Regulation of skin pigmentation and thickness by Dickkopf 1 (DKK1).
Dickkopf 1 (DKK1), an inhibitor of Wnt signaling, not only functions as a head inducer during development, but also regulates joint remodeling and bone formation, which suggests roles for DKK1 in the pathogenesis of rheumatoid arthritis and multiple myeloma. We recently demonstrated that levels of DKK1 in palmoplantar dermal fibroblasts are physiologically higher than those observed in non-palmoplantar dermal fibroblasts. Thus, the DKK1-rich mesenchyme in palmoplantar dermis affects the overlying epithelium and induces a palmoplantar phenotype in the epidermis. More specifically, DKK1 suppresses melanocyte function and growth through the regulation of microphthalmia-associated transcription factor (MITF) and beta-catenin. Furthermore, DKK1 induces the expression of keratin 9 and alpha-Kelch-like ECT2-interacting protein (alphaKLEIP) but downregulates the expression of beta-catenin, glycogen synthase kinase 3beta, protein kinase C, and proteinase-activated receptor-2 (PAR-2) in keratinocytes. Treatment of reconstructed skin with DKK1 reproduces the hypopigmentation and thickening of skin through Wnt/beta-catenin signaling. These studies elucidate why human palmoplantar skin is thicker and paler than non-palmoplantar skin through the secretion of DKK1 by fibroblasts that affect the overlying epidermis. Thus, DKK1 may be useful for reducing skin pigmentation and for thickening photo-aged skin and palmoplantar wounds caused by diabetes mellitus and rheumatic skin diseases.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 73-75; doi:10.1038/jidsymp.2009.4.
Yamaguchi
Yuji
Y
Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. yujin@med.nagoya-cu.ac.jp
Morita
Akimichi
A
Maeda
Akira
A
Hearing
Vincent J
VJ
D005347:Fibroblasts / Q000502:physiology; D005528:Foot; D006225:Hand; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D015603:Keratinocytes / Q000502:physiology; D008544:Melanocytes / Q000502:physiology; D008954:Models, Biological; D015398:Signal Transduction; D012867:Skin / Q000033:anatomy & histology*; D012879:Skin Physiological Phenomena; D012880:Skin Pigmentation / Q000502:physiology*
C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
J Biol Chem. 2007 Sep 21;282(38):27557-61
17635904
Br J Dermatol. 2006 Sep;155(3):522-31
16911276
Cell. 2007 Jun 29;129(7):1311-23
17604720
FASEB J. 2008 Apr;22(4):1009-20
17984176
Sci Am. 2008 Apr;298(4):56-63
18380142
Exp Cell Res. 2000 Jan 10;254(1):25-32
10623462
J Dermatol. 2001 Oct;28(10):521-34
11732719
Mol Biol Cell. 2004 Mar;15(3):1172-84
14668487
J Cell Biol. 2004 Apr 26;165(2):275-85
15117970
J Cell Biol. 1986 Aug;103(2):657-67
2426283
N Engl J Med. 2003 Dec 25;349(26):2483-94
14695408
J Invest Dermatol. 2007 May;127(5):1217-25
17159916
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12877-82
12297622
Genes Dev. 2008 Feb 1;22(3):303-7
18245445
Br J Dermatol. 2004 Nov;151(5):1019-28
15541080
FASEB J. 2006 Jul;20(9):1486-8
16793869
Br J Dermatol. 2005 Apr;152(4):664-72
15840096
Arch Dermatol. 2001 May;137(5):621-8
11346340
Nature. 1998 Jan 22;391(6665):357-62
9450748
J Am Acad Dermatol. 2007 Aug;57(2):322-6
17637445
J Invest Dermatol. 1999 Apr;112(4):483-8
10201533
J Biol Chem. 1999 Jul 2;274(27):19465-72
10383463
Nat Med. 2007 Feb;13(2):156-63
17237793
J Biol Chem. 2005 Jan 21;280(3):2309-23
15504735