title: Expression of catalytically active matrix metalloproteinase-1 in dermal fibroblasts induces collagen fragmentation and functional alterations that resemble aged human skin.
abstract: Increased expression of matrix metalloproteinase-1 (MMP-1) and reduced production of type I collagen by dermal fibroblasts are prominent features of aged human skin. We have proposed that MMP-1-mediated collagen fibril fragmentation is a key driver of age-related decline of skin function. To investigate this hypothesis, we constructed, characterized, and expressed constitutively active MMP-1 mutant (MMP-1 V94G) in adult human skin in organ culture and fibroblasts in three-dimensional collagen lattice cultures. Expression of MMP-1 V94G in young skin in organ culture caused fragmentation and ultrastructural alterations of collagen fibrils similar to those observed in aged human skin in vivo. Expression of MMP-1 V94G in dermal fibroblasts cultured in three-dimensional collagen lattices caused substantial collagen fragmentation, which was markedly reduced by MMP-1 siRNA-mediated knockdown or MMP inhibitor MMI270. Importantly, fibroblasts cultured in MMP-1 V94G-fragmented collagen lattices displayed many alterations observed in fibroblasts in aged human skin, including reduced cytoplasmic area, disassembled actin cytoskeleton, impaired TGF-β pathway, and reduced collagen production. These results support the concept that MMP-1-mediated fragmentation of dermal collagen fibrils alters the morphology and function of dermal fibroblasts and provide a foundation for understanding specific mechanisms that link collagen fibril fragmentation to age-related decline of fibroblast function.
authors.affiliation: Department of Dermatology, University of Michigan, 1301 E Catherine, R6447 Med Sci I, Ann Arbor, MI 48109-5609, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xia
authors.forename: Craig
authors.initials: C
authors.lastname: Hammerberg
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Tianyuan
authors.initials: T
authors.lastname: He
authors.forename: Taihao
authors.initials: T
authors.lastname: Quan
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Fisher
mesh_terms: D000199:Actins / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000369:Aged, 80 and over; D048430:Cell Shape; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015595:Skin Aging; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature; D013997:Time Factors; D014162:Transfection; D055815:Young Adult
chemical_list: D000199:Actins; C097658:CGS 27023A; D024042:Collagen Type I; D006877:Hydroxamic Acids; D011719:Pyrazines; D034741:RNA, Small Interfering; D013449:Sulfonamides; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: aging; extracellular matrix; matrix metalloproteinase; molecular biology of aging