title: Tumor necrosis factor-α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase (MMP)-1 and MMP-3 ex vivo.
abstract: Tumor necrosis factor (TNF)-α induces matrix metalloproteinases (MMPs) that may disrupt skin integrity. We have investigated the effects and mechanisms of exogenous TNF-α on collagen degradation by incubating human skin explants in defined serum-free media with or without TNF-α (10ng/ml) in the absence or presence of the nonselective MMP inhibitor GM6001 for 8 days. The basal culture conditions promoted type I collagen catabolism that was accelerated by TNF-α (p<0.005) and accomplished by MMPs (p<0.005). Levels of the collagenases MMP-8 and MMP-13 were insignificant and neither MMP-2 nor MMP-14 were associated with increased collagen degradation. TNF-α increased secretion of MMP-1 (p<0.01) but had no impact on MMP-1 quantities in the tissue. Immunohistochemical analysis confirmed similar tissue MMP-1 expression with or without TNF-α with epidermis being the major source of MMP-1. Increased tissue-derived collagenolytic activity with TNF-α exposure was blocked by neutralizing MMP-1 monoclonal antibody and was not due to down-regulation of tissue inhibitor of metalloproteinase-1. TNF-α increased production (p<0.01), tissue levels (p<0.005) and catalytic activity of the endogenous MMP-1 activator MMP-3. Type I collagen degradation correlated with MMP-3 tissue levels (rs=0.68, p<0.05) and was attenuated with selective MMP-3 inhibitor. Type I collagen formation was down-regulated in cultured compared with native skin explants but was not reduced further by TNF-α. TNF-α had no significant effect on epidermal apoptosis. Our data indicate that TNF-α augments collagenolytic activity of MMP-1, possibly through up-regulation of MMP-3 leading to gradual loss of type I collagen in human skin.
authors.affiliation: Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: saag0005@regionh.dk.
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Ågren
authors.affiliation: Department of Plastic, Hand- and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Schnabel
authors.affiliation: Department of Pathology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lise H
authors.initials: LH
authors.lastname: Christensen
authors.affiliation: Department of Plastic, Reconstructive and Aesthetic Surgery, Klinikum Bremen-Mitte, Bremen, Germany; Centre for Biomolecular Interactions, University of Bremen, Bremen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Mirastschijski
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D008875:Middle Aged; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D024042:Collagen Type I; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: Aging; C-terminal telopeptide of type I collagen; Cytokine; Extracellular matrix proteins; Protease inhibitors; Type I C-terminal collagen propeptide; UK370106