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Recent progress in melasma pathogenesis
Ai-Young Lee

DOI: 10.1111/pcmr.12404
Volume 28, Issue 6, Pages 648–660

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Pigment Cell Melanoma Res. 28; 648–660 REVIEW

Recent progress in melasma pathogenesis

Ai-Young Lee

Department of Dermatology, Dongguk University Ilsan Hospital, Ilsandong-gu, Goyang-si, Gyeonggi-do, South KEYWORDS melasma/pathogenesis/UV/estrogen/
Korea UV exposure-independent factors/dermal factors/
microRNAs
CORRESPONDENCE Ai-Young Lee, e-mails: lay5604@naver.com; leeay@dumc.org
PUBLICATION DATA Received 17 April 2015, revised
and accepted for publication 27 July 2015, published
online 31 July 2015

doi: 10.1111/pcmr.12404

Summary
Melasma is a common skin pigmentation condition. Given therapeutic difficulty as one of the biggest concerns,
understanding of the etiology and pathogenesis of melasma becomes essential. UV irradiation, female sex
hormones, and inflammatory processes are addressed as triggering factors with genetic predisposition. The
mechanism of UV-induced melanogenesis has been extensively investigated as a model system to study
melasma pathogenesis. Hitherto, treatment modalities for melasma are similar to other hyperpigmentation
disorders. However, individual triggering factors induce a separate pigmentation disease, whose pathogenic
mechanisms and clinical phenotypes are different from the ones encountered in melasma. Fortunately, there
have been ongoing updates on melasma pathogenesis with regard to major triggering factors. Presence of
certain factors working independently of UV exposure and role of dermal factors and microRNAs are being
identified as novel discoveries about melasma pathogenesis. In this review, the melasma pathogenesis is
reviewed in association with updated and new findings.

hyperpigmentation disorders. Genes that encode tyrosi-

Introduction
Melasma is a pattern of acquired hyperpigmentation and
one of the most common pigmentation disorders involv-
ing the face. Three types of melasma exist, as classified
according to their distribution on the face, which include
centrofacial, malar, and mandibular patterns (Mandry
Pag
an and S
anchez, 2000; Sanchez et al., 1981). Another
classification of melasma according to the location of the
pigment as epidermal, dermal, or mixed type (Gilchrest
et al., 1977) may perhaps facilitate in predicting the
treatment outcome, which is the most imperative issue in
melasma, particularly in dermal type of melasma (Cayce
et al., 2004). With particular emphasis on facial involve-
ment and therapeutic difficulty, melasma has consider-
able impact on the quality of life of affected individuals.
Although hyperpigmentation results from diverse disor-
ders, to date, no differences in treatment modalities for
these disorders have been presented (Grimes, 2009;
Guerrero, 2012; Lynde et al., 2006; Molinar et al., 2014;
Pe
rez-Bernal et al., 2000; Stratigos and Katsambas,
2004). This phenomenon suggests that common patho-
genic mechanisms could be involved in various skin
nase, a key enzyme in melanogenesis, and the tyrosi-
nase-related proteins (TRPs) TRP-1 and TRP-2 are
commonly involved in the pigmentation disorders induced
by many exogenous and endogenous factors, and
microphthalmia-associated transcription factor (MITF)
plays a fundamental role in the transcriptional regulation
of these genes. A thorough understanding of the etiology
and pathogenesis of melasma in particular and skin
hyperpigmentation disorders in general is crucial to the
appropriate management of melasma.
Genetic backgrounds, chronic exposure to ultraviolet
(UV) radiation, and female sex hormones have been
implicated as the main causes of melasma. Recently,
involvement of inflammatory processes in melasma
development has also been considered (Handel et al.,
2014a; Noh et al., 2014). Each of these factors simulta-
neously induces a separate pigmentation disease, such
as pigmentation induced by chronic UV irradiation (pho-
toaging), drug (oral contraceptives)-induced pigmentation,
or post-inflammatory hyperpigmentation (PIH). In fact,
PIH is one of the common hyperpigmentation disorders in
company with melasma and lentigines (Cayce et al.,

648 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Melasma pathogenesis

2004; Nicolaidou et al., 2007). There is a possibility of co-
existence of these hyperpigmentations in the same
patients. Therefore, these conditions should be differen-
tiated to investigate the pathogenesis of melasma. Their
clinical characteristics are different from melasma
(Table 1), with the exception of pigmentation due to oral
contraceptives, which frequently induce skin pigmenta-
tion of the melasma type (Baker, 1969; Resnik, 1967).
Post-inflammatory hyperpigmentation develops at any
age on the site of inflammation without specific site
predilection caused by physical or chemical injury, skin
irritation, contact dermatitis, or dermatosis (Eimpunth
et al., 2013; Stulberg et al., 2003). The pigmentation
induced by chronic UV exposures could be accompanied
by characteristic findings of photoaging, such as wrinkles,
tactile roughness, and loss of skin tone/resilience. The
vital difference lies in the pigmentary change in these
disorders, which tends to be recovered, whereas that in
melasma does not (Table 1). A complex interplay of these
factors may make the outcome of melasma more
difficult. Microscopically, increased melanin in epidermal
keratinocytes, dermal macrophages, or both is a common
finding in hyperpigmentation disorders including melasma
(Callender et al., 2011; Dereure, 2001; Grimes et al.,
2005; Pathak and Fanselow, 1983). On the other hand,
hyperpigmentation from repeated UV irradiation is usually
accompanied by changes from chronic sun exposure,
such as massive elastosis, collagen degeneration, and
twisted dilated dermal microvasculature (Gilchrest, 1996).
However, these changes are not specific for repeated UV
exposure. Despite no obvious signs of photoaging in
appearance, more prominent solar elastosis (Grimes
et al., 2005; Hern
andez-Barrera et al., 2008; Kang et al.,
2002), dilated dermal microvasculature (Kim et al., 2007),
and basement membrane disruption with protrusion of
melanocytes into dermis (Torres-Alvarez
et al., 2011)
have been observed in melasma (Table 1). Similarities in
the microscopic findings between skin with chronic UV
exposure and melasma skin emphasize a potential role of
cutaneous photoaging due to cumulative sun exposure in
melasma (Hern
andez-Barrera et al., 2008).
However, a role of UV exposure-independent factors in
melasma pathogenesis has been identified (Kim et al.,
2010, 2013a). Our understanding of the mechanism
concerning the effect of estrogen on skin pigmentation
and/or melasma has also been updated (Kim et al., 2012;
Kippenberger et al., 1998; McLeod et al., 1994). Recently,
novel cellular and molecular mechanisms for skin pigmen-
tation including melasma have been identified in the
context of cell-to-cell interaction between melanocytes
and dermal fibroblasts (Cardinali et al., 2009; Choi et al.,
2010; Kang et al., 2006; Kim et al., 2013a,b; Poon et al.,
2005; Shin et al., 2012; Yamaguchi et al., 2004) and
microRNAs (Dynoodt et al., 2013; Kim et al., 2014a,b,c).
In this review, factors implicated in melasma development
are reviewed with focus particularly on the updated action
mechanism of UV exposure and estrogens, along with the
newly identified mechanism pertaining to UV exposure-
independent factors, dermal factors, and microRNAs.
Update on factors implicated as main
causes in melasma
Genetic factors in melasma development
Genetic predisposition is considered one of the main
causes implicated in melasma development, with sun

Table 1. Characteristics of melasma versus related hyperpigmentation disorders

Characteristic
Disorder clinical finding Microscopic finding Outcome References

Melasma Facial pigmentation Increased melanin in Chronic course with Sanchez et al. (1981),
with centrofacial, epidermal keratinocytes, exacerbation Mandry Pag
an
malar, and mandibular dermal macrophages, or and S
anchez (2000),
distribution both Kang et al. (2002),
Elastosis, collagen Grimes et al. (2005),
degeneration, and dilated Hern
andez-
dermal microvasculature Barrera et al. (2008),
Kim et al. (2007),


Torres-Alvarez et al. (2011)
UV-induced Pigmentation, with Normalize after Gilchrest (1996)
hyperpigmentation wrinkles, tactile elimination of specific
roughness, and/or cause
loss of skin tone/
resilience
Oral contraceptives- Similar to those Increased melanin in epidermal Resnik (1967),
induced of melasma keratinocytes, dermal Baker (1969)
hyperpigmentation macrophages, or both
Post-inflammatory No specific site Stulberg et al. (2003),
hyperpigmentation predilection, Eimpunth et al. (2013)
pigmentation on the
site of inflammation

ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 649

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659
 Melasma pathogenesis

Figure 1. Schematic view of melanogenesis

induced by external stimuli, particularly UV
radiation. Direct effects on melanocytes and
indirect effects on keratinocytes/fibroblasts
releasing melanogenic factors, such as
proopiomelanocortin (POMC)-derived peptides
(MSH, ACTH), ET-1, SCF, bFGF, or NGF, are
involved in melanogenesis. Protein kinase C
(PKC), NO, and cAMP are major intracellular
signal transduction pathways. The black ovals
indicate melanosomes (DAG, 1,2-
diacylglycerol; NO, nitric oxide; MSH,
melanocyte-stimulating hormone; ACTH,
adrenocorticotrophic hormone; ET-1,
endothelin-1; SCF, stem cell factor; bFGF,
basic fibroblast growth factor; NGF, nerve
growth factor; MC1R, melanocortin-1 receptor;
TYR, tyrosinase; TRP, tyrosinase-related
protein).

In melasma, DNA damage from direct effect of UV
photons (Eller et al., 1996) or DAG/arachidonic acid
pathways released from melanocyte membranes (Cars-
berg et al., 1995) are not delineated. On the other hand,
cross talk between melanocytes and keratinocytes has
been considered as a melanogenic mechanism in
melasma as in other skin hyperpigmentation conditions,
including UV-induced melanogenesis. In melasma
patients, the expression of certain keratinocyte-derived
paracrine factors is elevated in hyperpigmented lesional
skin relative to normally pigmented skin (Table 3). Con-
focal microscopic examination and Western blotting have

Table 3. Expression of paracrine melanogenic factors in melasma that have been identified in other skin hyperpigmentation conditions

Conditions in which the References in the

Origin Factors factor has been detected context of melasma

Keratinocytes Neural endopeptidase UV-induced hyperpigmentation Bak et al. (2009)

NGF UV-induced hyperpigmentation Kim et al. (2013a,b)
Alpha-MSH UV-induced hyperpigmentation Im et al. (2002),
Miot et al. (2010)
bFGF UV-induced hyperpigmentation No report identified
ET-1 UV-induced hyperpigmentation No report identified
iNOS UV-induced hyperpigmentation Jo et al. (2009)
Mast cell Histamine UV-induced hyperpigmentation, PIH, No report identified
Urticaria pigmentosa
Fibroblasts SCF UV-induced hyperpigmentation, Kang et al. (2006),
post-laser hyperpigmentation,

Torres-Alvarez et al. (2011)
familial hyperpigmentation
bFGF Post-laser hyperpigmentation
HGF Post-laser hyperpigmentation No report identified
KGF PIH No report identified
DKK1 Physiological No report identified
Neuregulain-1 Physiological No report identified
VGEF UV-induced hyperpigmentation Kim et al. (2007)

NGF, nerve growth factor; MSH, melanocyte-stimulating hormone; MC1R, melanocortin-1 receptor; bFGF, basic fibroblast growth factor; ET-1,
endothelin-1; iNOS, inducible nitric oxide synthase; WIF-1, Wnt inhibitory factor 1; SCF, stem cell factor; HGF, hepatocyte growth factor; KGF,
keratinocyte growth factor; DKK1, dickkopf 1; VEGF, vascular endothelial growth factor; PIH, post-inflammatory hyperpigmentation; Familial
hyperpigmentation, familial progressive hyperpigmentation-like disorder.

ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 651
Lee
shown greater expression of NGF receptor with neural
endopeptidase in the hyperpigmented lesional skin in six
patients (Bak et al., 2009). Increased NGF expression in
melasma skin of eight patients has also been examined
immunohistochemically (Kim et al., 2013a,b). Similar
immunohistochemistry result of increased alpha-MSH
expression in lesional epidermis has been reported in ten
Korean women (Im et al., 2002) and in 24 Brazilian
women (Miot et al., 2010). Another UV-induced paracrine
melanogenic factor from keratinocytes is NO (Rome
ro-
Graillet et al., 1997). The role of NO has also been
suggested in melasma based on the immunohistochem-
ical observation of increased inducible NO synthase
expression in basal layer keratinocytes of hyperpig-
mented lesional skin from nine patients and RT-PCR
from additional three patients (Jo et al., 2009). Paracrine
melanogenic factors could also be released from dermal
fibroblasts in melasma as in UV irradiation (Table 3);
immunohistochemistry has shown increased SCF in
hyperpigmented dermis when compared to normally
pigmented dermis in melasma patients (Kang et al.,


2006; Torres-Alvarez et al., 2011).
A complex interaction of causative factors, but not a
single factor, is likely to be involved in melasma develop-
ment. Although the role of UV exposure has been well
established, the mechanism of UV-induced pigmentation
may not be the same for skin pigmentation conditions
induced by different causes. In addition, UV irradiation may
not be always necessary in melasma development. We
have identified that downregulation in the expression of
H19 RNA, which has been detected in microarray analysis
for comparison of hyperpigmented skin specimens with
normally pigmented biopsied skin specimens from patients
with melasma, stimulates melanogenesis and melano-
some transfer (Kim et al., 2010). H19 RNA downregulation
has been examined in the hyperpigmented skin of the
patients, but not in the UV-exposed hyperpigmented skin
(Figure 2). In addition, no alterations were observed in H19
RNA knockdown-induced melanogenesis in the presence
of UV irradiation, although UV irradiation alone and H19
knockdown alone increased tyrosinase expression. We
Postinflammatory hyperpigmentation
Keratinocyte-derived
paracrine melagenic
factors
Fibroblast-derived
paracrine melagenic
factors
H19 RNA ↓
WIF-1 ↓
UV-induced pigmentation
652
also identified Wnt inhibitory factor1 (WIF-1) (Figure 2)
(Kim et al., 2013a,b), as another factor involved in melasma
pathogenesis without any expression changes by UV
irradiation. This will be dealt with in detail in the later
section examining dermal factors.
Role of female sex hormones in melasma
development
Melasma is considered as a common physiological skin
change during pregnancy (Elling and Powell, 1997;
Muallem and Rubeiz, 2006; Sodhi and Sausker, 1988),
and as an undesirable cutaneous effect of oral contra-
ceptives (Foldes, 1988). Epidemiological data revealed
the occurrence of melasma in 14.5–56% of pregnant
women and in 11.3–46% of individuals who used oral
contraceptives in different countries, including Singapore
(Goh and Dlova, 1999), Iran (Moin et al., 2006), Tunisian
(Guinot et al., 2010), India (Achar and Rathi, 2011;
KrupaShankar et al., 2014), and Brazil (Handel et al.,
2014b; Tamega Ade et al., 2013). Despite a large differ-
ence in the prevalences of melasma among different
ethnic groups and skin phototypes, the preferential
development of melasma during the reproductive lifespan
of women and the association of melasma with oral
contraceptives suggest that female sex hormones are
another important precipitating factor for the develop-
ment and aggravation of this disease. In contrast, the
dissenting opinion that hormones only weakly influence
melasma has also been offered (Passeron, 2013).
With respect to female sex hormones, estrogens and
progesterones have been implicated in the development
of melasma. The activities of estrogens and proges-
terones are mediated by specific receptors expressed in
human skin, including the estrogen receptors (ERs) ER-
alpha/ER-beta and progesterone receptors (PRs), respec-
tively (Pelletier and Ren, 2004; Thornton, 2002). Conflict-
ing results regarding the effects of these hormones,
particularly progesterones, have been obtained. Melasma
has been reported as an adverse reaction of contraceptives
containing the synthetic progestin levonorgestrel (Chom-
pootaweep et al., 1996), and the expression of PR
Figure 2. Factors involved in e melanogenesis
in melasma versus other hyperpigmentation
disorders. Decreased expression of H19 RNA
Melasma
and WIF-1 is involved in the pathogenesis of
melasma, but not post-inflammatory
hyperpigmentation and UV-induced
pigmentation (WIF-1, Wnt inhibitory factor 1).
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
 Melasma pathogenesis

proteins is increased in hyperpigmented skin in melasma

(Jang et al., 2010; Tamega Ade et al., 2015), suggesting
that progesterone plays a role in the development of
melasma. Conversely, the prevention of melasma by
progesterone components in oral contraceptives has
been suggested based on findings that progesterone
reduces proliferation without significant effects on tyrosi-
nase activity, counteracting the stimulatory effects of
estrogen in cultured melanocytes (Wiedemann et al.,
2009). An increase in male melasma patients due to the
advent of finasteride, an anti-androgen (Famenini et al.,
2014), also suggests that increased progesterone is
unrelated to the development of melasma, because
finasteride inhibits progesterone synthesis (Freeman
et al., 1993) without changing estrogen levels (Vermeulen
et al., 1991). Certain factors which could alter the sex
hormone metabolism, including interindividual variation in
the enzymes (Orme et al., 1989), may contribute to
generate the conflicting result. Other cellular and para-
crine regulatory factors have been also suggested to be
involved in estrogen responses (Feucht et al., 1988; Ing
and Tornesi, 1997), which may require a careful research
design and an analysis of the result for in vitro studies.
Immunohistochemistry revealed increased ER expression
in the affected skin (Lieberman and Moy, 2008), although
significant immunohistochemical expression of ER-beta
has been presented in melasma-affected dermis, but not
in epidermis (Jang et al., 2010). Increased ER expression
indicates a potential role of estrogen in melasma. Estro-
gens are considered to stimulate melanogenesis in
cultured human melanocytes by inducing synthesis of
melanogenic enzymes such as tyrosinase, TRP-1, TRP-2,
and MITF (Jian et al., 2011; Kim et al., 2012; Kippen-
berger et al., 1998). Melanocytes express ERs (Jee et al., Figure 3. Mechanism involved in estrogen-induced melanogenesis
1994; Kim et al., 2012), which are involved in estrogen- and PDZK1 role in melasma. (A) By binding to ERs, estrogen
induced melanogenesis, because the inhibition of ER by enhances cAMP levels and upregulates CREB, MITF, and tyrosinase
its antagonist leads to reduction in melanogenesis (Kim family protein expression, with the involvement of the PKA pathway.
et al., 2012). In addition, estrogen-induced melanogene- (B) PDZK1 could facilitate the estrogen action by interaction with
other proteins including ion exchangers, resulting in the stimulation
sis could be associated with the activation of the cAMP-
of melanogenesis and melanosome transfer in melasma patients
PKA pathway, because estrogens enhance cAMP levels (ER, estrogen receptor; PKA, protein kinase A; CREB, cAMP
and upregulation of tyrosinase and MITF attenuation by responsive-element-binding protein; CBP, CREB-binding protein;
blocking the PKA pathway, which has previously been MITF, micropthalmia-associated transcription factor; TYR, tyrosinase;
reported (Jian et al., 2011) (Figure 3A). TRP, tyrosinase-related protein; PDZK1, PDZ domain protein kidney
We have identified upregulation of PDZ domain protein 1; NHE, sodium–hydrogen exchanger; CFTR, cystic fibrosis
transmembrane conductance regulator).
kidney 1 (PDZK1) expression in the hyperpigmented skin
of melasma patients using real-time PCR and immuno-
histochemical staining (Kim et al., 2012). Cultured normal tyrosinase expression in melanocyte monocultures and
human keratinocytes and melanocytes express PDZK1, melanocyte–keratinocyte co-cultures. In addition, PDZK1
and PDZK1 overexpression of keratinocytes alone, overexpression increases estrogen-stimulated tyrosinase
melanocytes alone, or both increases the expression of expression and melanosome transfer with ER-alpha and
tyrosinase, CREB, and MITF in melanocyte monocultures ER-beta expression (Kim et al., 2012). As the name
or melanocyte–keratinocyte co-cultures. PDZK1 is a NHERF suggests, PDZK1 interacts with ion exchangers
member of the sodium–hydrogen exchanger regulatory such as NHE, cystic fibrosis transmembrane conductance
factor (NHERF) family, called NHERF-3. As estrogen regulator (CFTR), and SLC26A family with potential
exerts actions through NHERF1 or PDZK1 regulation in relationship between each ER subtype (ER-alpha or ER-
ER-containing breast cancer cells (Ediger et al., 1999; beta) and NHE3 or CFTR expression, respectively.
Ghosh et al., 2000), estrogen increases PDZK1 with Sodium–hydrogen exchanger regulatory factor family

ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 653
Lee
proteins mediate the most abundant protein–protein
interactions; therefore, PDZK1 could facilitate the estro-
gen action by interaction with other proteins including
ion exchangers, resulting in the stimulation of melano-
genesis and melanosome transfer in melasma patients
(Figure 3B).
Newly discovered factors in melasma
pathogenesis
Dermal factors implicated in melasma
The dermal resident cells, mast cells, and fibroblasts have
been presented with regard to skin pigmentation. Given
urticaria pigmentosa is a cutaneous mastocytosis charac-
terized by skin pigmentation, the role of mast cells in skin
pigmentation has been considered. Although SCF, also
known as mast cell growth factor, is involved in cuta-
neous mastocytosis and melanogenesis in urticarial
pigmentosa (Costa et al., 1996; Kunisada et al., 1998;
Longley et al., 1993), it is not originated from mast cells.
Meanwhile, histamine released from mast cells is iden-
tified to be involved in melanogenesis in urticarial
pigmentosa as well as post-inflammatory pigmentation
and UV-induced pigmentation (Tomita et al., 1989;
Yoshida et al., 2002). As in melanogenesis induced by
interaction between POMC-derived peptides and MC1R
(Abdel-Malek et al., 1999; Chakraborty et al., 1999),
histamine increases melanin synthesis by binding to
histamine receptor in melanocytes, particularly H2,
through intracellular cAMP and subsequent PKA activa-
tion (Yoshida et al., 2000).
Role of histamine in melasma has not been presented
(Table 3), although an increase in the number of mast
cells has been detected in pigmented lesional dermis
of melasma patients (Hern
andez-Barrera et al., 2008;


Torres-Alvarez et al., 2011).
The role of dermal fibroblasts in skin pigmentation has
been presented in both physiological and pathological skin
conditions. In case of physiological conditions, dickkopf 1
(DKK1) has been identified to play a role in hypopig-
mented phenotype of palmoplantar skin (Yamaguchi
et al., 2004); DKK1 is secreted by fibroblasts. As an
inhibitor of the canonical Wnt signaling pathway, DKK1
suppresses melanocyte function and growth through the
regulation of MITF and beta-catenin. Role of fibroblast-
derived factors in the regulation of human skin color has
also been identified; Fibroblasts in dark skin secrete
neuregulin-1, which exerts its action on melanocytes to
increase melanogenesis (Choi et al., 2010). In patholog-
ical skin pigmentation conditions, the role of paracrine
factors derived from dermal fibroblasts has been pre-
sented; increased SCF secretion from fibroblasts
exposed to UV radiation is involved in skin hyperpigmen-
tation induced by chronic sunlight exposure (Shin et al.,
2012). Keratinocyte growth factor (KGF) is mentioned as
fibroblast-derived growth factor in PIH (Cardinali et al.,
2012). Fibroblasts exposed to sublethal laser fluence
654
increase melanogenic factors, such as SCF, bFGF, and
hepatocyte growth factor (HGF), resulting in post-laser
hyperpigmentation (Poon et al., 2005). Increased expres-
sion of SCF, HGF, and KGF in dermal fibroblasts of
hyperpigmented skin also suggests a role of fibroblast-
derived paracrine factors in familial progressive hyperpig-
mentation-like disorder (Cardinali et al., 2009).
With reference to melasma, there are only few data
related to fibroblast-derived dermal factors (Table 3).
Immunohistochemistry data from melasma patients sug-
gest a role of increased SCF in dermis along with
increased c-KIT in epidermis in pigmentation (Kang et al.,


2006; Torres-Alvarez et al., 2011). Meanwhile, we
demonstrated that reduced WIF-1 expression in the
hyperpigmented skin of melasma patients increases
melanognesis and melanosome transfer, irrespective of
UV irradiation (Kim et al., 2013a,b). WIF-1, as a secreted
antagonist of Wnt signaling, belongs to the secreted
Frizzled-related protein class, which inhibits both the
canonical and non-canonical Wnt pathway (Hsieh et al.,
1999). WIF-1 is expressed in both cultured normal human
keratinocytes and fibroblasts, but not in melanocytes. The
decreased expression of WIF-1 not only in keratinocytes
but also in fibroblasts reduces WIF-1 binding to Wnts in
melanocytes, exerting the action through the canonical
Wnt/beta-catenin pathway resulting in MITF upregulation
and the non-canonical pathway resulting in translocation
of nuclear factor of activated T cells (NFAT) to nucleus
(Figure 4).
The potential role of altered dermal vasculature has also
been considered in melasma patients and UV-irradiated
individuals (Yano et al., 2005). Immunohistochemistry
data revealed an increase in dermal blood vessel number
and vascular endothelial growth factor (VEGF) expression
in pigmented lesion of melasma (Kim et al., 2007)
(Table 3). Although VEGF can increase the number and
diameter of peripheral blood vessels (Chen et al., 2014),
the role of VEGF in skin pigmentation has not been clearly
elucidated. In addition, the therapeutic outcomes of
copper bromide combined with a yellow laser that emits
dual wavelengths, enabling the selective and simultane-
ous destruction of both blood vessels and melanin-
containing cells, have not been encouraging (Eimpunth
et al., 2014). Therapeutic effect of tranexamic acid, which
reduces pigmentation and vessel number (Na et al.,
2013), may support a role of altered dermal vasculature
in melasma. However, tranexamic acid acts as a plasmin
inhibitor and an antifibrinolytic agent (Longstaff, 1994).
Research has not demonstrated the inhibition of vascular
ectasia by tranexamic acid. Although randomized, com-
parative clinical trials have indicated that tranexamic acid
treatment produces favorable outcomes for PIH and
melasma (Budamakuntla et al., 2013; Cho et al., 2013;
Shin et al., 2013), other trials have not supported this
finding (Kanechorn Na Ayuthaya et al., 2012; Kato et al.,
2011). Therefore, the mechanism of action of tranexamic
acid in melasma treatment remains unclear.
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Figure 4. Role of WIF-1 in fibroblasts (or
keratinocytes) in melanogenesis. Reduced
WIF-1 expression in fibroblasts (or
keratinocytes) increases Wnt expression and
action in melanocytes through the canonical
Wnt/beta-catenin pathway with
microphthalmia-associated transcription factor
(MITF) upregulation and the non-canonical
pathway with NFATc2 translocation to nucleus
(WIF-1, Wnt inhibitory factor 1; LEF-1,
lymphocyte enhancer binding factor 1; NFAT,
nuclear factor of activated T cells).
MicroRNAs and their targets in melasma
development
MicroRNAs (miRNAs) are small, 20–24 nucleotide,
endogenously expressed non-coding RNAs. MiRNAs
anneal to the 30 untranslated region of mRNAs in a
sequence-specific fashion and then either block transla-
tion or promote transcript degradation, thus playing a
major role in post-transcriptional regulation of gene
expression (Filipowicz et al., 2008). Based on the asso-
ciation between miRNAs and a broad range of patholog-
ical conditions, such as cancer, cardiovascular diseases,
diabetes, liver diseases, respiratory diseases, psychiatric
diseases, neurological diseases, and inflammatory and
autoimmune diseases, the discovery of miRNAs
becomes one of the major scientific breakthroughs in
the current field of cell biology and medical science (Ha,
2011). In pigmentation field, the role of miRNAs is
continuously emerging (Mione and Bosserhoff, 2015).
MiR-25 in alpacas reduces melanogenesis through MITF
as a direct target, with its abundance in alpacas turning up
white hair (Zhu et al., 2010). MiR-137 also targets MITF
with downregulation of tyrosinase, TRP-1, and TRP-2
expression in transgenic mice with miR-137 overexpres-
sion (Dong et al., 2012). In addition to miRNAs’ induction,
their silencing affects skin pigmentation. In fish skin
pigmentation, miR-429 targets Foxd3, and its silencing
increases Foxd3 expression and thereby reduction in
MITF (Yan et al., 2013). Role of miRNAs in skin pigmen-
tation is also identified in human melanocytes; MiR-145
regulates melanogenesis and melanosome translocation
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Melasma pathogenesis
of human melanocytes under the external stimuli of
forskolin and UV irradiation through Myo5a as a target
(Dynoodt et al., 2013). In addition, miR-125b is identified
as a regulator of steady-state melanogenesis in the
absence of external stimuli, such as forskolin treatment
and UV irradiation (Kim et al., 2014a).
Potential role of miRNAs has been presented in
melasma; in the process of examining the mechanism
of H19 non-coding RNA downregulation in melasma (Kim
et al., 2010), we identified a potential role of miRNA in
melanogenesis and melanosome transfer with its targets
(Figure 5; Kim et al., 2014a,b). Expression of a H19 RNA-
derived miRNA, miR-675, is reduced in the hyperpig-
mented skin of melasma patients (Kim et al., 2014a). In
addition, miR-675 overexpression decreases the expres-
sion of tyrosinase, TRP-1, and TRP-2, whereas its
knockdown increases their expression. Although melano-
genesis occurs in melanocytes, miR-675 is released
from keratinocytes. Exosomes, which are small mem-
brane vesicles of endocytic origin and released into the
extracellular environment, contain intact and functional
miR-675 as reported (Valadi et al., 2007) as a means of
cell–cell communication between keratinocytes and
melanocytes (Kim et al., 2014a,b,c). MiRNAs exert action
through targets, and we identified MITF as a target of
miR-675, with a potential role of miR-675 reduction in
MITF upregulation in melasma patients (Kim et al.,
2014a). Individual miRNAs can target multiple mRNAs
(Kasinski and Slack, 2011), and cadherin 11 (CDH11) is
identified as another target of miR-675 (Kim et al.,
655
Lee

Figure 5. Schematic view of the role of H19-

derived miR-675 in keratinocytes in melasma.
MiR-675 is delivered from keratinocytes to
melanocytes and fibroblasts via membrane-
bound exosomes. MiR-675 could exert the
action through either microphthalmia-
associated transcription factor (MITF) in
melanocytes or CDH11 in fibroblasts/
keratinocytes as its target. CDH11 in
fibroblasts or keratinocytes is involved in
melanogenesis via the canonical Wnt and AKT
activation pathways in neighboring
melanocytes through the induction of N-
cadherin (CDH, cadherin; AKT, apoptosis
signal-regulating kinase; TYR, tyrosinase; TRP,
tyrosinase-related protein).

2014b). Increased CDH expression is also examined in Table 4. Working mechanisms and current therapeutic modalities
hyperpigmented skin of melasma patients, suggesting for melasma
the role of CDH11 in melasma. Although CDH11 expres-
Therapeutic
sion is not detectable in melanocytes, CDH11 in fibrob- Groups Targets modalities
lasts or keratinocytes stimulated melanogenesis via the
canonical Wnt and apoptosis signal-regulating kinase Common to Upregulation of Skin lightening
(AKT) activation pathways in co-cultured melanocytes various skin tyrosinase/MITF agents, such as
through the induction of N-cadherin. hyperpigmentation through intracellular hydroquinone with
disorders signaling pathways or without tretinoin
and corticosteroids,
Perspectives azelaic acid, and kojic
acid, among others
Melasma is a common skin pigmentation condition. Interventions, such
Published articles regarding melasma have largely as chemical peels,
focused on the treatment of this condition. This review lasers, and IPL
notes that multiple signaling pathways, including the Triggering factor UV radiation Strict use of
sunscreen
MSH/cAMP, KIT, and Wnt pathways, are involved in the
Dermal vessel Tranexamic acid
upregulation of tyrosinase and MITF, resulting in the ectasia (with attention
stimulation of melanogenesis and the development of devoted to potential
melasma. The concurrent activation of these pathways is thrombus formation)
a cornerstone of most hyperpigmentation syndromes Female sex Not clearly
(Speeckaert et al., 2014). Therefore, it is somewhat hormones recommended
understandable that the same therapeutic modalities Inflammation Corticosteroids
(but not clearly
(e.g. skin lightening agents with or without certain
recommended)
interventions) are used for melasma (Gupta et al., 2006)
and for other hyperpigmentation disorders (Table 4). IPL, intense pulsed light therapy; MITF, microphthalmia-associated
An effort to inhibit triggering factors or signaling transcription factor.
pathways involved in melasma could help to improve
the effects of popular therapeutic modalities (Table 4).
The results of epidemiological studies examining the roles Dlova, 1999; Guinot et al., 2010; Handel et al., 2014b;
of family history, UV irradiation, and pregnancy/contra- Hexsel et al., 2014; KrupaShankar et al., 2014; Moin
ceptives in melasma (Achar and Rathi, 2011; Goh and et al., 2006; Tamega Ade et al., 2013) differ across broad

656 ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

ranges, suggesting that these findings are of limited
value. Experimental data from melasma patients have
largely been obtained from microscopic or immunohisto-
chemical studies. Nonetheless, in association with UV
exposure, melasma and skin changes due to chronic UV
irradiation exhibit similar histopathologic findings (Grimes
et al., 2005; Hern
andez-Barrera et al., 2008; Kang et al.,


2002; Torres-Alvarez et al., 2011); reports have also
stated that paracrine melanogenic factors are derived
from both keratinocytes (Bak et al., 2009; Im et al., 2002;
Jo et al., 2009; Miot et al., 2010) and fibroblasts (Kang


et al., 2006; Torres-Alvarez et al., 2011). These ongoing
updates emphasize the role of UV radiation and propose
strict use of sunscreen for the management of melasma,
although more stable and intense effect of visible light
irradiation on skin pigmentation may provide a clue in
explaining partial protective effect of sunscreens (Mah-
moud et al., 2010). With respect to the role of female sex
hormones in the progression of melasma, the effects of
estrogen, such as increased ER expression in hyperpig-
mented lesions (Jang et al., 2010; Lieberman and Moy,
2008), and PDZK1, a factor that facilitates estrogen
activity by acting as a scaffold in interactions with other
proteins (Kim et al., 2012), have been more consistent
than the effects of progesterones; however, the question
of which contraceptives are appropriate remains unre-
solved. Based on the ectasia of dermal vessels in
melasma, tranexamic acid has been clinically tested in
recent years; however, tranexamic acid should be used
cautiously in the treatment of melasma because this
compound can potentially promote thrombus formation
(Sperzel and Huetter, 2007) and because its administra-
tion has generated conflicting therapeutic results. With
respect to the PIH implicated in the development of
melasma, inflammatory features have been examined in
melasma patients (Handel et al., 2014a; Noh et al., 2014);
however, the roles of histamine from mast cells and KGF
from dermal fibroblasts have been identified in PIH but
not in melasma. A great deal of additional work may be
necessary to identify the role of PIH in melasma.
Certain triggering factors independent of UV exposure,
such as H19 RNA and WIF-1 (Kim et al., 2010, 2013a,b),
and the roles of miRNAs, particularly miRNAs derived
from the H19 non-coding RNA (Kim et al., 2014a,b),
have also been identified in melasma via their direct
targets. Despite recent progress in understanding the
pathogenesis of melasma, the associations between
melasma and each triggering factor have only been
partially identified. It remains unclear which triggering
factors play more important roles in this pathogenesis.
In addition, not every patient with melasma exhibits the
same clinical and histological features, suggesting that
melasma could involve various mechanisms. For
instance, relatively severe actinic damage is observed
in mandibular melasma (Mandry Pag
an and S
anchez,
2000). To develop desirable treatment modalities, the
identification of causative factors based on genomic and/
ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Melasma pathogenesis
or proteomic analysis and validation of patient skin
specimens (which are diagnosed correctly) would be
required. Identified causative factors could be exploited
as therapeutic agents (particularly if the expression or
function of these factors was reduced) or as biological
targets used to develop therapeutic compounds for
melasma. They could also be utilized to identify the
important contributing factors for individual patients.
Causative factors would be more useful, if they could be
classified as melasma specific, which needs more steps
for validation in other hyperpigmentation conditions as
well as in different types of melasma. It is apparent that
the identification of melasma-specific triggering factors
will pave desirable way to pursue personalized therapy
in future.
Acknowledgements
This work was supported by the National Research Foundation of
Korea (NRF) grant funded by the Korea Government (MSIP) (No.
NRF-2014R1A2A2A09051812).
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