title: Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid.
abstract: MT1-MMP (MMP14) is a collagenolytic enzyme located at the cell surface and implicated in extracellular matrix (ECM) remodeling. Mmp14(-/-) mice present dwarfism, bone abnormalities, and premature death. We demonstrate herein that the loss of MT1-MMP also causes cardiac defects and severe metabolic changes, and alters the cytoskeleton and the nuclear lamina structure. Moreover, the absence of MT1-MMP induces a senescent phenotype characterized by up-regulation of p16(INK4a) and p21(CIP1/WAF) (1), increased activity of senescence-associated β-galactosidase, generation of a senescence-associated secretory phenotype, and somatotroph axis alterations. Consistent with the role of retinoic acid signaling in nuclear lamina stabilization, treatment of Mmp14(-/-) mice with all-trans retinoic acid reversed the nuclear lamina alterations, partially rescued the cell senescence phenotypes, ameliorated the pathological defects in bone, skin, and heart, and extended their life span. These results demonstrate that nuclear architecture and cell senescence can be modulated by a membrane protease, in a process involving the ECM as a key regulator of nuclear stiffness under cell stress conditions.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Soria-Valles
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Osorio
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gutiérrez-Abril
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garabaya
authors.affiliation: Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Alina
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fueyo
authors.affiliation: Servicio de Anatomía Patológica, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: María Soledad
authors.initials: MS
authors.lastname: Fernández-García
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain.
authors.forename: Xose S
authors.initials: XS
authors.lastname: Puente
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA) Universidad de Oviedo, Oviedo, Spain clo@uniovi.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism; D008136:Longevity / Q000187:drug effects; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009685:Nuclear Envelope / Q000235:genetics / Q000648:ultrastructure; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; C507096:Mmp14 protein, mouse; D014212:Tretinoin; D053511:Matrix Metalloproteinase 14
keywords: aging; extracellular matrix; metalloprotease; nuclear lamina; retinoids