Melanogenesis: Everything you need to know about the physiology of the pigmentation system.

Melanogenesis describes the complex and essential process through which melanin is produced and distributed by melanosomes in the epidermis or hair follicles. This pigment, typically black or brown in colour, helps to determine the colour of the skin, hair, body hair, and the iris of the eye.

Melanins are synthesised within specific organelles, the melanosomes, which are themselves contained within melanocytes, these are globular-shaped cells equipped with numerous cellular extensions (melanocyte dendrites) that allow them to come into contact with several keratinocytes, reaching up to the spinous layer (one of the layers of the epidermis). They are established at the dermo-epidermal junction which rests on the basal membrane of the epidermis. The number of melanocytes varies depending on the regions of the body: we count approximately 1,000 to 1,500 per mm2 on the body and 2,000 or more per mm2 on the face.

Melanin is produced as a result of a cascade of reactions:

1. Synthesis of enzymes necessary for this mechanism : Among the enzymes involved in this process, we have tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). These are proteins capable of triggering, activating, and regulating the various chemical reactions leading to the synthesis of melanin pigments. They are synthesised at the level of the rough endoplasmic reticulum (RER), and then transported to the Golgi apparatus via vesicles;

2. Melanosome Formation : Melanosomes are cytoplasmic organelles within which the enzymes formed in the previous stage are contained. They are formed by the fusion of micro-vesicles. At this stage, the melanosomes are still non-pigmented (immature) and the tyrosinases are inactive;

3. Melanin Synthesis : Melanin originates from the enzymatic transformation of tyrosine, an amino acid supplied by the bloodstream, under the action of tyrosinase. Following minor divergences in the synthesis pathway, two types of melanin pigments can be produced: the eumelanins (or granular pigments) ranging from black to brown and the pheomelanins (or diffuse pigments) ranging from yellow to reddish-brown with the involvement of sulphur compounds (either in the form of an amino acid, cysteine, or in the form of a tripeptide, glutathione);

   Note : In fair skin, melanosomes are few in number and often incompletely matured, in addition to being rapidly degraded, making the skin less photo-protected and therefore more exposed to sun damage (burns, sunburns...), whereas in dark skin, they are numerous and mature.

4. Transfer of melanosomes from melanocytes to keratinocytes: Numerous melanosomes migrate from the cell body, where they are produced, to the tips of the melanocyte dendrites, where they accumulate, before being transferred to the surrounding keratinocytes in the upper layers of the epidermis to ensure the pigmentation of the epidermis and its photoprotection against UV rays. Each melanocyte is in contact with approximately 36 keratinocytes to which the melanosomes migrate;

5. Degradation of melanosomes in keratinocytes: Once the transfer to adjacent epidermal cells is completed, the melanosomes are then gradually eliminated with the keratinocytes during their ascent to the skin surface.

Note : The differences in skin pigmentation are due to the proportion of each type of melanin synthesised and the size of the melanosomes (therefore the amount of melanin), not the number of melanocytes, which remain substantially equivalent across different skin tones.

Beyond colouring hair, eyelashes, eyes, and skin, the primary physiological role of melanin is to serve as a protective system for the epidermis and deeper layers against external aggressions, particularly UV radiation. Indeed, melanin production is an adaptive response of the body to prolonged sun exposure. It thus plays a photoprotective role.

Thus, tanning is nothing more than the skin's natural protection mechanism against UV rays.

Indeed, when exposed to the sun, epidermal cells undergo the assault of UVA and UVB rays, which can lead to metabolic defects (ageing), cell death and the development of skin cancer. To protect against the damage induced by UV rays, the melanogenesis mechanism is then triggered. The melanin produced clusters around the nucleus of the keratinocytes to form a "filter" (a phenomenon known as capping) with the aim of protecting the DNA (genetic material) from the mutagenic and carcinogenic effects of UV rays.

It will absorb up to 90% of UV rays with long wavelengths extending into the visible spectrum that have penetrated the corneal layer, preventing them from traversing the epidermis. Even though UVA rays are responsible for the rapid, but non-persistent, pigmentation of the skin through the oxidation of existing melanin, it is the UVB rays that are responsible for the more enduring tan. Despite this photoprotection system, approximately 15% of UVB rays still manage to reach the basal layer and 50% of UVA rays penetrate the dermis.

Melanin also has the ability to capture free radicals generated within melanocytes and keratinocytes by UV radiation, thus limiting premature skin ageing.

However, the production of melanin tends to decrease with age. Yet, the protective effect of melanin is only valid if it is present in sufficient quantities. Therefore, a deficiency in melanin sometimes generates pigmentation disorders during ageing, such as vitiligo, a skin disease that manifests itself through the appearance of white spots or even senile lentigos. This decrease in melanin synthesis is actually due to a decline in the number of melanocytes that are no longer renewed and in their activity. Indeed, the activity and number of melanocytes decrease by 10 to 20% per decade from the age of 30.

Note : The activity of epidermal melanocytes is continuous, whereas that of the hair follicle melanocytes follows the rhythm of the hair cycle.

A number of intrinsic and extrinsic factors can trigger the melanin production process, including:

• UV Irradiation: UV rays are well known for stimulating melanogenesis by increasing the synthesis of melanin and accelerating its transfer to the epidermal cells. This is particularly evident in the appearance of small, dark, round or oval spots on frequently exposed parts of the body (face, neck, backs of hands...), these are solar lentigines;

• Hormonal Variations : Pigmentation can be modulated by hormones carried by the blood supply, such as theoestrogen, which has a stimulating role inducing hyperactivity in melanocytes. This phenomenon results in the formation of irregular beige to brown areas on the body, known as melasma. It primarily tends to appear in adult women during pregnancy or when taking oral contraception;

• Inflammation : Certain inflammatory molecules (prostaglandins, leukotrienes, thromboxanes) enhance the activity of tyrosinase, a key enzyme in melanogenesis, and are thus responsible for thepost-inflammatory hyperpigmentation (residual hyperpigmented spots that persist after the healing of a skin condition such as theacne).

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