Bone morphogenetic proteins differentially regulate pigmentation in human skin cells

Abstract

SummaryBone 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.

Paracrine regulation of melanogenesis

“…Later study further revealed that BMP6 increases melanin synthesis in normal human melanocytes by upregulating tyrosinase expression and activity, while BMP4 shows an inhibitory effect on melanin production. Moreover, BMP6 also stimulates melanin transfer from melanocytes to keratinocytes in fully matched melanocyte–keratinocyte cocultures, while BMP4 works in an opposite manner . In addition, UVB upregulates the expression of BMP6 in human epidermal keratinocytes, while it downregulates the expression of antimelanogenic BMP4.…”

Regulation of melanocyte stem cells in the pigmentation of skin and its appendages: Biological patterning and therapeutic potentials

“…Bmp2 and Bmp4 in the dermis and subcutaneous adipose tissue inhibit transitioning of hair cycling from telogen to anagen . Bmp2/4 also inhibits TYR activity and melanogenesis, suggesting that dermis‐ and subcutaneous adipose tissue‐derived Bmp might also serve to maintain McSCs quiescence. On the other hand, adipose regeneration is in synchrony with the activation of HFSCs.…”

Bone Morphogenetic Protein Signaling Suppresses Wound-Induced Skin Repair by Inhibiting Keratinocyte Proliferation and Migration

“…In anagen HFs, BMP signalling inhibits proliferation and promotes differentiation of hair matrix keratinocytes into hair shaft and inner root sheath lineages (Andl et al , 2004; Kobielak et al , 2003; Kulessa et al , 2000; Ming Kwan et al , 2004; Sharov et al , 2006; Yuhki et al , 2004), as well as regulating melanogenesis (Park et al , 2009; Sharov et al , 2005; Singh et al , 2012; Yaar et al , 2006). Additionally, BMPs contribute to the regulation of epidermal differentiation by activating BMPR-1B which is expressed in the suprabasal epidermis (Hwang et al , 2001; Sharov et al , 2003; Yu et al , 2010).…”