title: Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin.
abstract: Aged human skin is fragile because of fragmentation and loss of type I collagen fibrils, which confer strength and resiliency. We report here that dermal fibroblasts express increased levels of collagen-degrading matrix metalloproteinases-1 (MMP-1) in aged (>80 years old) compared with young (21 to 30 years old) human skin in vivo. Transcription factor AP-1 and alpha2beta1 integrin, which are key regulators of MMP-1 expression, are also elevated in fibroblasts in aged human skin in vivo. MMP-1 treatment of young skin in organ culture causes fragmentation of collagen fibrils and reduces fibroblast stretch, consistent with reduced mechanical tension, as observed in aged human skin. Limited fragmentation of three-dimensional collagen lattices with exogenous MMP-1 also reduces fibroblast stretch and mechanical tension. Furthermore, fibroblasts cultured in fragmented collagen lattices express elevated levels of MMP-1, AP-1, and alpha2beta1 integrin. Importantly, culture in fragmented collagen raises intracellular oxidant levels and treatment with antioxidant MitoQ(10) significantly reduces MMP-1 expression. These data identify positive feedback regulation that couples age-dependent MMP-1-catalyzed collagen fragmentation and oxidative stress. We propose that this self perpetuating cycle promotes human skin aging. These data extend the current understanding of the oxidative theory of aging beyond a cellular-centric view to include extracellular matrix and the critical role that connective tissue microenvironment plays in the biology of aging.
authors.affiliation: Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan 48109-5609, USA. gjfisher@umich.edu
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.forename: Trupta
authors.initials: T
authors.lastname: Purohit
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shao
authors.forename: Moon Kyun
authors.initials: MK
authors.lastname: Cho
authors.forename: Tianyuan
authors.initials: T
authors.lastname: He
authors.forename: James
authors.initials: J
authors.lastname: Varani
authors.forename: Sewon
authors.initials: S
authors.lastname: Kang
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000328:Adult; D000367:Age Factors; D000369:Aged, 80 and over; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D024042:Collagen Type I / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D038982:Integrin alpha2beta1 / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D042282:Microdissection; D009924:Organ Culture Techniques; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015595:Skin Aging / Q000473:pathology / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000975:Antioxidants; D024042:Collagen Type I; D038982:Integrin alpha2beta1; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D020781:Matrix Metalloproteinase 1