INTRODUCTION
Recent reports show a significant increase in the number of people with
alopecia (Jang et al., 2013). In the skin of alopecia patients, many
hair follicles overstay in their resting stage in which dermal papilla
(DP) cells and keratinocytes, the two key players of hair cycle
regulation, are inactive (Alonso & Fuchs, 2006; Botchkarev &
Kishimoto, 2003; Sennett & Rendl, 2012). Inactivation of these cells is
caused by various factors, and the inactivation leads to miniaturized
hair follicles, resulting hair loss (Kligman, 1959; Price, 1999). Even
though researchers have focused on developing drugs to cure alopecia,
only two drugs, minoxidil (MNX) and finasteride, have been approved by
the US Food and Drug Administration for clinical treatment of androgenic
alopecia (Libecco & Bergfeld, 2004; Linas & Nies, 1981; Price, 1999).
Although both drugs are effective in promoting hair growth, neither can
initiate hair follicle neogenesis effectively due to complicated process
of the hair regeneration (Paus, 2006).
Wnt/β-catenin signaling pathway plays an important role in hair
morphogenesis, growth initiation, and regeneration (Andl, Reddy,
Gaddapara, & Millar, 2002; Huelsken, Vogel, Erdmann, Cotsarelis, &
Birchmeier, 2001; Iida, Ihara, & Matsuzaki, 2007; Ito et al., 2007;
Kishimoto, Burgeson, & Morgan, 2000). The activated Wnt/β-catenin
signaling pathway initiates embryonic hair formation in the epidermis
and promotes the formation of dermal condensates (Andl et al., 2002;
Huelsken et al., 2001). In addition, DP cells require activation of this
pathway to initiate hair-inducing activity that prolongs the anagen
phase (Kishimoto et al., 2000). The hair-inducing ability of DP cells
can be confirmed by analyzing the expression of alkaline phosphatase
(ALP) (Iida et al., 2007; S. H. Lee et al., 2012). Recent studies showed
that the activation of Wnt/β-catenin signaling can recover ALP
expression in long-term cultured primary DP cells (Yamauchi & Kurosaka,
2009).
Hair growth promoting drugs targeting Wnt/β-catenin signaling are not
currently available. However small molecules are needed that, unlike
MNX, can activate this pathway to enhance hair follicle neogenesis (S.
H. Lee et al., 2017).
KY19382 is, one of the newly synthesized analogs of
indirubin-3’-monoxime (I3O), a glycogen synthase kinase-3β (GSK-3β)
inhibitor, and has a significant ability to activate the Wnt/β-catenin
signaling. Indirubin is an active ingredient of the indigo plant,
Danggui Longhui Wan, used as a traditional anti-leukemia medicine (Xiao,
Hao, Liu, & Qian, 2002). I3O is known as a Wnt/β-catenin activator that
stabilizes β-catenin via inhibition of GSK-3β, and has been shown to
accelerate bone growth and inhibit adipogenesis (O. M. Choi et al.,
2014; Zahoor, Cha, & Choi, 2014; Zahoor, Cha, Min do, & Choi, 2014).
Furthermore, we recently found that KY19382 elongated tibial length by
inactivating GSK-3β and blocking the binding of CXXC-type zinc finger
protein 5 (CXXC5) and Dishevelled (Dvl) (S. Choi et al., 2019).
Moreover, PTD-DBM, a peptide that interferes with CXXC5-Dvl interaction
via binding to the PDZ domain of Dvl, stimulated wound-induced hair
follicle neogenesis (WIHN) and hair regrowth (Lee et al., 2017).
However, this peptide is limited for routine application due to its cost
and stability.
In this study, we selected KY19382 as an optimal compound that can
stimulate hair growth. KY19382 activated the Wnt/β-catenin signaling
higher than I3O and showed low cytotoxicity in human DP cells. The
KY19382 elongated vibrissa hair shaft and mouse dorsal hair. Moreover,
KY19382 significantly induced the hair follicle neogenesis as shown in
hairless mice injected with dermal cells and keratinocytes and wounded
mice treated with KY19382. Overall, KY19382 is an effective
Wnt/β-catenin signaling activator that can be used for treatment of
alopecia with high efficacy and safety.
METHODS