title: Fibroblast-Derived MMP-14 Regulates Collagen Homeostasis in Adult Skin.
abstract: Proteolytic activities in the extracellular matrix by the matrix metalloproteinase (MMP)-14 have been implicated in the remodeling of collagenous proteins during development. To analyze the function of fibroblast-derived MMP-14 in adult skin homeostasis, we generated mice with inducible deletion of MMP-14 in the dermal fibroblast (MMP-14(Sf-/-)). These mice are smaller and display a fibrosis-like phenotype in the skin. The skin of these mice showed increased stiffness and tensile strength but no altered collagen cross-links. In vivo, we measured a significantly increased amount of collagen type I accumulated in the skin of MMP-14(Sf-/-) mice without an increase in collagen fibril diameters. However, bleomycin-induced fibrosis in skin proceeded in a comparable manner in MMP-14(Sf+/+) and MMP-14(Sf-/-) mice, but resolution over time was impaired in MMP-14(Sf-/-) mice. Increased accumulation of collagen type I was detected in MMP-14(Sf-/-) fibroblasts in culture without significant enhancement of collagen de novo synthesis. This points to a degradative but not synthetic phenotype. In support of this, MMP-14(Sf-/-) fibroblasts lost their ability to process fibrillar collagen type I and to activate proMMP-2. Taken together, these data indicate that MMP-14 expression in fibroblasts plays a crucial role in collagen remodeling in adult skin and largely contributes to dermal homeostasis underlying its pathogenic role in fibrotic skin disease.
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany. Electronic address: Paola.Zigrino@uni-koeln.de.
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
authors.affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany; Institute of Virology and Cell Biology, University of Lübeck, Lübeck, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brinckmann
authors.affiliation: Institute of Biomechanics and Orthopaedics, German Sport University and Cologne Center for Musculoskeletal Biomechanics, University of Cologne, Cologne, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Niehoff
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: Nives
authors.initials: N
authors.lastname: Giebeler
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Eckes
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Kadler
authors.affiliation: Department of Dermatology and Venerology, University of Cologne, Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000737:chemistry; D003094:Collagen / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D020869:Gene Expression Profiling; D006706:Homeostasis; D007249:Inflammation; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013314:Stress, Mechanical; D013718:Tensile Strength; D014945:Wound Healing
chemical_list: C507096:Mmp14 protein, mouse; D001761:Bleomycin; D003094:Collagen; D053511:Matrix Metalloproteinase 14