Loss of MT1-MMP causes cell senescence and nuclear defects which can be reversed by retinoic acid
Open accessAbstract
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.
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Senescence activation depends on the interaction of cells with ligands in the ECM.
“Senescence activation is governed by intracellular and extracellular signals and highly depends on the interaction of the cells with ligands in the ECM”
From Integrin Beta 3 Regulates Cellular Senescence by Activating the TGF-β Pathway (2017) · cites this paper as Gutiérrez-Fernández et al., 2015
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- Authors
- Gutiérrez‐Fernández, A., Soria‐Valles, C., Osorio, F. G., Gutiérrez‐Abril, J., Garabaya, C., Aguirre, A., Fueyo, A., Fernández‐García, M. S., Puente, X. S., & López‐Otín, C.
- Affiliations
- Universidad de Oviedo (ES)
- Hospital Universitario Central de Asturias (ES)
- Venue
- The EMBO Journal
- Published
- 2015-05-19
- Volume
- 34
- Issue
- 14
- Pages
- 1875-1888
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4547893
- OpenAlex
- W2160641789
- Cited by
- 96
- References
- 66
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 12 · 2023: 9 · 2022: 13 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 9 · 2017: 9 · 2016: 8 · 2015: 1
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
- Funders
- MINECO
- RTICC
- Obra Social Cajastur‐Asturias
- Investigator of the Botin Foundation
- Santander Universities Global Division
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- MT1-MMP, MMP-14, collagenolytic protease, cellular senescence, nuclear lamina, retinoic acid, extracellular matrix remodeling, premature aging, p16INK4a, p21, senescence-associated secretory phenotype, cardiac defects, bone abnormalities, dwarfism, cytoskeleton, nuclear stiffness
- MeSH terms
- Adipose Tissue, Animals, Blood Glucose, Extracellular Matrix, Humans, Hypoglycemia, Longevity, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Envelope, Tretinoin, Cellular Senescence, Mice, Knockout, Myocytes, Cardiac, Matrix Metalloproteinase 14, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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