title: Matrix metalloproteinase (MMP)-19-deficient fibroblasts display a profibrotic phenotype.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive and usually lethal interstitial lung disease of unknown etiology characterized by aberrant activation of epithelial cells that induce the migration, proliferation and activation of fibroblasts. The resulting distinctive fibroblastic/myofibroblastic foci are responsible for the excessive extracellular matrix (ECM) production and abnormal lung remodeling. We have recently found that matrix metalloproteinase 19 (MMP-19)-deficient (Mmp19-/-) mice develop an exaggerated bleomycin-induced lung fibrosis, but the mechanisms are unclear. In this study, we explored the effect of MMP-19 deficiency on fibroblast gene expression and cell behavior. Microarray analysis of Mmp19-/- lung fibroblasts revealed the dysregulation of several profibrotic pathways, including ECM formation, migration, proliferation, and autophagy. Functional studies confirmed these findings. Compared with wild-type mice, Mmp19-/- lung fibroblasts showed increased α1 (I) collagen gene and collagen protein production at baseline and after transforming growth factor-β treatment and increased smooth muscle-α actin expression (P < 0.05). Likewise, Mmp19-deficient lung fibroblasts showed a significant increase in proliferation (P < 0.01) and in transmigration and locomotion over Boyden chambers coated with type I collagen or with Matrigel (P < 0.05). These findings suggest that, in lung fibroblasts, MMP-19 has strong regulatory effects on the synthesis of key ECM components, on fibroblast to myofibroblast differentiation, and in migration and proliferation.
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico;
authors.forename: Paul
authors.initials: P
authors.lastname: Jara
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico;
authors.forename: Jazmin
authors.initials: J
authors.lastname: Calyeca
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico;
authors.forename: Yair
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico;
authors.forename: Luis
authors.initials: L
authors.lastname: Plácido
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Guoying
authors.initials: G
authors.lastname: Yu
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut;
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, Mexico;
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Cisneros
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico; apardos@unam.mx.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D053505:Matrix Metalloproteinases, Secreted / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000201:enzymology* / Q000473:pathology; D024041:Non-Fibrillar Collagens / Q000096:biosynthesis / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D053505:Matrix Metalloproteinases, Secreted; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII; C108362:matrix metalloproteinase 19
keywords: collagen; fibroblasts; lung fibrosis; matrix metalloproteinase