title: Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis.
abstract: Matrix metalloproteinase- (MMP-9) is involved in processes that occur during cutaneous wound healing such as inflammation, matrix remodeling, and epithelialization, To investigate its role in healing, full thickness skin wounds were made in the dorsal region of MMP-9-null and control mice and harvested up to 14 days post wounding. Gross examination and histological and immunohistochemical analysis indicated delayed healing in MMP-9-null mice. Specifically, MMP-9-null wounds displayed compromised reepithelialization and reduced clearance of fibrin clots. In addition, they exhibited abnormal matrix deposition, as evidenced by the irregular alignment of immature collagen fibers. Despite the presence of matrix abnormalities, MMP-9-null wounds displayed normal tensile strength. Ultrastructural analysis of wounds revealed the presence of large collagen fibrils, some with irregular shape. Keratinocyte proliferation, inflammation, and angiogenesis were found to be normal in MMP-9-null wounds. In addition, VEGF levels were similar in control and MMP-9-null wound extracts. To investigate the importance of MMP-9 in wound reepithelialization we tested human and murine keratinocytes in a wound migration assay and found that antibody-based blockade of MMP-9 function or MMP-9 deficiency retarded migration. Collectively, our observations reveal defective healing in MMP-9-null mice and suggest that MMP-9 is required for normal progression of wound closure.
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics and Department of Pathology, Yale University, New Haven, CT 06519, United States. themis.kyriakides@yale.edu
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
authors.forename: Drausin
authors.initials: D
authors.lastname: Wulsin
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Skokos
authors.forename: Philip
authors.initials: P
authors.lastname: Fleckman
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pirrone
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
authors.forename: Paul
authors.initials: P
authors.lastname: Bornstein
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D003094:Collagen / Q000378:metabolism* / Q000502:physiology; D004848:Epithelium / Q000254:growth & development; D005109:Extracellular Matrix / Q000378:metabolism* / Q000502:physiology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D012867:Skin / Q000293:injuries*; D013718:Tensile Strength; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D005337:Fibrin; D003094:Collagen; D020780:Matrix Metalloproteinase 9