Beehler B C, Chen S, Tramposch K M
Dermatology Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Buffalo, New York 14213, USA.
Arch Dermatol Res. 1995;287(5):488-93. doi: 10.1007/BF00373433.
The rhino mouse comedolytic model and the hairless mouse photoaging model are established animal models for screening the in vivo activity of retinoids. However, the expression of the retinoic acid receptors (RARs) and cellular retinoic acid-binding proteins (CRABPs), known to regulate retinoid activity, is not completely understood in these mouse mutants. For this purpose, mRNA was isolated from rhino and hairless mouse skin and the gene expression of the RARs and CRABPs was measured by Northern blot hybridization. Results showed that RAR gamma was the predominantly expressed RAR in both mouse strains. Two isoforms of RAR gamma, RAR gamma 1 and RAR gamma 2, were detected with RAR gamma 1 being the more strongly expressed. RAR alpha was also detected, but to a lesser degree than RAR gamma. RAR beta expression was not detectable by our methodology. Additionally, topical treatment of these mice with 0.1% all-trans-retinoic acid (tRA) cream resulted in no significant alteration in the expression of the RAR genes. By contrast, CRABP-II was induced 2-4 fold by topical tRA treatment. CRABP-I, expressed to a lesser degree than CRABP-II, was not inducible. The relative expression of the RARs, CRABPs, and inducibility of CRABP-II by tRA in both rhino and hairless mouse skin paralleled that reported for human and mouse skin. These observations suggest that the altered phenotype observed in the rhino mouse most likely does not result from an altered expression level of these genes. The results also support these two animals as models for evaluating the therapeutic potential of retinoids.
犀牛小鼠粉刺溶解模型和无毛小鼠光老化模型是用于筛选维甲酸类药物体内活性的动物模型。然而，在这些小鼠突变体中，对于已知可调节维甲酸类药物活性的维甲酸受体（RARs）和细胞维甲酸结合蛋白（CRABPs）的表达情况尚未完全了解。为此，从犀牛小鼠和无毛小鼠的皮肤中分离出mRNA，并通过Northern印迹杂交法检测RARs和CRABPs的基因表达。结果显示，RARγ是两种小鼠品系中主要表达的RAR。检测到RARγ的两种亚型，即RARγ1和RARγ2，其中RARγ1表达更强。也检测到了RARα，但其表达程度低于RARγ。用我们的方法未检测到RARβ的表达。此外，用0.1%全反式维甲酸（tRA）乳膏局部治疗这些小鼠，RAR基因的表达没有显著变化。相比之下，局部tRA治疗可使CRABP-II的表达诱导增加2至4倍。CRABP-I的表达程度低于CRABP-II，且不可诱导。在犀牛小鼠和无毛小鼠皮肤中，RARs、CRABPs的相对表达以及tRA对CRABP-II的诱导情况与人和小鼠皮肤的报道相似。这些观察结果表明，在犀牛小鼠中观察到的表型改变很可能不是由这些基因表达水平的改变所致。这些结果也支持将这两种动物作为评估维甲酸类药物治疗潜力的模型。
