Department of Immunology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea; Brain Science and Engineering Institute, Kyungpook National University, Daegu, Republic of Korea.
Department of Immunology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
Biochem Biophys Res Commun. 2020 Aug 27;529(3):766-772. doi: 10.1016/j.bbrc.2020.06.098. Epub 2020 Jul 19.
Androgenetic alopecia (AGA) is a common genetic disorder, and a X-chromosomal locus that contains the androgen receptor (AR) and ectodysplasin A2 receptor (EDA2R) genes represents a major susceptibility locus for AGA. In our previous study, we reported that ectodysplasin-A2 (EDA-A2) induces apoptosis in cultured human hair follicle (HF) cells and promotes the regression of HFs in mice. However, the role of the EDA-A2/EDA2R in AGA remains unknown, as the causative gene in this pathway has not yet been identified and potential functional connections between EDA-A2 signaling and the androgen pathway remain unclear. In this study, we investigated the expression of EDA2R in balding HFs and matched with non-balding HFs. The EDA2R level was upregulated in the balding dermal papilla (DP) cells compared with non-balding DP cells derived from patients with AGA. However, EDA2R was strongly expressed in both balding and non-balding outer root sheath (ORS) cells. We screened EDA-A2-regulated genes in balding DP cells and identified dickkopf 1 (DKK-1) as catagen inducer during the hair cycle. The mRNA and protein expression levels of DKK-1 were both upregulated by EDA-A2. In addition, DKK-1 expression was induced by EDA-A2 both in cultured human HFs and in mouse HFs. Moreover, the EDA-A2-induced apoptosis of DP and ORS cells was reversed by the antibody-mediated neutralization of DKK-1. Collectively, our data strongly suggest that EDA-A2 induces DKK-1 secretion and causes apoptosis in HFs by binding EDA2R, which is overexpressed in the bald scalp. EDA-A2/EDA2R signaling could inhibit hair growth through DKK-1 induction, and an inhibitor of EDA-A2/EDA2R signaling may be a promising agent for the treatment and prevention of AGA.
雄激素性脱发（AGA）是一种常见的遗传性疾病，X 染色体上包含雄激素受体（AR）和外胚层发育不良蛋白 A2 受体（EDA2R）基因的基因座是 AGA 的主要易感基因座。在我们之前的研究中，我们报道了外胚层发育不良蛋白 A2（EDA-A2）可诱导培养的人毛囊（HF）细胞凋亡，并促进小鼠 HF 退化。然而，EDA-A2/EDA2R 在 AGA 中的作用尚不清楚，因为该途径中的致病基因尚未确定，并且 EDA-A2 信号与雄激素途径之间的潜在功能联系尚不清楚。在这项研究中，我们研究了脱发 HF 中 EDA2R 的表达，并与非脱发 HF 进行了匹配。与AGA 患者非脱发真皮乳头（DP）细胞相比，脱发 DP 细胞中 EDA2R 水平上调。然而，EDA2R 在脱发和非脱发的外根鞘（ORS）细胞中均强烈表达。我们筛选了脱发 DP 细胞中 EDA-A2 调节的基因，并发现 dickkopf 1（DKK-1）是毛发生长周期中的退行基因诱导剂。在 EDA-A2 作用下，DKK-1 的 mRNA 和蛋白表达水平均上调。此外，在培养的人 HF 和小鼠 HF 中，EDA-A2 均诱导 DKK-1 的表达。此外，EDA-A2 诱导的 DP 和 ORS 细胞凋亡可通过 DKK-1 的抗体中和而逆转。总之，我们的数据强烈表明，EDA-A2 通过在脱发头皮中过度表达的 EDA2R 诱导 DKK-1 分泌并导致 HF 凋亡。EDA-A2/EDA2R 信号可能通过诱导 DKK-1 抑制毛发生长，而 EDA-A2/EDA2R 信号的抑制剂可能是治疗和预防 AGA 的有前途的药物。
