title: Pulmonary fibroblasts mobilize the membrane-tethered matrix metalloprotease, MT1-MMP, to destructively remodel and invade interstitial type I collagen barriers.
abstract: In acute and chronic lung disease, widespread disruption of tissue architecture underlies compromised pulmonary function. Pulmonary fibroblasts have been implicated as critical effectors of tissue-destructive extracellular matrix (ECM) remodeling by mobilizing a spectrum of proteolytic enzymes. Although efforts to date have focused on the catabolism of type I collagen, the predominant component of the lung interstitial matrix, the key collagenolytic enzymes employed by pulmonary fibroblasts remain unidentified. Herein, membrane type-1 matrix metalloprotease (MT1-MMP) is identified as the dominant and direct-acting protease responsible for the type I collagenolytic activity mediated by both mouse and human pulmonary fibroblasts. Furthermore, MT1-MMP is shown to be essential for pulmonary fibroblast migration within three-dimensional (3-D) hydrogels of cross-linked type I collagen that recapitulate ECM barriers encountered in the in vivo environment. Together, these findings demonstrate that MT1-MMP serves as a key effector of type I collagenolytic activity in pulmonary fibroblasts and earmark this pericellular collagenase as a potential target for therapeutic intervention.
authors.affiliation: Divisions of Molecular Medicine & Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.forename: Daniel
authors.initials: D
authors.lastname: Keena
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Willis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D002908:Chronic Disease; D024042:Collagen Type I; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D020100:Hydrogels; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D061251:Primary Cell Culture; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D024042:Collagen Type I; D020100:Hydrogels; C507096:Mmp14 protein, mouse; D034741:RNA, Small Interfering; D020781:Matrix Metalloproteinase 1; C425310:Mmp1a protein, mouse; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14