Phosphodiesterase-4 Inhibitors Increase Pigment Cell Proliferation and Melanization in Cultured Melanocytes and within a 3-Dimensional Skin Equivalent Model.

Nathaniel B Goldstein, Zachary B K Berk, Landon C Tomb, Junxiao Hu, Laura G Hoaglin, Dennis R Roop, Roni Adiri, Yonghua Zhuang, Juliana M Canosa, Paul Sanders, David A Norris, Karl Nocka, Amy Cha, Stanca A Birlea
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Abstract

Vitiligo is a common chronic autoimmune disease characterized by white macules and patches of the skin, having a negative impact on patients' life and without any definitive cure at present. Identification of new compounds to reverse depigmentation is therefore a pressing need for this disease. The pharmacologic compounds phosphodiesterase-4 inhibitors (PDE4is) are small molecules with immunomodulatory properties used for treatment of inflammatory dermatoses. PDE4is have shown repigmentation effects in patients with vitiligo, in some case reports. We characterized the proliferative and melanogenic potential of 2 known PDE4is-crisaborole and roflumilast-and of a more recently designed compound, PF-07038124. We used 2 in vitro model systems-the primary human melanocyte culture and a 3-dimensional cocultured skin model (MelanoDerm)-with an exploratory testing platform composed of complementary assays (spectrophotometry, melanin and proliferation assays, immunostaining, Fontana-Masson staining, RT-qPCR, western blot, and whole-transcriptome RNA sequencing). We identified that treatment with PDE4is was associated with increased melanocyte proliferation and melanization in both in vitro models and with increase in the melanogenic genes and proteins expression in cultured melanocytes. These effects were found to be enhanced by addition of α-melanocyte-stimulating hormone. Our findings support the further evaluation of PDE4is with or without α-melanocyte-stimulating hormone agonists in vitiligo trials.

磷酸二酯酶-4 抑制剂可增加培养黑色素细胞和三维皮肤等效模型中色素细胞的增殖和黑色素化。
白癜风是一种常见的慢性自身免疫性疾病,其特征是皮肤上出现白色斑丘疹和斑块,对患者的生活造成负面影响,目前还没有任何确切的治疗方法。因此,寻找能逆转脱色的新化合物是这种疾病的迫切需要。药理化合物磷酸二酯酶-4 抑制剂(PDE4i)是一种具有免疫调节特性的小分子化合物,用于治疗炎症性皮肤病。在一些病例报告中,PDE4i 对白癜风患者有色素恢复作用。我们对两种已知的 PDE4i(crisaborole 和 roflumilast)以及最近设计的一种化合物 PF-07038124 的增殖和黑色素生成潜力进行了鉴定。我们使用了两个体外模型系统,即原代人类黑色素细胞培养和三维共培养皮肤模型(MelanoDermTM),以及一个由互补性检测方法(分光光度法、黑色素和增殖检测、免疫染色、Fontana-Masson 染色、qRT-PCR、Western 印迹和全转录组 RNA 序列测定)组成的探索性测试平台。我们发现,在两种体外模型中,PDE4i 的治疗都与黑色素细胞增殖和黑色素化的增加有关,并与培养的黑色素细胞中黑色素生成基因和蛋白表达的增加有关。加入α-MSH后,这些效应都会增强。我们的研究结果支持在白癜风试验中进一步评估加入或不加入α-MSH激动剂的PDE4i。
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