Estrogen promotes cutaneous wound healing via estrogen receptor β independent of its antiinflammatory activities
Open accessAbstract
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, ERα and ERβ, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERα and ERβ in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERβ actually delayed wound healing. Moreover, healing in epidermal-specific ERβ null mice (K14-cre/ERβL2/L2) largely resembled that in global ERβ null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERβ, in marked contrast to most other tissues in the body where ERα is predominant. Surprisingly, agonists to both ERα and ERβ 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.
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Topical application of estrogens or ER agonists in aged females and males can improve healing, partially due to reduced MIF and activation of keratinocytes.
“Topical application of estrogens or ER agonists in both aged females and males can improve healing, which may be partially due to the reduced expression of macrophage migration inhibitory factor (MIF) and activation of keratinocytes [145–147].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [147]
The Results and Discussion report that an ERβ agonist improved wound repair in estrogen-deprived mice and that estrogen’s beneficial effect is predominantly mediated by epidermal ERβ. The Materials and Methods describe systemic treatment, not topical application; the cited passages do not establish improved healing in aged males or implicate reduced MIF expression. The Abstract also says antiinflammatory activity is not the principal factor in accelerated healing. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredERβ plays a critical role in wound healing.
“ERβ has been shown to play a critical role in wound healing37,38.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [38]
Estrogen promotes wound healing mainly through ERβ, not ERα.
“it has been reported that estrogen promotes wound healing mainly through ERβ, not ERα38.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [38]
ERβ is important in wound healing.
“and so is ERβ37,38 in wound healing”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [38]
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- Authors
- Campbell, L., Emmerson, E., Davies, F., Gilliver, S. C., Krust, A., Chambon, P., Ashcroft, G. S., & Hardman, M. J.
- Affiliations
- University of Manchester (GB)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Hardman, Matthew J.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-08-23
- Volume
- 207
- Issue
- 9
- Pages
- 1825-1833
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2931162
- OpenAlex
- W2098424795
- Cited by
- 175
- References
- 32
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 11 · 2023: 5 · 2022: 11 · 2021: 6 · 2020: 15 · 2019: 12 · 2018: 9 · 2017: 10 · 2016: 12 · 2015: 13 · 2014: 19 · 2013: 7 · 2012: 12
- FWCI
- 8.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Keywords
- estrogen, skin wound healing, estrogen receptor beta, estrogen receptor alpha, epidermis, anti-inflammatory activity, hormone replacement therapy, postmenopausal women, ovariectomy, skin repair
- MeSH terms
- Animals, Cell Movement, Dermatitis, Estrogens, Female, Fibroblasts, Mice, Inbred C57BL, Skin, Wound Healing, Mice, Knockout, Estrogen Receptor alpha, Estrogen Receptor beta, Mice
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