11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

Abstract

Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11β-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing.

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

“…A reduction in skin thickness is a well-established side effect of GC excess, and we have previously shown 11β-HSD1 to play a central role in age-associated skin thinning (18). CORT dramatically reduced skin thickness in WT mice (Fig.…”

“…Preclinical and clinical studies have shown selective 11β-HSD1 inhibitors to improve insulin sensitivity, reduce dyslipidemia, and reverse central obesity in patients with type 2 diabetes (12,13). Furthermore, we have recently demonstrated that 11β-HSD1 blockade prevents age-and photosensitivity-induced skin structure and function defects (18). Although these compounds are still being evaluated clinically, their potential to block the adverse side-effect profile associated with GC excess is an exciting prospect.…”

“…6B). This was accompanied by decreased expression of a number of genes involved in collagen biosynthesis and processing that we have shown to be GC-regulated in skin (18), including collagen 1 (col1a1) (the major structural component of the dermis) (Fig. 6C), prolyl hydroxylase (leprel1), and lysyl hydroxylase (PLOD1) (both catalyze the hydroxylation of collagen at proline and lysine residues, respectively, a key step in collagen cross-linking) (Fig.…”

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

“…11βHSD1 deficiency is also associated with enhanced angiogenesis in ischaemic tissues, resulting, for example, in improved left ventricular function following myocardial infarction in mice and potentially improving wound healing [97,98], a common problem in diabetes. Increased 11βHSD1 activity in ageing human fibroblasts leads to skin ageing and impaired wound healing, and topical application of an 11βHSD1 inhibitor improves wound healing in humans [99,100].…”

091 Epidermal mineralocorticoid receptor plays beneficial and adverse effects in skin and mediates glucocorticoid responses

“…It is also widely recognized that epidermal keratinocytes are able to synthesize GCs in response to wounding; consistently, local blockade of GC production using inhibitors of 11b-hydroxysteroid dehydrogenase type 1 accelerated wound healing (Vukelic et al, 2011;Tiganescu et al, 2013;Youm et al, 2013, Slominsky et al, 2014). …”