Increased glucocorticoid activation during mouse skin wound healing

Abstract

Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, where de novo steroidogenesis from cholesterol has also been reported. To examine the regulation of 11b-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11b-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11b-HSD1 localizing to infiltrating inflammatory cells. 11b-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11b-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11b-HSD1 activates considerably more corticosterone than is generated de novo from progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11b-HSD1 inhibitors to accelerate wound repair.

The role of nuclear hormone receptors in cutaneous wound repair

“…Thus, it is not surprising that topical application of glucocorticotropic and adrenocorticotropic hormones leads to impaired wound healing in rheumatoid arthritis patients . Furthermore, pharmacological inhibition of 11 β ‐hydroxysteroid dehydrogenase (11 β ‐HSD1), the cortisone reductase that generates active hormone cortisol, was shown to accelerate wound repair based on findings that showed more de novo 11 β ‐HSD1‐derived corticosterone in mouse skin compared with precursor progesterone itself . These results implicate the potential for pharmacological inhibition of 11 β ‐HSD1 to improve tissue injury.…”

The Dehydrogenase Hypothesis

“…11β (Beta)-HSD1 has been shown to have a pivotal role in skin repair following injury [ 88 ] and tissue remodeling [ 85 ]. In mice 11β (Beta)-HSD1 is contributory to impaired wound healing.…”

“…Both isozymes are expressed in blood vessel walls [ 90 ] and heart [ 91 ], however oxo reductase directionality (11β (Beta)-HSD1) predominates in vascular smooth muscle [ 88 ]. There is evidence linking 11β (Beta)-HSD1 activity with atherosclerosis.…”

Wounding alters blood chemistry parameters and skin mineralocorticoid receptors in house sparrows (Passer domesticus)

“…Therefore, if CORT's role in wound‐healing is to help control the inflammation and cell proliferation involved in the healing process, one way to augment hormonal impacts on wounded skin is by increasing receptor concentrations. However, to our knowledge, only one study has examined changes in skin corticosteroid receptors with wounding (Tiganescu et al, ). This study examined GR and MR mRNA expression in laboratory mice, and found decreased MR expression two and four days post‐wounding (Tiganescu et al, ).…”

“…However, to our knowledge, only one study has examined changes in skin corticosteroid receptors with wounding (Tiganescu et al, ). This study examined GR and MR mRNA expression in laboratory mice, and found decreased MR expression two and four days post‐wounding (Tiganescu et al, ). However, because GR and MR mRNA expression and protein expression may not be correlated (Medina et al, ), and because the CORT response can be altered by domestication for laboratory conditions (Kunzl and Sachser, ; Gulevich et al, ), it is unclear whether GR and MR concentrations in the skin of a wild animal might change in response to wounding.…”