title: Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β-catenin nuclear translocation and cross-talk with TGF-β signaling in keratinocytes.
abstract: Orchidectomy in rodents and lower testosterone levels in men are associated with improved cutaneous wound healing. However, due to the adverse effects on skeletal and sexual tissues, systemic androgen blockade is not a viable therapeutic intervention. Accordingly, we tested the hypothesis that topical application of an androgen antagonist would elicit accelerated wound healing without systemic androgen antagonism. Full-thickness cutaneous wounds were created on adult C57BL6/J mice. Daily topical application of androgen receptor antagonist, flutamide, resulted in improved gap closure similar to orchiectomized controls and faster than orchidectomized mice treated with topical testosterone. In vivo data showed that the effects of androgen antagonism on wound closure primarily accelerate keratinocytes migration without effecting wound contraction. Consequently, mechanisms of testosterone action on reepithelialization were investigated in vitro by scratch wounding assays in confluent keratinocytes. Testosterone inhibited keratinocyte migration and this effect was in part mediated through promotion of nuclear translocation of β-catenin and by attenuating transforming growth factor-β (TGF-β) signaling through β-catenin. The link between Wnt and TGF beta signaling was confirmed by blocking β-catenin and by following TGF-β-induced transcription of a luciferase reporter gene. Together, these data show that blockade of β-catenin can, as a potential target for novel therapeutic interventions, accelerate cutaneous wound healing.
authors.affiliation: Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Toraldo
authors.forename: Shalender
authors.initials: S
authors.lastname: Bhasin
authors.forename: Mena
authors.initials: M
authors.lastname: Bakhit
authors.forename: Wen
authors.initials: W
authors.lastname: Guo
authors.forename: Carlo
authors.initials: C
authors.lastname: Serra
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Safer
authors.forename: Jag
authors.initials: J
authors.lastname: Bhawan
authors.forename: Ravi
authors.initials: R
authors.lastname: Jasuja
mesh_terms: D000279:Administration, Cutaneous; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020239:Receptor Cross-Talk / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects / Q000378:metabolism*; D014178:Translocation, Genetic / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000726:Androgen Antagonists; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D005485:Flutamide