Cell cycle regulator p16 is known a biomarker and an effector of aging. However, its function in intervertebral disc degeneration (IVDD) is unclear. In this study, p16 expression levels were found positively correlated with severity of human IVDD. In a mouse tail suspension (TS)-induced IVDD model, lumbar intervertebral disc height index and matrix protein expression levels were reduced significantly were largely rescued by p16 deletion. In TS mouse discs, reactive oxygen species levels, proportions of senescent cells, and senescence-associated secretory phenotype (SASP) were increased; cell cycling was delayed; and expression was downregulated for Sirt1, superoxide dismutase 1/2, cyclin-dependent kinases 4/6, phosphorylated retinoblastoma protein, and transcription factor E2F1/2. However, these effects were rescued by p16 deletion. Our results demonstrate that p16 plays an important role in IVDD pathogenesis and that its deletion attenuates IVDD by promoting cell cycling and inhibiting SASP, cell senescence, and oxidative stress.
All data generated or analysed during this study are included in the manuscript and supporting files.
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Animal use was approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (approval number: IACUC-1709021).
Human subjects: This work was implemented by the approval of the Ethics Committee of The First Affiliated Hospital of Nanjing Medical University (approval number: 2018-SR-233). Before the operation, the informed consents of the patients have been obtained, including the patient's voluntary donation of the diseased nucleus pulposus tissue extracted from the operation, and their consents that all specimens will be used for scientific research and the results obtained will be published in scientific journals.
© 2020, Che et al.
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During parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.
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