title: 17beta-estradiol inhibits wound healing in male mice via estrogen receptor-alpha.
abstract: Although estrogens have long been known to accelerate healing in females, their roles in males remain to be established. To address this, we have investigated the influence of 17beta-estradiol on acute wound repair in castrated male mice. We report that sustained exposure to estrogen markedly delays wound re-epithelialization. Our use of hairless mice revealed this response to be largely independent of hair follicle cycling, whereas other studies demonstrated that estrogen minimally influences wound inflammation in males. Additionally, we report reduced collagen accumulation and increased gelatinase activities in the wounds of estrogen-treated mice. Increased wound matrix metalloproteinase (MMP)-2 activity in these animals may i) contribute to their inability to heal skin wounds optimally and ii) stem, at least in part, from effects on the overall levels and spatial distribution of membrane-type 1-MMP and tissue inhibitor of MMP (TIMP)-3, which respectively facilitate and prevent MMP-2 activation. Using mice rendered null for either the alpha or beta isoform of the estrogen receptor, we identified estrogen receptor-alpha as the likely effector of estrogen's inhibitory effects on healing.
authors.affiliation: Faculty of Life Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gilliver
authors.forename: Elaine
authors.initials: E
authors.lastname: Emmerson
authors.forename: Laura
authors.initials: L
authors.lastname: Campbell
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hardman
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D002369:Castration; D004789:Enzyme Activation; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D010052:Ovariectomy; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D047628:Estrogen Receptor alpha; D061965:Matrix Metalloproteinase Inhibitors; D004958:Estradiol; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14
references.citation: J Investig Dermatol Symp Proc. 2003 Jun;8(1):100-3
references.pmid: 12895004
references.citation: Br J Dermatol. 2001 Nov;145(5):854-5
references.pmid: 11736924
references.citation: Nat Med. 1997 Nov;3(11):1209-15
references.pmid: 9359694
references.citation: Genome Biol. 2008;9(5):R80
references.pmid: 18477406
references.citation: J Invest Dermatol. 1993 Jul;101(1):64-8
references.pmid: 8392530
references.citation: Mol Endocrinol. 2004 Jun;18(6):1411-27
references.pmid: 15001666
references.citation: Wound Repair Regen. 2009 Jan-Feb;17(1):42-50
references.pmid: 19152650
references.citation: J Invest Dermatol. 2005 Jun;124(6):1149-61
references.pmid: 15955089
references.citation: J Clin Endocrinol Metab. 1991 Nov;73(5):1016-25
references.pmid: 1719016
references.citation: J Clin Invest. 2002 Sep;110(5):615-24
references.pmid: 12208862
references.citation: J Pathol. 2009 Jan;217(1):73-82
references.pmid: 18855875
references.citation: J Invest Dermatol. 1999 Jun;112(6):971-6
references.pmid: 10383747
references.citation: Endocr Rev. 2006 Oct;27(6):677-706
references.pmid: 16877675
references.citation: J Immunol. 2001 Dec 1;167(11):6533-44
references.pmid: 11714822
references.citation: J Am Acad Dermatol. 2005 Oct;53(4):555-68; quiz 569-72
references.pmid: 16198774
references.citation: J Invest Dermatol. 2008 May;128(5):1311-8
references.pmid: 18037901
references.citation: J Cell Biol. 1997 Apr 7;137(1):67-77
references.pmid: 9105037
references.citation: Endocrinology. 2008 Feb;149(2):551-7
references.pmid: 17974625
references.citation: J Cutan Pathol. 1992 Aug;19(4):309-14
references.pmid: 1430470
references.citation: Endocrinology. 2008 Nov;149(11):5747-57
references.pmid: 18653719
references.citation: Mol Cell Biochem. 2005 Jan;269(1-2):209-16
references.pmid: 15786734
references.citation: Biochem J. 1992 May 1;283 ( Pt 3):637-41
references.pmid: 1317162
references.citation: J Clin Invest. 2003 May;111(9):1309-18
references.pmid: 12727922
references.citation: J Invest Dermatol. 2002 Nov;119(5):1053-8
references.pmid: 12445192
references.citation: Acta Derm Venereol Suppl (Stockh). 2000;210:3-17
references.pmid: 10884942
references.citation: Am J Physiol Renal Physiol. 2002 Jan;282(1):F164-9
references.pmid: 11739124
references.citation: J Clin Endocrinol Metab. 2002 Feb;87(2):589-98
references.pmid: 11836290
references.citation: Anal Biochem. 1980 Feb;102(1):196-202
references.pmid: 7188842
references.citation: Biochim Biophys Acta. 1998 Mar 5;1406(2):169-74
references.pmid: 9573355
references.citation: J Cell Sci. 2006 Feb 15;119(Pt 4):722-32
references.pmid: 16449322
references.citation: J Burn Care Rehabil. 2000 Sep-Oct;21(5):395-402
references.pmid: 11020045
references.citation: J Exp Med. 2003 Jun 2;197(11):1467-76
references.pmid: 12782713
references.citation: FEBS Lett. 1996 May 6;385(3):238-40
references.pmid: 8647259
references.citation: Exp Cell Res. 1974 May;86(1):95-105
references.pmid: 4857507
references.citation: Am J Pathol. 2005 Dec;167(6):1561-74
references.pmid: 16314470
references.citation: Hum Pathol. 1999 Jul;30(7):795-802
references.pmid: 10414498
references.citation: J Biol Chem. 2006 Apr 14;281(15):10337-46
references.pmid: 16469749
references.citation: Lab Invest. 2007 Sep;87(9):871-81
references.pmid: 17607299
references.citation: Cell Tissue Res. 1997 Dec;290(3):581-91
references.pmid: 9369533
references.citation: Am J Pathol. 1999 Oct;155(4):1137-46
references.pmid: 10514397
references.citation: Histochem J. 1979 Jul;11(4):447-55
references.pmid: 91593
references.citation: Endocrinology. 2009 Jun;150(6):2749-57
references.pmid: 19196797
references.citation: J Pathol. 1997 Sep;183(1):80-9
references.pmid: 9370952
references.citation: Development. 2000 Oct;127(19):4277-91
references.pmid: 10976058