Advanced regulation via new pathway inhibition

In Asian culture, lighter and even complexion is associated with higher social status (wealth and education) and a darker complexion has been associated with people who work in the field and are more exposed to sunlight. Eighty per cent of Asian women report concern over skin darkening, compared to 10% of women in Europe. For Western culture a darker, more tanned complexion is usually associated with a healthy glow, but hyperpigmentation or brown spots is one of the most common condition afflicting people in Western countries. Interesting new progress has been recently achieved in our understanding of skin pigmentation. Skin colour is the sum of our constitutive and facultative (UV-induced) pigmentation and varies from one individual to another.1 Given its impact on the development of skin melanoma, the effects of UV and sun exposure on facultative pigmentation have been extensively characterised. It is noteworthy that for quite a while it has been recognised that sun exposure triggers the production of alpha-melanocyte-stimulating hormone (?-MSH), acting through the melanocortin-1 receptor (MC1R) at the surface of melanocytes, to initiate a cascade of intracellular signalling events leading to the activation of tyrosinase and other enzymes and proteins involved in skin pigmentation.2 Less known was the pathway involved in the control of our constitutive skin pigmentation. A first step was accomplished with the identification of transforming growth factor-?1 (TGF-?1) as a major epidermal paracrine modulator of this aspect of skin pigmentation.3 More recently, evidence suggesting that melanogenesis can be modulated by TGF-??through the down-regulation of microphtalmia-associated transcription factor (MITF) and tyrosinase.4-10 MITF is currently believed to be a master regulator of melanocyte-specific transcription of genes coding for major proteins involved in melanogenesis. These include tyrosinase, TRP-1, and TRP-2.10 MITF integrates signals originating from several pathways (Fig. 1). For instance, ?-MSH, signalling through cAMP and PKA, phosphorylates and activates CREB (a nuclear factor) to bind and turn on MITF, promoting melanogenesis.11 On the other hand, TGF-?, can promote MITF degradation as well as reduce its promoter activity, leading to a decrease of melanin content.12 The effect of TGF-??on MITF is sufficient to suppress ?-MSH stimulation of melanogenesis in melanoma cells.13 The fact that MITF responds to both ?-MSH and TGF-??places it at the centre of both constitutive and facultative pigmentation. In an effort to mimic the natural anti-melanogenic activity of TGF-?, a new biomimetic peptide, ?-White (INCI Name: Water (and) Butylene glycol (and) Hydrogenated Lecithin (and) Oleate (and) Oligopeptide-68 (and) Disodium EDTA), was developed based on the known amino acid sequence of the growth factor. To maximise skin penetration, ?-White (now referred to as ‘the new peptide’) was encapsulated in a liposome preparation. The present article provides evidence that the new peptide, acting at the level of MITF, inhibits both the constitutive and the facultative melanogenic activities of melanocytes in vitro. Additionally, in vivo skin lightening efficacy of the product is described.

Results and discussion

Binding to TGF-??receptor