Department of Cosmetic Health Science, Gifu Pharmaceutical University, Gifu, Japan.
Department of Research and Development, Ichimaru Pharcos Co. Ltd., Motosu, Gifu, Japan.
Sci Rep. 2020 Mar 18;10(1):4930. doi: 10.1038/s41598-020-61931-1.
GPNMB is involved in multiple cellular functions including cell adhesion, stress protection and stem cell maintenance. In skin, melanocyte-GPNMB is suggested to mediate pigmentation through melanosome formation, but details of keratinocyte-GPNMB have yet to be well understood. We confirmed the expression of GPNMB in normal human epidermal keratinocytes (NHEKs) by reducing the expression using siRNA. A higher calcium concentration of over 1.25 mM decreased the GPNMB expression. Histological staining showed that GPNMB was expressed in the basal layer of normal skins but completely absent in vitiligo skins. The normal expression of GPNMB in nevus depigmentosus skin suggested that lack of GPNMB is characteristic of vitiligo lesional skins. IFN-γ and IL-17A, two cytokines with possible causal roles in vitiligo development, inhibited GPNMB expression in vitro. Approximately 4-8% of the total GPNMB expressed on NHEKs were released possibly by ADAM 10 as a soluble form, but the process of release was not affected by the cytokines. The suppressive effect of IFN-γ on GPNMB was partially via IFN-γ/JAK2/STAT1 signaling axis. Decreased GPNMB expression in keratinocytes may affect melanocyte maintenance or survival against oxidative stress although further studies are needed. These findings indicate a new target for vitiligo treatment, focusing on the novel role of IFN-γ and IL-17 in downregulating keratinocyte-GPNMB.
GPNMB 参与多种细胞功能，包括细胞黏附、应激保护和干细胞维持。在皮肤中，黑素细胞-GPNMB 被认为通过黑素体形成来介导色素沉着，但角质形成细胞-GPNMB 的细节尚未得到很好的理解。我们通过 siRNA 降低表达来证实 GPNMB 在正常人表皮角质形成细胞（NHEKs）中的表达。超过 1.25 mM 的高钙离子浓度降低了 GPNMB 的表达。组织学染色显示 GPNMB 在正常皮肤的基底层表达，但在白癜风皮肤中完全缺失。色素减退性神经纤维瘤皮肤中 GPNMB 的正常表达表明 GPNMB 的缺失是白癜风病变皮肤的特征。在体外，两种可能在白癜风发病机制中起因果作用的细胞因子 IFN-γ 和 IL-17A 抑制了 GPNMB 的表达。约 4-8%的 NHEKs 上表达的总 GPNMB 可能作为一种可溶性形式被 ADAM 10 释放，但该释放过程不受细胞因子的影响。IFN-γ 对 GPNMB 的抑制作用部分通过 IFN-γ/JAK2/STAT1 信号通路。角质形成细胞中 GPNMB 表达的降低可能会影响黑素细胞的维持或对氧化应激的存活，尽管还需要进一步的研究。这些发现表明了一种新的白癜风治疗靶点，重点关注 IFN-γ 和 IL-17 下调角质形成细胞-GPNMB 的新作用。
