected by dot blot and Northern blot hybridizations. Hybridizations with human fibronectin and beta-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-trans-retinoic 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.Images