The cell cycle regulator p16 is known as 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 to be positively correlated with the 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 the senescence-associated secretory phenotype (SASP) were all 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 cycle and inhibiting SASP, cell senescence, and oxidative stress.

A hallmark of aged mesenchymal stem/progenitor cells (MSCs) in bone marrow is the pivot of differentiation potency from osteoblast to adipocyte coupled with a decrease in self-renewal capacity. However, how these cellular events are orchestrated in the aging progress is not fully understood. In this study, we have used molecular and genetic approaches to investigate the role of forkhead box P1 (FOXP1) in transcriptional control of MSC senescence. In bone marrow MSCs, FOXP1 expression levels declined with age in an inverse manner with those of the senescence marker p16^INK4A. Conditional depletion of Foxp1 in bone marrow MSCs led to premature aging characteristics, including increased bone marrow adiposity, decreased bone mass, and impaired MSC self-renewal capacity in mice. At the molecular level, FOXP1 regulated cell-fate choice of MSCs through interactions with the CEBPβ/δ complex and recombination signal binding protein for immunoglobulin κ J region (RBPjκ), key modulators of adipogenesis and osteogenesis, respectively. Loss of p16^INK4A in Foxp1-deficient MSCs partially rescued the defects in replication capacity and bone mass accrual. Promoter occupancy analyses revealed that FOXP1 directly represses transcription of p16^INK4A. These results indicate that FOXP1 attenuates MSC senescence by orchestrating their cell-fate switch while maintaining their replicative capacity in a dose- and age-dependent manner.

We compared the perioperative results and complications associated with PLIF and TLIF, and collected evidence for choosing the better fusion method. A literature survey of the MEDLINE and EMBASE databases identified 7 comparative observational studies that met our inclusion criteria. Checklists by Cowley were used to evaluate the risk of bias of the included studies. A database including patient demographic information, perioperative results, and complications was established. The summary odds ratio and weighed mean difference with 95% confidence interval were calculated with a random-effects model. We found that PLIF had a higher complication rate (P <0.00001), and TLIF reduced the rate of durotomy (P = 0.01). No statistical difference was found between the two groups with regard to clinical satisfaction (P = 0.54), blood loss (P = 0.14), vertebral root injury (P = 0.08), graft malposition (P = 0.06), infection (P = 0.36), or rate of radiographic fusion (P = 0.27). The evidence indicated that PLIF required longer operative time (P = 0.03). The evidence indicated that TLIF could reduce the complication rate and durotomy. Neither TLIP nor PLIF was found superior in terms of clinical satisfaction or radiographic fusion rate. PLIF might result in longer time in surgery.

Disruption of the blood-spinal cord barrier (BSCB) leads to inflammatory cell infiltration and neural cell death, thus, contributing to poor functional recovery after spinal cord injury (SCI). Previous studies have suggested that Sirtuin 1 (SIRT1), an NAD⁺-dependent class III histone deacetylase, is abundantly expressed in endothelial cells and promotes endothelial homeostasis. However, the role of SIRT1 in BSCB function after SCI remains poorly defined. Here, we report that SIRT1 is highly expressed in spinal cord endothelial cells, and its expression significantly decreases after SCI. Using endothelial cell-specific SIRT1 knockout mice, we observed that endothelial cell-specific knockout of SIRT1 aggravated BSCB disruption, thus, resulting in widespread inflammation, neural cell death and poor functional recovery after SCI. In contrast, activation of SIRT1 by the agonist SRT1720 had beneficial effects. In vitro, knockdown of SIRT1 exacerbated IL-1β-induced endothelial barrier disruption in bEnd.3 cells, whereas overexpression of SIRT1 was protective. Using RNA-seq and IP/MS analysis, we identified p66Shc, a redox protein, as the potential target of SIRT1. Further studies demonstrated that SIRT1 interacts with and deacetylates p66Shc, thereby attenuating oxidative stress and protecting endothelial barrier function. Overall, our results indicate that SIRT1 decreases endothelial ROS production and attenuates BSCB disruption by deacetylating p66Shc after SCI, and suggest that SIRT1 activation has potential as a therapeutic approach to promote functional recovery against BSCB disruption following SCI.

The transcriptional repressor Bmi‐1 is involved in cell‐cycle regulation and cell senescence, the deficiency of which has been shown to cause oxidative stress. This study investigated whether Bmi‐1 deficiency plays a role in promoting disc degeneration and the effect of treatment with antioxidant N‐acetylcysteine (NAC) on intervertebral disc degeneration. Bmi‐1^−/− mice were treated with the antioxidant NAC, supplied in drinking water (Bmi‐1^−/−+NAC). For in vitro experiments, mouse intervertebral discs were cultured under low oxygen tension and serum‐limiting conditions in the presence of tumour necrosis factor α and interleukin 1β in order to mimic degenerative insult. Disc metabolism parameters in these in vitro and in vivo studies were evaluated by histopathological, immunohistochemical and molecular methods. Bmi‐1^−/− mice showed lower collagen Ⅱ and aggrecan levels and higher collagen Ⅹ levels than wild‐type and Bmi‐1^−/−+NAC mice. Bmi‐1^−/− mice showed significantly lower superoxide dismutase (SOD)‐1, SOD‐2, glutathione peroxidase (GPX)‐1 and GPX‐3 levels than their wild‐type littermates and Bmi‐1^−/−+ NAC mice. Relative to Bmi‐1^−/− mice, the control and Bmi‐1^−/−+NAC mice showed significantly lower p16, p21, and p53 levels. These results demonstrate that Bmi‐1 plays an important role in attenuating intervertebral disc degeneration in mice by inhibiting oxidative stress and cell apoptosis.

Intervertebral disk degeneration (IDD) is a major cause of low back pain that becomes a prevalent age‐related disease. However, the pathophysiological processes behind IDD are rarely known. Here, we used bioinformatics analysis based on the microarray datasets (GSE34095) to identify the differentially expressed genes (DEGs) as biomarkers and therapeutic targets in degenerated discs. From the previous studies, oxidative stress has been notified as a positive inducement of IDD, which causes DNA damage and accelerates cell senescence. Polyamine oxidase (PAOX), a member of the observed 1057 DEGs, is involved in polyamine metabolism and influences the oxidative balance in cells. However, it is uncertain if the IDD is implicated in the dysregulation of PAOX and polyamine metabolism. This study firstly verified the PAOX upregulation in human degenerated disc samples and applied an IL‐1β‐induced nucleus pulposus (NP) cell degeneration model to demonstrate that spermidine supplementation balanced polyamine metabolism and delayed NP cell senescence. Moreover, we confirmed that spermidine/N‐acetylcysteine supplementation or Cdkn2a gene deletion stabilized the polyamine metabolism, suppressed oxidative stress, and therefore delayed the progress of IDD in older mice. Collectively, our study highlights the role of polyamine metabolism in IDD and foresees spermidine would be the advanced therapeutical drug for IDD.