Utilize este identificador para referenciar este registo: https://hdl.handle.net/1822/67330

Títulop16Ink4a deletion in cells of the intervertebral disc affects their matrix homeostasis and senescence associated secretory phenotype without altering onset of senescence
Autor(es)Novais, Emanuel J.
Diekman, Brian O.
Shapiro, Irving M.
Risbud, Makarand V.
Palavras-chaveAggrecans
Aging
Animals
Cellular Senescence
Collagen
Cyclin-Dependent Kinase Inhibitor p16
Disease Models, Animal
Extracellular Matrix
Homeostasis
Humans
Intervertebral Disc Degeneration
Mice
Phenotype
Gene Deletion
p16
p19
Ink4a
Senescence
Mouse models
Nucleus pulposus
SASP
Aggrecan
Data2019
EditoraElsevier
RevistaMatrix Biology
CitaçãoNovais, E. J., Diekman, B. O., Shapiro, I. M., & Risbud, M. V. (2019). p16Ink4a deletion in cells of the intervertebral disc affects their matrix homeostasis and senescence associated secretory phenotype without altering onset of senescence. Matrix Biology, 82, 54-70
Resumo(s)Intervertebral disc degeneration is an important contributor to chronic low back and neck pain. Although many environmental and genetic factors are known to contribute to disc degeneration, age is still the most significant risk factor. Recent studies have shown that senescence may play a role in age-related disc degeneration and matrix catabolism in humans and mouse models. Clearance of p16Ink4a-positive senescent cells reduces the degenerative phenotype in many age-associated diseases. Whether p16Ink4a plays a functional role in intervertebral disc degeneration and senescence is unknown. We first characterized the senescence status of discs in young and old mice. Quantitative histology, gene expression and a novel p16tdTom reporter mice showed an increase in p16Ink4a, p21 and IL-6, with a decrease in Ki67 with aging. Accordingly, we studied the spinal-phenotype of 18-month-old mice with conditional deletion of p16Ink4a in the disc driven by Acan-CreERT2 (cKO). The analyses of discs of cKO and age-matched control mice showed little change in cell morphology and tissue architecture. The cKO mice exhibited changes in functional attributes of aggrecan as well as in collagen composition of the intervertebral disc. While cKO discs exhibited a small decrease in TUNEL positive cells, lineage tracing experiments using ZsGreen reporter indicated that the overall changes in cell fate or numbers were minimal. The cKO mice maintained expression of NP-cell phenotypic markers CA3, Krt19 and GLUT-1. Moreover, in cKO discs, levels of p19Arf and RB were higher without alterations in Ki67, γH2AX, CDK4 and Lipofuscin deposition. Interestingly, the cKO discs showed lower levels of SASP markers, IL-1β, IL-6, MCP1 and TGF-β1. These results show that while, p16Ink4a is dispensable for induction and maintenance of senescence, conditional loss of p16Ink4a reduces apoptosis, limits the SASP phenotype and alters matrix homeostasis of disc cells.
TipoArtigo
URIhttps://hdl.handle.net/1822/67330
DOI10.1016/j.matbio.2019.02.004
ISSN0945-053X
Versão da editorahttps://www.sciencedirect.com/science/article/pii/S0945053X18304645
Arbitragem científicayes
AcessoAcesso restrito UMinho
Aparece nas coleções:ICVS - Artigos em revistas internacionais / Papers in international journals

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