Department of Dermatology, Dongguk University Ilsan Hospital, Goyang-si, Gyenggi-do, South Korea.
J Invest Dermatol. 2012 Nov;132(11):2622-31. doi: 10.1038/jid.2012.175. Epub 2012 Jun 14.
The pathogenesis of melasma is unknown, although the potential role of estrogen has been considered. Microarray and real-time PCR analyses revealed that upregulation of PDZ domain protein kidney 1 (PDZK1) is clinically correlated with melasma. Although there has been no report that PDZK1 is involved in pigmentation and/or melanogenesis, PDZK1 expression can be induced by estrogen. In this study, the role of PDZK1 upregulation in melasma was examined, particularly in connection with estrogen, using biopsied skin specimens from 15 patients and monocultures and cocultures of melanocytes and keratinocytes with or without overexpression or knockdown of PDZK1. Estrogen upregulated PDZK1. Overexpression of PDZK1 increased tyrosinase expression and melanosome transfer to keratinocytes, whereas PDZK1 knockdown reduced estrogen-induced tyrosinase expression, through regulation of expression of estrogen receptors (ERs) ER-α and ER-β. The PDZK1-induced tyrosinase expression and melanosome transfer was regulated by ion transporters such as sodium-hydrogen exchanger (NHE), cystic fibrosis transmembrane conductance regulator (CFTR), and SLC26A3, which showed a specific association with each ER subtype. In the melanosome transfer, PDZK1 also increased phosphorylation of ezrin/radixin/moesin (ERM) and ras-related C3 botulinum toxin substrate 1, but not the expression of proteinase-activated receptor-2. Collectively, upregulation of PDZK1 could have an important role in the development of melasma in connection with estrogen through NHE, CFTR, and SLC26A3.
黄褐斑的发病机制尚不清楚，尽管雌激素的潜在作用已被考虑在内。微阵列和实时 PCR 分析显示，PDZ 结构域蛋白肾脏 1（PDZK1）的上调与黄褐斑具有临床相关性。虽然没有报道 PDZK1 参与色素沉着和/或黑色素生成，但雌激素可以诱导 PDZK1 的表达。在这项研究中，使用 15 名患者的活检皮肤标本以及黑素细胞和角质形成细胞的单培养物和共培养物，检查了 PDZK1 上调在黄褐斑中的作用，特别是与雌激素的关系，这些细胞经过 PDZK1 的过表达或敲低处理。雌激素上调 PDZK1。PDZK1 的过表达增加了酪氨酸酶的表达和黑素小体向角质形成细胞的转移，而 PDZK1 的敲低通过调节雌激素受体 (ER) ER-α 和 ER-β 的表达降低了雌激素诱导的酪氨酸酶表达。PDZK1 诱导的酪氨酸酶表达和黑素小体转移受离子转运蛋白（如钠氢交换器 (NHE)、囊性纤维化跨膜电导调节剂 (CFTR) 和 SLC26A3）的调节，这些蛋白与每种 ER 亚型都有特定的关联。在黑素小体转移中，PDZK1 还增加了 ezrin/radixin/moesin（ERM）和 ras 相关 C3 肉毒杆菌毒素底物 1 的磷酸化，但不增加蛋白酶激活受体-2 的表达。总的来说，PDZK1 的上调可能通过 NHE、CFTR 和 SLC26A3 在与雌激素相关的黄褐斑发展中发挥重要作用。
