Estrogen promotes cutaneous wound healing via estrogen receptor beta independent of its antiinflammatory activities.
Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type-specific role of the two estrogen receptors, ERalpha and ERbeta, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERalpha and ERbeta in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERbeta actually delayed wound healing. Moreover, healing in epidermal-specific ERbeta null mice (K14-cre/ERbeta(L2/L2)) largely resembled that in global ERbeta null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERbeta, in marked contrast to most other tissues in the body where ERalpha is predominant. Surprisingly, agonists to both ERalpha and ERbeta are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing.
Campbell
Laura
L
Faculty of Life Sciences, University of Manchester, Manchester, England, UK.
Emmerson
Elaine
E
Davies
Faith
F
Gilliver
Stephen C
SC
Krust
Andre
A
Chambon
Pierre
P
Ashcroft
Gillian S
GS
Hardman
Matthew J
MJ
D000818:Animals; D002465:Cell Movement; D003872:Dermatitis / Q000378:metabolism* / Q000473:pathology*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000172:deficiency / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012867:Skin / Q000293:injuries / Q000378:metabolism*; D014945:Wound Healing
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens