Inhibition of Melanosome Transfer Results in Skin Lightening1

Abstract

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.

Modifying skin pigmentation – approaches through intrinsic biochemistry and exogenous agents

“…As mentioned above, the PAR2 receptor on keratinocytes plays an important role in regulating the uptake of melanosomes by keratinocytes. RWJ-50353, a serine protease inhibitor, leads to depigmentation in reconstructed skin and in dark-skinned Yucatan swine by affecting melanosome transfer and distribution [98]. In vitro, centaureidin [99], a flavone from Achillea millefolium (common yarrow), and methylophiopogonanone B [100] (MOPB), a homoisoflavonoid from Ophiopogon japonicus (mondo grass), block melanosome transfer by inducing the retraction of melanocyte dendrites through activation of GTPase Rho (the master regulator of dendrite formation in melanocytes) [101]).…”

The Dilute Locus and Griscelli Syndrome: Gateways Towards a Better Understanding of Melanosome Transport

“…Moreover, melanosomes are still recognizable as membranous structures in the cytoplasm of keratinocytes where they are sequestered together with lysosomes of the keratinocytes to form secondary lysosomes. Seiberg et al (68) found that the protease-activated receptor 2 (PAR-2) expressed on keratinocytes may regulate pigmentation via keratinocyte -melanocyte phagocytosis-like interactions.…”

Mangosteen leaf extract increases melanogenesis in B16F1 melanoma cells by stimulating tyrosinase activity in vitro and by up-regulating tyrosinase gene expression

“…The skin pigmentation processes involve de novo synthesis of melanin in melanocytes and the transfer of synthesized melanin packed in melanosomes to neighboring keratinocytes, which eventually turns the skin to a dark color (24,25). Melanosomes contain three types of enzymes: tyrosinase; TRP1; DCT (TRP2) (26).…”