Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype

Ngo, Kevin; Patil, Prashanti; McGowan, Sara J.; Niedernhofer, Laura J.; Robbins, Paul D.; Kang, James D.; Sowa, Gwendolyn; Vo, Nam

doi:10.1016/j.mad.2017.08.007

Cited by 36 publications

(41 citation statements)

References 41 publications

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“…In contrast, matrix PG synthesis capacity, assessed by 35 S‐sulphate incorporation using disc organotypic culture, was lower in discs from older, compared to younger, mice (Figure c). These in vivo correlations between disc cellular senescence and perturbed matrix homeostasis are consistent with our recent cell culture study demonstrating a matrix imbalance phenotype of senescent disc cells (Ngo, Patil et al, ).…”

Section: Resultssupporting

confidence: 91%

“…Indeed, in this study, we saw a concomitant reduction in levels of the major disc protease, MMP13, and aggrecan fragmentation in Old‐GCV compared to Old‐Veh mice, suggesting cellular senescence phenotype as the source of the inflammatory proteins that trigger the degeneration cascade. This claim is substantiated by the report published by Ngo et al, which showed decreased PG synthesis capacity, enhanced aggrecan fragmentation, as well as increased production of several cytokines and matrix proteases in oxidative stress‐induced senescent human NP cells (Ngo, Patil et al, ). Together, these studies support the causal role for senescent cells in driving matrix homeostatic imbalance in aging discs.…”

Section: Discussionmentioning

confidence: 66%

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Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

et al. 2019

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Rationale Age‐related changes in the intervertebral discs are the predominant contributors to back pain, a common physical and functional impairment experienced by older persons. Cellular senescence, a process wherein cells undergo growth arrest and chronically secrete numerous inflammatory molecules and proteases, has been reported to cause decline in the health and function of multiple tissues with age. Although senescent cells have been reported to increase in intervertebral degeneration (IDD), it is not known whether they are causative in age‐related IDD. Objective The study aimed to elucidate whether a causal relationship exists between cellular senescence and age‐related IDD. Methods and Results To examine the impact of senescent cells on age‐associated IDD, we used p16‐3MR transgenic mice, which enables the selective removal of p16Ink4a‐positive senescent cells by the drug ganciclovir. Disc cellularity, aggrecan content and fragmentation alongside expression of inflammatory cytokine (IL‐6) and matrix proteases (ADAMTS4 and MMP13) in discs of p16‐3MR mice treated with GCV and untreated controls were assessed. In aged mice, reducing the per cent of senescent cells decreased disc aggrecan proteolytic degradation and increased overall proteoglycan matrix content along with improved histological disc features. Additionally, reduction of senescent cells lowered the levels of MMP13, which is purported to promote disc degenerative changes during aging. Conclusions The findings of this study suggest that systemic reduction in the number of senescent cells ameliorates multiple age‐associated changes within the disc tissue. Cellular senescence could therefore serve as a therapeutic target to restore the health of disc tissue that deteriorates with age.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

et al. 2019

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“…These H 2 O 2 ‐induced senescent disc cells exhibited SASP, as characterized by their secretion of high levels of MMPs and pro‐inflammatory cytokines. These senescent disc cells also showed growth arrest and perturbed matrix homeostasis, that is, reduced matrix synthesis capacity (anabolism) and increased matrix degradation (catabolism) . However, to determine the causative role of cellular senescence in driving disc aging, genetic and pharmacological in vivo strategies are needed to study the effects of ablation of senescent cells on age‐associated IDD.…”

Section: Biochemical Cascade Of Intervertebral Disc Agingmentioning

confidence: 99%

Molecular mechanisms of biological aging in intervertebral discs

Hartman

Patil

et al. 2016

Journal Orthopaedic Research

298

277

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Advanced age is the greatest risk factor for the majority of human ailments, including spine-related chronic disability and back pain, which stem from age-associated intervertebral disc degeneration (IDD). Given the rapid global rise in the aging population, understanding the biology of intervertebral disc aging in order to develop effective therapeutic interventions to combat the adverse effects of aging on disc health is now imperative. Fortunately, recent advances in aging research have begun to shed light on the basic biological process of aging. Here we review some of these insights and organize the complex process of disc aging into three different phases to guide research efforts to understand the biology of disc aging. The objective of this review is to provide an overview of the current knowledge and the recent progress made to elucidate specific molecular mechanisms underlying disc aging. In particular, studies over the last few years have uncovered cellular senescence and genomic instability as important drivers of disc aging. Supporting evidence comes from DNA repair-deficient animal models that show increased disc cellular senescence and accelerated disc aging. Additionally, stress-induced senescent cells have now been well documented to secrete catabolic factors, which can negatively impact the physiology of neighboring cells and ECM. These along with other molecular drivers of aging are reviewed in depth to shed crucial insights into the underlying mechanisms of age-related disc degeneration. We also highlight molecular targets for novel therapies and emerging candidate therapeutics that may mitigate age-associated IDD.

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“…One of the major features of IDD is decrease of the proteoglycan (PG) content of IVDs (23). LPS, an admitted strong promoter of inflammation, can reduce the PG content, thus leading to IDD (24,25).…”

Section: Discussionmentioning

confidence: 99%

Role of miR‑589‑3p in human lumbar disc degeneration and its potential mechanism

Wang

2017

Exp Ther Med

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Abstract. The present study aimed to investigate the role of miR-589-3p in lumbar disc degeneration (LDD) and to explore the underlying mechanisms. Nucleus pulposus (NP) cells were stimulated with lipopolysaccharide (LPS) to simulate an in vitro model of intervertebral disc degeneration. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of microRNA (miR)-589-3p in the NP cells, and the results demonstrated that the increased expression of miR-589-3p in LPS stimulated NP cells compared with the control. To further investigate the role of miR-589-3p in LDD, a human NP cell line with high/low miR-589-3p expression was generated using miR-589-3p mimics/inhibitors. In addition, a human NP cell inflammation model was conducted by LPS (10 µM) treatment. Western blot analysis and RT-qPCR were performed for detection of associated genes and proteins. Protein levels of pro-inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 were evaluated by ELISA. Flow cytometry was used for cell apoptosis determination. Furthermore, Targetscan was used to predict potential targets of miR-589-3p, and a dual luciferase reporter assay was used to verify the prediction. The findings verified that miR-589-3p was significantly upregulated in LDD. In vitro, miR-589-3p mimics/inhibitors significantly increased/reduced the production of TNF-α, IL-1β and IL-6 in LPS stimulated NP cells. Furthermore, miR-589-3p mimics/inhibitors significantly promoted/inhibited LPS stimulated NP cell apoptosis. MiR-589-3p mimics/inhibitors significantly repressed/enhanced type II collagen and aggrecan expression in LPS stimulated NP cells. In addition, it was demonstrated that mothers against decapentaplegic homolog (Smad) 4 was a direct target gene of miR-589-3p, and was negatively regulated by miR-589-3p in NP cells. In conclusion, miR-589-3p may function as a promoter in LDD development via the regulation of Smad4.

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Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype

Cited by 36 publications

References 41 publications

Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

Molecular mechanisms of biological aging in intervertebral discs

Role of miR‑589‑3p in human lumbar disc degeneration and its potential mechanism

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Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype

Cited by 36 publications

References 41 publications

Systemic clearance of p16INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

Systemic clearance of p16INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

Molecular mechanisms of biological aging in intervertebral discs

Role of miR‑589‑3p in human lumbar disc degeneration and its potential mechanism

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Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration

Systemic clearance of p16^INK4a‐positive senescent cells mitigates age‐associated intervertebral disc degeneration