A novel actor in skin biology: the mineralocorticoid receptor

The glucocorticoid receptor (GR) is a modulator of skin homoeostasis, and local application of glucocorticoids is common in dermatology. In addition to their beneficial effects, glucocorticoids may induce deleterious side effects such as skin atrophy and delayed wound healing. The mechanisms that underly such undesirable effects remain incompletely understood. Therefore, it deserves more careful scrutiny to which extend these may depend on glucocorticoid activation of the mineralocorticoid receptor (MR), in addition to GR stimulation. The MR is a nuclear receptor sharing structural and functional similarities with the GR. The MR is a classical regulator of renal sodium reabsorption; it also mediates multiple physiological and pathological effects in other tissues as the brain and the cardiovascular system, among others 1. Interestingly, the MR is also expressed in the epidermis, where its role is not fully understood. The first systematic attempt to identify a role for the MR in keratinocytes was through by a conditional mouse model expressing the human MR under the control of a keratinocyte-specific promotor 2 that could be turned on either during embryogenesis (but pups died few days after birth) or after birth. Postnatal induction of MR was associated with severe abnormalities in hair follicle morphogenesis and progressive alopecia. Prenatal induction of the transgene resulted in epidermal atrophy and reduction of the number of hair follicles at birth. This developmental phenotype was close to that presented by mice overexpressing the GR in keratinocytes 3. One key question that arose from these pioneering studies was whether these two receptors were essentially functionally redundant in the epidermis, or whether each exerts some specific roles. On this background, the paper of Boix et al. 4 extends our knowledge on the role of the epidermal MR through analysis of the skin phenotype of mice with MR knockout. This report shows that MR expression in the skin of control mice varies during development, with peak levels at E16.5, and subsequent decrease to very low values after birth and thereafter [at variance to human skin, where strong MR protein expression is seen in adults 5]. Constitutive MR KO embryos exhibit an increased epidermal thickness and abnormal expression of differentiation markers, yet without major alteration in the establishment of epidermal barrier formation and hair follicle density. Noticeably the skin phenotype normalizes a few days after birth, possibly due to compensatory events. No information on postnatal and adult phenotype could be drawn from this mouse model of generalized knockout (mice die within 10 days from renal sodium loss); therefore, use of a keratinocyte-specific MR null mouse model 2 would be most helpful to complete these results. Interestingly, the skin phenotype reported by Boix et al. 4 is at least partially distinct from that of GR knockout mice, which present with delayed epidermal barrier formation (not achieved by MR knockout), while epidermal hypertrophy is observed both in MR- and GR-null embryos 6, 7. MR or GR knockout mice do not show evidence for alterations in the density of hair follicles at birth. Therefore, while epidermal MR and GR seem to have overlapping roles to control keratinocyte growth, they cannot compensate completely for loss of one of these receptors, indicating that they exert as yet undetermined, but specific functions in the epidermis. It should also be noted that there is no strict mirror phenotype when the receptors are overexpressed or functionally invalidated; however, both experimental manoeuvres are useful to dissect specific skin abnormalities. Both GR and MR are ligand-activated transcription factors. Of note, the MR has the same high affinity for cortisol and for its classical ligand aldosterone 8, and glucocorticoid-activated MR is involved in several pathological situations, as glucocorticoid plasma levels are much higher than those of aldosterone (Fig. 1). Cutaneous glucocorticoid availability also depends on local synthesis (de novo synthesis from cholesterol) and on local metabolism: they can be inactivated by the enzyme HSD2 (11 beta hydroxysteroid dehydrogenase type 2) or regenerated from inactive glucocorticoids by the enzyme HSD1 (11 beta hydroxysteroid dehydrogenase type 1) 9. The report of Boix et al. 4 is also interesting in that it shows both enzymes to be expressed at much higher levels during skin development than in adult mouse skin, suggesting that they can modulate intra-cutaneous glucocorticoid concentrations during embryogenesis, thus influencing the activity of MR- and/or GR-dependent signalling. In human epidermis, the activity of HSD1 largely predominates, as the activity of HSD2 is minimal here 10. Noticeably the expression of HSD1 increases with both ageing and UVB exposure, and aged skin presents similarities with glucocorticoid-treated skin. Indeed, HSD1 KO mice are protected from classical skin ageing-related phenomena 9, 11. In a mouse model of skin ageing (UV irradiation and metabolic syndrome), topical MR blockade could improve some features of skin ageing 12. From these observations, it can be proposed that the epidermal MR may be overactivated in some clinical situations of glucocorticoid excess. The cutaneous abnormalities observed in mice overexpressing the MR (epidermal atrophy and progressive alopecia) should draw our attention to the possibility to use topical MR blockers to limit the clinical impact of MR-mediated signalling. We have reported recently that the glucocorticoid-induced epidermal atrophy following 1-month application of the potent glucocorticoid clobetasol to healthy volunteers can be limited by co-application of a pharmacological MR antagonist (spironolactone). In this study, the benefit of adding MR blockers to glucocorticoid-exposed human skin has been confirmed and followed-up in cultured human skin explant experiments. Spironolactone may also interfere with the androgen receptor, but evidence for MR-specific effect was provided by the use of the highly specific MR antagonist eplerenone, which does not interact with other receptors and which highly efficiently restored glucocorticoid-induced impaired keratinocyte proliferation 5. Novel formulations of MR blockers for topical administration, therefore, promise to limit glucocorticoid-induced skin atrophy 5. In conclusion, signalling via the MR deserves to be widely appreciated as an important player in dermato-endocrinology, whose impact in skin pathology remains to be fully characterized 8. NF and VTN wrote the paper. The authors do not have conflict of interest.