Bone morphogenetic proteins differentially regulate pigmentation in human skin cells.
Bone morphogenetic proteins (BMPs) are a large family of multi-functional secreted signalling molecules. Previously BMP2/4 were shown to inhibit skin pigmentation by downregulating tyrosinase expression and activity in epidermal melanocytes. However, a possible role for other BMP family members and their antagonists in melanogenesis has not yet been explored. In this study we show that BMP4 and BMP6, from two different BMP subclasses, and their antagonists noggin and sclerostin were variably expressed in melanocytes and keratinocytes in human skin. We further examined their involvement in melanogenesis and melanin transfer using fully matched primary cultures of adult human melanocytes and keratinocytes. BMP6 markedly stimulated melanogenesis by upregulating tyrosinase expression and activity, and also stimulated the formation of filopodia and Myosin-X expression in melanocytes, which was associated with increased melanosome transfer from melanocytes to keratinocytes. BMP4, by contrast, inhibited melanin synthesis and transfer to below baseline levels. These findings were confirmed using siRNA knockdown of BMP receptors BMPR1A/1B or of Myosin-X, as well as by incubating cells with the antagonists noggin and sclerostin. While BMP6 was found to use the p38MAPK pathway to regulate melanogenesis in human melanocytes independently of the Smad pathway, p38MAPK, PI3-K and Smad pathways were all involved in BMP6-mediated melanin transfer. This suggests that pigment formation may be regulated independently of pigment transfer. These data reveal a complex involvement of regulation of different members of the BMP family, their antagonists and inhibitory Smads, in melanocytes behaviour.
Centre for Skin Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP,  UK.
Suman K
SK
Singh
Waqas A
WA
Abbas
Desmond J
DJ
Tobin
D000328:Adult; D000368:Aged; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D055418:Bone Morphogenetic Protein 6 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D018920:Coculture Techniques; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000528:radiation effects; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects / Q000648:ultrastructure; D008875:Middle Aged; D008954:Models, Biological; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009218:Myosins / Q000378:metabolism; D010858:Pigmentation / Q000187:drug effects* / Q000528:radiation effects; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D012867:Skin / Q000166:cytology*; D051785:Smad Proteins / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; C498718:MYO10 protein, human; D008543:Melanins; D051785:Smad Proteins; D014442:Monophenol Monooxygenase; D048051:p38 Mitogen-Activated Protein Kinases; D052004:Bone Morphogenetic Protein Receptors; D009218:Myosins