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. 2013 Jul;123(7):3051-60.
doi: 10.1172/JCI64162. Epub 2013 Jun 3.

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

Ana Tiganescu  1 , Abd A Tahrani, Stuart A Morgan, Marcela Otranto, Alexis Desmoulière, Lianne Abrahams, Zaki Hassan-Smith, Elizabeth A Walker, Elizabeth H Rabbitt, Mark S Cooper, Kurt Amrein, Gareth G Lavery, Paul M Stewart
Affiliations

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

Ana Tiganescu et al. J Clin Invest. 2013 Jul.

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.

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Figures

Figure 1
Figure 1. 11β-HSD1 activity increases in aging skin ex vivo.
(A) 11β-HSD1 activity (percentage of conversion of 100 nM cortisone to cortisol) was greater in aged (>60 years) versus young (20–30 years) human skin in both PP (n = 20) and PE (n = 20) biopsies. Activity was also greater in donor-matched PE versus PP samples from young (n = 20) and aged (n = 20) donors. (B) 11β-HSD1 activity (pmol/mg/h) was also greater in older (91–99 weeks; n = 5) versus younger (11–20 weeks; n = 10) mouse skin. *P < 0.05; **P < 0.01.
Figure 2
Figure 2. 11β-HSD1 expression increases in PE skin.
11β-HSD1 staining was increased in epidermal keratinocytes (asterisk) and dermal fibroblasts (arrows) in PE sections (B) relative to donor-matched PP (A) sections (n = 14). Original magnification, ×20. (C) Quantification of tissue staining confirmed elevated dermal and epidermal 11β-HSD1 protein expression (fold change in PE relative to PP sections; n = 14). Endogenous epidermal melanin was used as a positive control and showed the expected increased staining in PE versus PP samples (n = 18). *P < 0.05; **P < 0.01.
Figure 3
Figure 3. Reversal of dermal atrophy in aged 11β-HSD1–null mice.
(A) Comparison of young and aged WT skin sections (n = 4) revealed a grossly altered dermal organization of collagen in the latter, with a loss of structure and tissue integrity (arrows). (B) 11β-HSD1 activity (n = 15) and mRNA (n = 6) were negligible in 11β-HSD1–null mouse skin compared with WT littermates (n = 3). (C) Aged KO mice displayed a striking improvement in dermal structural organization compared with their WT littermates, reverting to a phenotype more comparable to young mice. AT = adipose tissue. Scale bars: 50 μM. ***P < 0.001.
Figure 4
Figure 4. Improved collagen density in aged 11β-HSD1–null mice.
Collagen staining intensity appeared greater in aged KO (B) versus WT (A) mouse skin sections, contributing to the improved structural appearance in these mice. (C) Quantification of staining confirmed an increased collagen density in aged KO versus WT mice (n = 4), with a similar trend in young mice (n = 4). Scale bars: 50 μM. *P < 0.05.
Figure 5
Figure 5. Improved collagen synthesis gene expression in aged 11β-HSD1–null mice.
(A) Expression of the prolyl hydroxylase LEPREL1 decreased in the aged WT mice (n = 3) relative to the younger animals (n = 5). This was reversed in the aged KO mice (n = 4). (B) Similarly, the age-induced decrease in lysyl hydroxylase PLOD1 expression was partially rescued in aged KO mice. (C) TIMP4 expression was also reduced in aged WT, but not KO, mice relative to young WT mice. (D) COL1A1 expression was unaltered with age or genotype. (E and F) An age-induced decrease in MMP2 and MMP3 was also observed but was unaffected by genotype. *P < 0.05; **P < 0.01; ***P < 0.001. NS, nonsignificant.
Figure 6
Figure 6. Accelerated wound healing in 11β-HSD1 inhibitor–treated mice.
(A) Representative images showing improved wound closure in mice treated every 2–3 days with 1% RO151. (B) Accelerated re-epithelialization was recorded at each time point measured (n = 5–12). *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 7
Figure 7. Accelerated healing in aged 11β-HSD1 KO mice.
(A) Representative images showing accelerated wound closure in aged 11β-HSD1 KO mice. (B) Increased healing was observed at 4 days, with a similar trend at 2 days (n = 6). *P < 0.05.
Figure 8
Figure 8. GC treatment impairs multiple elements of collagen biosynthesis and processing.
GC treatment of primary HDFs decreased collagen transcription (1) and altered collagen metabolizing enzymes (7) as previously shown. We found additional GC _targets, including reduced expression of collagen posttranslational hydroxylation enzymes (3), collagen chaperone (4), and all lysyl oxidase enzyme isoforms required for collagen inter- and intrafibril cross-link formation (6).
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