The skin consists mainly of three layers, namely, starting from the outermost: epidermis, dermis and hypodermis.
The epidermis consists in particular of keratinocytes (primarily), melanocytes (involved in skin pigmentation) and Langerhans cells. Its function is to protect the body from the external environment and ensure its integrity, and notably to block the penetration of microorganisms or of chemical substances, and prevent evaporation of the water contained in the skin.
For this purpose, the keratinocytes undergo a continuous process of directed maturation, in which the keratinocytes located in the basal layer of the epidermis form, in the terminal stage of their differentiation, corneocytes, which are cells resulting from cornification (a particular form of apoptosis). These corneocytes are very inter-cohesive, fully keratinized in the form of cornified envelopes and surrounded by an extracellular medium that is very rich in lipids. The constituent elements of these cells, as well as the enzymes that regulate their detachment to permit desquamation, are mainly synthesized by the keratinocytes of the underlying cellular layer, the stratum granulosum or granular layer. The granular keratinocytes correspond to the last nucleated stage of keratinocyte differentiation, before cornification, which is accompanied by nuclear lysis with stoppage of all activity of transcription and translation. It is at this stage that there is culmination of the production of the precursors of the cornified envelope and other specific cellular constituents indispensable to the barrier function of the epidermis such as ceramides, cholesterol and free fatty acids. The cornified envelope formed during cornification replaces the lipid bilayer of granular keratinocytes. It represents 7% of the dry weight of the stratum corneum. It consists of proteins that are bound to one another or to the lamellar lipid envelope covalently by transglutaminases, forming a macromolecular complex that is particularly stable, insoluble and impermeable, which is essential for the physical strength and the barrier function of the stratum corneum.
Epidermal differentiation is a complex phenomenon requiring fine regulation of the expression of the genes permitting manufacture of the various constituents of the keratinocytes and then of the corneocytes. A great many transcription factors are involved in this process. The genes of numerous proteins of the cornified envelope are localized within one and the same cluster of 2.5 Mb called the “Epidermal Differentiation Complex” (EDC) in position 1q21.3. The EDC comprises more than 50 different genes, expressed principally in the epidermis. Most of the genes coding for the structural proteins necessary for terminal differentiation, such as loricrin, filaggrin and involucrin, are found there. The EDC also contains several families of genes, at least 18 of which code for the late proteins of the Late Cornified Envelope (LCE) (Marshall et al. 2001, Differentially expressed late constituents of the epidermal cornified envelope. Proc Natl Acad Sci USA. 98: 13031-6). In the course of cornification, these proteins of the LCE family are incorporated in the cornified envelope owing to the action of transglutaminases, which establish an ε-(γ-glutamyl) lysyl linkage between a donor glutamine residue and an acceptor amine group, in a calcium-dependent manner.
The barrier function of the epidermis may be disturbed in certain climatic conditions (under the effect of cold and/or wind, for example); under the effect of stress or fatigue; under the effect of certain chemical factors (pollution, ultraviolet radiation, alcohol, irritating soaps, domestic cleaning products, detergents, etc.).
Many skin disorders that are characterized by production of a thickened stratum corneum and by abnormal desquamation, i.e. hyperkeratosis, also display an altered barrier function. Hyperkeratosis can occur on all anatomic skin areas and in very varied clinical contexts. Its underlying physiopathology and its causes are varied. As examples we may mention: xerosis (or dry skin), ichthyoses, psoriasis, certain benign or malignant tumoral lesions, reactive hyperkeratoses. Conversely, certain pathological manifestations involve thinning of the epidermis and especially of the stratum corneum, which is reflected in excessive fragility of the skin. The latter can occur in various anatomical regions, its cause is variable and it can be constitutional or acquired. As examples we may mention: trophic skin disorders of the lower limbs in patients with vascular disorders, varices, arteriopathies (diabetes, arteriosclerosis, etc.), trophic skin disorders in the context of an algodystrophic syndrome, trophic disorders following abnormal healing.
The barrier function of the epidermis may also be disturbed during aging. Thus, older subjects, and notably those over 50 years of age, are often found to have a xerosis or a dryness of the mucosae, linked to a decrease in secretion of sebum, hormonal changes or to slowing of the flow of water through the epidermis. These disturbances of the barrier of the epidermis cause a decrease in the amount of organized water, a desynchronization of the synthesis or a change in the structure and/or composition of the bilayers of the granular layer. These changes thus promote desquamation of the stratum corneum, penetration of allergens, of irritants or of microorganisms, which thus cause dry skin, which may give rise to sensations of discomfort such as tightness or redness, as well as affecting the radiance of the complexion and the flexibility of the skin.
To prevent this phenomenon or correct it, it is known to apply cosmetic or pharmaceutical compositions on the skin, said compositions containing hygroscopic agents, such as sugars or polyols, or urea and lactic acid (components of the NMF, Natural Moisturizer Factor) intended to capture the water present in the skin and thus block its evaporation. Classically, fats have also been used for forming an occlusive film on the skin, such as petroleum jelly, which helps to block the evaporation of water. Moreover, these compositions frequently incorporate active ingredients acting on one or more of the various biological targets involved either in the processes of regeneration of the skin, in particular in the differentiation of the keratinocytes, synthesis of the epidermal lipids and cohesion of the corneocytes, or in the endogenous synthesis of constituents of the natural moisturizer factor (NMF) of the skin, in particular in the synthesis of proteoglycans.
However, there is still a need for new cosmetic or pharmaceutical active ingredients for more effectively combating dry skin, disorders of the barrier function and/or development of fragility of the epidermis.