Yamaguchi1,2,3, Y., Passeron1, T., Hoashi1, T., Watabe1, H., Rouzaud1, F., Yasumoto1, K., Hara1, T., Tohyama2, C., Katayama2, I., Miki1, T., and Hearing1, V.J. 1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; 2Department of Dermatology, Osaka University Graduate School of Medicine, Osaka, Japan; and 3Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

This study by researchers at the National Cancer Institute (USA), Osaka University Graduate School of Medicine (Japan) and Nagoya City University Graduate School of Medical Sciences (Japan) demonstrated the ability to reproduce the expression patterns of key proteins observed in human palmoplantar skin by treating MelanoDerm, MatTek’s reconstructed human skin model containing both keratinocytes and melanocytes, with DKK1. The epidermis (containing primarily keratinocytes and melanocytes) overlies the dermis (containing primarily fibroblasts) of human skin. Researchers at the National Cancer Institute (USA), Osaka University Graduate School of Medicine (Japan) and Nagoya City University Graduate School of Medical Sciences (Japan) previously reported that dickkopf 1 (DKK1) secreted by fibroblasts in the dermis elicits the hypopigmented phenotype of palmoplantar skin due to suppression of melanocyte function and growth via the regulation of two important signaling factors, microphthalmia-associated transcription factor (MITF) and â-catenin. These researchers now report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin, and that treatment of reconstructed skin (MelanoDerm) with DKK1 induces a thicker and less pigmented epidermis. DNA microarray analysis revealed many genes regulated by DKK1, and several with critical expression patterns were validated by reverse transcriptase-polymerase chain reaction and Western blotting. DKK1 induced the expression of keratin 9 and á-Kelch-like ECT2 interacting protein (áKLEIP) but down-regulated the expression of â-catenin, glycogen synthase kinase 3â, protein kinase C, and proteinase-activated receptor-2 (PAR-2), which is consistent with the expression patterns of those proteins in human palmoplantar skin. Treatment of reconstructed skin (MelanoDerm) with DKK1 reproduced the expression patterns of those key proteins observed in palmoplantar skin. These findings further elucidate why human skin is thicker and paler on the palms and soles than on the trunk through topographical and site-specific differences in the secretion of DKK1 by dermal fibroblasts that affects the overlying epidermis.


Alpha-Kelch-like ECT2 interacting protein (aKLEIP), Beta-catenin, Dermis, Dickkopf 1 (DKK1), Epidermis, Extracellular-signal regulated kinase (ERK), Fibroblasts, Glycogen synthase kinase 3-beta, Hypopigmented phenotype, Keratin 9, Keratinocytes, MEL-300-A, MEL-NMM-113, Melanin content, Melanin uptake, MelanoDerm, Melanocytes, Microphthalmia-associated transcription factor (MITF), Palmoplantar skin, Protein kinase C, Proteinase-activated receptor-2 (PAR-2), Skin pigmentation, Skin thickness, Tissue thickness, Wnt inhibitor, Wnt signaling pathway, Wnt/beta-catenin signaling

Materials Tested

Dickkkopf 1

Request a copy of this paper, click here.