Glucocorticoid receptors, epidermal homeostasis and hair follicle differentiation

Glucocorticoids (GCs) exert their biological and therapeutical actions through the GC receptor (GR), a ligand-dependent transcription factor. Synthetic GC derivatives are widely prescribed for treating numerous cutaneous inflammatory and immune diseases due to their great efficacy. However, chronic treatment with GCs produces adverse side-effects including skin atrophy, delayed wound healing, and in certain cases, GC resistance. The mechanisms underlying the therapeutic actions of the GR in skin have been extensively studied; in contrast, the role of GR as a modulator of epidermal development and homeostasis has received less attention. The ubiquitous functional inactivation of GR results in defective epidermal formation although the underlying mechanisms have not been fully characterized. The use of transcriptomic approaches both in vitro and in vivo allowed the identification of genes that are regulated by GR in developing and adult skin. A main goal to understand the role of GR in skin biology is to identify primary transcriptional targets as well as the signaling pathways mediating GR action. Furthermore, it will be important to decipher the contribution of GR in the different cellular compartments of the skin, including keratinocytes of the interfollicular epidermis and hair follicles, and their respective stem cell progenitors. Additionally, recent findings indicating that the skin acts as a true peripheral endocrine organ implies greater complexity than originally thought. The local production of GCs and other steroid hormones should be considered as a modulator of skin function under homeostatic and diseased conditions. Finally, studying GR function in skin should take into account that the mineralocorticoid receptor may also mediate GC actions and/or regulate transcription either by itself or in combination with GR. Addressing these issues should help to elucidate the mechanisms by which Gr contributes to establishment of a competent epidermal barrier and may also have implications in the context of dermatological treatments based on GC-analogs.