title: 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.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Tiganescu
authors.forename: Abd A
authors.initials: AA
authors.lastname: Tahrani
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.forename: Marcela
authors.initials: M
authors.lastname: Otranto
authors.forename: Alexis
authors.initials: A
authors.lastname: Desmoulière
authors.forename: Lianne
authors.initials: L
authors.lastname: Abrahams
authors.forename: Zaki
authors.initials: Z
authors.lastname: Hassan-Smith
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walker
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Rabbitt
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cooper
authors.forename: Kurt
authors.initials: K
authors.lastname: Amrein
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D015870:Gene Expression; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D061251:Primary Cell Culture; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D014945:Wound Healing; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D003094:Collagen; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1