200. INHIBITION OF MELANOSOME TRANSFER RESULTS IN SKIN LIGHTENING.

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Seiberg, M., Paine, C., Sharlow, E., Andrade-Gordon, P., Costanzo*, M., Eisinger*, M., Shapiro, S.S. Skin Research Center, Johnson & Johnson CPWW, Skillman, New Jersey. U.S.A. *The R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A. J. Invest. Dermatol., 115, 162-167, (2000).

Summary: 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. RWJ50353 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.

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Applications: Melanogenesis, Skin pigmentation

Keywords: Inhibition, Keratinocyte-melanocyte interactions, MelanoDerm, Melanosome transfer, Protease-activated receptor 2, RWJ-50353, SLIGRL, Serine protease inhibitor, Skin lightening

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