title: Secreted versus membrane-anchored collagenases: relative roles in fibroblast-dependent collagenolysis and invasion.
abstract: Fibroblasts degrade type I collagen, the major extracellular protein found in mammals, during events ranging from bulk tissue resorption to invasion through the three-dimensional extracellular matrix. Current evidence suggests that type I collagenolysis is mediated by secreted as well as membrane-anchored members of the matrix metalloproteinase (MMP) gene family. However, the roles played by these multiple and possibly redundant, degradative systems during fibroblast-mediated matrix remodeling is undefined. Herein, we use fibroblasts isolated from Mmp13(-/-), Mmp8(-/-), Mmp2(-/-), Mmp9(-/-), Mmp14(-/-) and Mmp16(-/-) mice to define the functional roles for secreted and membrane-anchored collagenases during collagen-resorptive versus collagen-invasive events. In the presence of a functional plasminogen activator-plasminogen axis, secreted collagenases arm cells with a redundant collagenolytic potential that allows fibroblasts harboring single deficiencies for either MMP-13, MMP-8, MMP-2, or MMP-9 to continue to degrade collagen comparably to wild-type fibroblasts. Likewise, Mmp14(-/-) or Mmp16(-/-) fibroblasts retain near-normal collagenolytic activity in the presence of plasminogen via the mobilization of secreted collagenases, but only Mmp14 (MT1-MMP) plays a required role in the collagenolytic processes that support fibroblast invasive activity. Furthermore, by artificially tethering a secreted collagenase to the surface of Mmp14(-/-) fibroblasts, we demonstrate that localized pericellular collagenolytic activity differentiates the collagen-invasive phenotype from bulk collagen degradation. Hence, whereas secreted collagenases arm fibroblasts with potent matrix-resorptive activity, only MT1-MMP confers the focal collagenolytic activity necessary for supporting the tissue-invasive phenotype.
authors: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Farideh
authors: F
authors: Sabeh
authors: Xiao-Yan
authors: XY
authors: Li
authors: Thomas L
authors: TL
authors: Saunders
authors: R Grant
authors: RG
authors: Rowe
authors: Stephen J
authors: SJ
authors: Weiss
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D017364:Collagenases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000502:physiology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology; D053513:Matrix Metalloproteinase 16 / Q000235:genetics / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010958:Plasminogen / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000502:physiology
chemical_list: D024042:Collagen Type I; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D011480:Protease Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D019716:Tissue Inhibitor of Metalloproteinase-2; D000077214:Becaplermin; D010958:Plasminogen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D053513:Matrix Metalloproteinase 16; D020778:Matrix Metalloproteinase 2; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14