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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 p16INK4a and p21CIP1/WAF1, 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. Synopsis Alterations in the extracellular matrix caused by loss of protease MT1-MMP lead to cellular senescence, nuclear lamina abnormalities, and features of premature ageing that can be rescued by treatment with retinoic acid. Loss of MT1-MMP metalloprotease activity induces a cellular senescence phenotype. Deficient remodeling of the extracellular matrix alters the cytoskeleton and nuclear structure. All-trans retinoic acid treatment ameliorates the cellular senescence process. Alterations in the extracellular matrix caused by loss of protease MT1-MMP lead to cellular senescence, nuclear lamina abnormalities, and features of premature ageing that can be rescued by treatment with retinoic acid.