title: Pharmacological activation of estrogen receptors-α and -β differentially modulates keratinocyte differentiation with functional impact on wound healing.
abstract: Estrogen deprivation is considered responsible for many age-related processes, including poor wound healing. Guided by previous observations that estradiol accelerates re‑epithelialization through estrogen receptor (ER)‑β, in the present study, we examined whether selective ER agonists [4,4',4''-(4-propyl [1H] pyrazole-1,3,5-triyl)‑trisphenol (PPT), ER‑α agonist; 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), ER‑β agonist] affect the expression of basic proliferation and differentiation markers (Ki‑67, keratin‑10, ‑14 and ‑19, galectin‑1 and Sox‑2) of keratinocytes using HaCaT cells. In parallel, ovariectomized rats were treated daily with an ER modulator, and wound tissue was removed 21 days after wounding and routinely processed for basic histological analysis. Our results revealed that the HaCaT keratinocytes expressed both ER‑α and ‑β, and thus are well-suited for studying the effects of ER agonists on epidermal regeneration. The activation of ER‑α produced a protein expression pattern similar to that observed in the control culture, with a moderate expression of Ki‑67 being observed. However, the activation of ER‑β led to an increase in cell proliferation and keratin‑19 expression, as well as a decrease in galectin‑1 expression. Fittingly, in rat wounds treated with the ER‑β agonist (DPN), epidermal regeneration was accelerated. In the present study, we provide information on the mechanisms through which estrogens affect the expression patterns of selected markers, thus modulating keratinocyte proliferation and differentiation; in addition, we demonstrate that the pharmacological activation of ER-α and -β has a direct impact on wound healing.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, Košice, Slovak Republic.
authors.forename: Vlasta
authors.initials: V
authors.lastname: Peržeľová
authors.affiliation: Department of Heart Surgery, East‑Slovak Institute of Cardiovascular Diseases and Pavol Jozef Šafárik University, Košice, Slovak Republic.
authors.forename: František
authors.initials: F
authors.lastname: Sabol
authors.affiliation: Department of Surgery, Košice‑Šaca Hospital and Pavol Jozef Šafárik University, Košice, Slovak Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Vasilenko
authors.affiliation: Department for Biomedical Research, East‑Slovak Institute of Cardiovascular Diseases, Košice, Slovak Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Novotný
authors.affiliation: Department for Biomedical Research, East‑Slovak Institute of Cardiovascular Diseases, Košice, Slovak Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Kováč
authors.affiliation: Department for Biomedical Research, East‑Slovak Institute of Cardiovascular Diseases, Košice, Slovak Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Slezák
authors.affiliation: Department for Biomedical Research, East‑Slovak Institute of Cardiovascular Diseases, Košice, Slovak Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Ďurkáč
authors.affiliation: Department for Biomedical Research, East‑Slovak Institute of Cardiovascular Diseases, Košice, Slovak Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hollý
authors.affiliation: Department of Pathological Anatomy and Physiology, University of Veterinary Medicine and Pharmacy, Košice, Slovak Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Pilátová
authors.affiliation: Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Szabo
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, Košice, Slovak Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Varinská
authors.affiliation: Department of Pathological Anatomy and Physiology, University of Veterinary Medicine and Pharmacy, Košice, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Čriepoková
authors.affiliation: Institute of Histology and Embryology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Kučera
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig‑Maximilians‑University Munich, Munich, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Kaltner
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig‑Maximilians‑University Munich, Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: André
authors.affiliation: Institute of Physiological Chemistry, Faculty of Veterinary Medicine, Ludwig‑Maximilians‑University Munich, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Gabius
authors.affiliation: Department of Pharmacognosy and Botany, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Mučaji
authors.affiliation: Institute of Anatomy, First Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Smetana
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, Košice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Gál
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*; D011422:Propionates
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol