Inhibition of melanosome transfer results in skin lightening.
The chemical basis of melanogenesis is well documented, but the mechanism of melanosome transfer and the regulation of pigmentation by keratinocyte-melanocyte interactions are not well understood. Therefore we examined the effects of serine protease inhibitors on skin pigmentation and found that the protease-activated receptor 2, expressed on keratinocytes, may regulate pigmentation via keratinocyte-melanocyte interactions. Here we show that modulation of protease-activated receptor 2 activation affects melanosome transfer into keratinocytes, resulting in changes in pigment production and deposition. SLIGRL, the protease-activated receptor 2 activating peptide, enhanced melanosome ingestion by keratinocytes, thus increasing pigment deposition. RWJ-50353, a serine protease inhibitor, led to reduced pigment deposition in melanocytes and depigmentation. Electron microscopy studies illustrated an accumulation of immature melanosomes inside melanocytes and abnormal dendrite dynamics in RWJ-50353-treated epidermal equivalents. RWJ-50353 induced a visible and dose-dependent skin lightening effect in the dark-skinned 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 could lead to a new class of depigmenting agents.
Seiberg
M
M
Skin Research Center, Johnson & Johnson CPWW, Skillman, New Jersey, USA. mseiber@cpcus.jnj.com
Paine
C
C
Sharlow
E
E
Andrade-Gordon
P
P
Costanzo
M
M
Eisinger
M
M
Shapiro
S S
SS
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D020460:Melanosomes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D051379:Mice; D008854:Microscopy, Electron; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000502:physiology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000648:ultrastructure; D012880:Skin Pigmentation / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology
D006146:Guanidines; C100912:RWJ 50353; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles