The chemical basis of melanogenesis is well documented, but the mechanism o
f melanosome transfer and the regulation of pigmentation by keratinocyte-me
lanocyte interactions are not well understood. Therefore we examined the ef
fects of serine protease inhibitors on skin pigmentation and found that the
protease-activated receptor 2, expressed on keratinocytes, may regulate pi
gmentation via keratinocyte-melanocyte interactions. Here we show that modu
lation of protease-activated receptor 2 activation affects melanosome trans
fer into keratinocytes, resulting in changes in pigment production and depo
sition. SLIGRL, the protease-activated receptor 2 activating peptide, enhan
ced melanosome ingestion by keratinocytes, thus increasing pigment depositi
on. RWJ-50353, a serine protease inhibitor, led to reduced pigment depositi
on in melanocytes and depigmentation. Electron microscopy studies illustrat
ed an accumulation of immature melanosomes inside melanocytes and abnormal
dendrite dynamics in RWJ-50353-treated epidermal equivalents. RWJ-50353 ind
uced a visible and dose-dependent skin lightening effect in the dark-skinne
d Yucatan swine. Examinations by electron microscopy indicated that the in
vivo transfer of melanosomes from melanocytes to keratinocytes was affected
. Our data suggest that modulation of keratinocyte-melanocyte interactions
via the protease-activated receptor 2 pathway affects melanosome transfer.
The use of RWJ-50353 to modulate protease-activated receptor 2 activation c
ould lead to a new class of depigmenting agents.