SIRT1 inhibits apoptosis of degenerative human disc nucleus pulposus cells through activation of Akt pathway

Da-wu, Wang; Hu, Zhenming; Hao, Jie; He, Bin; Gan, Qiang; Zhong, Xiaoming; Zhang, Xiaojun; Shen, Jieliang; Ji, Fang; Jiang, Wei

doi:10.1007/s11357-012-9474-y

Cited by 65 publications

(51 citation statements)

References 43 publications

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“…The expression of Coll2α1 and aggrecan increased significantly, illustrating that the intervertebral disc degeneration occurrence and development were reversed. These results were similar to those obtained by others (Gagarina et al, 2010;Wang et al, 2012).…”

Section: Discussionsupporting

confidence: 93%

“…Current studies show that there is a close relationship between the intervertebral disc diseases and matrix metabolism imbalance (Matrisian, 1990;Boileau et al, 2011;Chen et al, 2011). Silence mating type information regulation 2 homolog 1 (SIRT1), by inhibiting the expression of matrix metalloproteinase-1 (MMP-1), promotes cartilage extracellular matrix synthesis (Wang et al, 2012). In this study, we detected the expression of SIRT1 and MMP-1 in degenerative human nucleus pulposus intervertebral disc specimens and analyzed the functions of SIRT1 and MMP-1 in the development of intervertebral disc degeneration, in order to find a novel target for the therapy of intervertebral disc degenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro

Wu¹,

Wang²,

Chen³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Intervertebral disc degeneration is the main cause of lumbago disease, in which the extracellular matrix structure and moisture in the nucleus pulposus is lost continuously. In this study, we aimed to detect differential expression of silence mating type information regulation 2 homolog 1 (SIRT1) and matrix metalloproteinase-1 (MMP-1) in human intervertebral disc nucleus pulposus cells and to explore the effects of SIRT1 and MMP-1 on the development of the intervertebral disc degeneration. Intervertebral disc nucleus pulposus specimens from 41 patients who underwent lumbar protrusion resection at HuiZhou Municipal Central Hospital, during the period from October 2011 to December 2013, were studied in comparison with 23 control cases from patients who underwent fractured lumbar resection. In degenerated human intervertebral disc nucleus pulposus cells, the expression of SIRT1 is decreased and MMP-1 is increased compared with that of the control cells. Resveratrol could reverse these effects, thereby increasing the expression of SIRT1 (0.87 ± 0.07 vs 0.54 ± 0.04), Coll2α1 (0.90 ± 0.08 vs 0.38 ± 0.01), and aggrecan (0.69 ± 0.07 vs 0.42 ± 0.05) and decreasing the expression of MMP-1 (0.61 ± 0.03 vs 0.93 ± 0.08). These results suggest that resveratrol could possibly reverse the process of intervertebral disc degeneration and thus could be applied as a potential drug for the disease.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro

Wu¹,

Wang²,

Chen³

et al. 2015

Genet. Mol. Res.

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“…Here, we identified FOXO3 as a novel mediator of NP cell adaptation to hypoxia and demonstrated that FOXO3 and, to a lesser extent, FOXO1 regulate the expression of autophagy genes and activation in NP cells. Although a causal relationship between autophagy defects and IDD has not yet been established, our findings showed that FOXO function promotes NP cell survival under oxidative and inflammatory stresses, major drivers of NP cell apoptosis and aging‐related IDD (Nasto et al, 2013; Wang et al, 2013; Yang et al, 2014), and thus suggest that activation of FOXO in aged IVD could increase autophagy and protect NP cells from stress‐induced apoptosis. Further supporting this hypothesis, various studies have shown that autophagy activation can protect NP cells against different apoptotic insults (Jiang, Jin, Wang, Jiang, & Dong, 2014; Jiang, Zhang, et al, 2014).…”

Section: Discussionmentioning

confidence: 55%

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

et al. 2018

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Intervertebral disk (IVD) degeneration is a prevalent age‐associated musculoskeletal disorder and a major cause of chronic low back pain. Aging is the main risk factor for the disease, but the molecular mechanisms regulating IVD homeostasis during aging are unknown. The aim of this study was to investigate the function of FOXO, a family of transcription factors linked to aging and longevity, in IVD aging and age‐related degeneration. Conditional deletion of all FOXO isoforms (FOXO1, 3, and 4) in IVD using the Col2a1Cre and AcanCreER mouse resulted in spontaneous development of IVD degeneration that was driven by severe cell loss in the nucleus pulposus (NP) and cartilaginous endplates (EP). Conditional deletion of individual FOXO in mature mice showed that FOXO1 and FOXO3 are the dominant isoforms and have redundant functions in promoting IVD homeostasis. Gene expression analyses indicated impaired autophagy and reduced antioxidant defenses in the NP of FOXO‐deficient IVD. In primary human NP cells, FOXO directly regulated autophagy and adaptation to hypoxia and promoted resistance to oxidative and inflammatory stress. Our findings demonstrate that FOXO are critical regulators of IVD homeostasis during aging and suggest that maintaining or restoring FOXO expression can be a therapeutic strategy to promote healthy IVD aging and delay the onset of IVD degeneration.

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“…Correspondingly, additional in vivo studies (14) demonstrated that Sirt1 exerts an anti-inflammatory effect in cartilage during OA. Moreover, mechanistic studies have provided further support that SIRT1 promotes chondrocyte survival through various pathways (15)(16)(17)(18)(19)-in particular, deacetylation of p65/ RelA-which reduces iNOS gene expression after IL-1b challenge of chondrocytes (20). Despite the wealth of information regarding the beneficial effects exerted by SIRT1 in maintaining chondrocyte survival and attenuating inflammation, very little is known about the impact of SIRT1 on cartilage destruction during OA.…”

mentioning

confidence: 99%

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

et al. 2017

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Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1b, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1b challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 2/2 presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes. FASEB J. 31, 3116-3125 (2017). www.fasebj.orgArticular cartilage undergoes age-related degenerative changes leading to the joint disease osteoarthritis (OA). Gradual loss of hyaline joint cartilage during OA is evoked through chronic synovitis, which involves the accumulation of proinflammatory cytokines, as IL1b, TNF-a, and IL6 within the joint (1-5), subsequently leading to a steady increase in matrix metalloproteinases (MMPs) and a disintegrin and MMP with thrombospondin motifs (ADAMTS) proteins, which further promote cartilage destruction (6-12). Recent experimental attempts ABBREVIATIONS: ACAN, aggrecan gene; ADAMTS, a disintegrin and metalloproteinase with thrombospondin-like motifs; BMP, bone morphogenic protein; ChIP, chromatin immunoprecipitation; COL2A1, collagen-2 a-1 gene; FBS, fetal bovine serum; FGF, fibroblast growth factor; GDF, growth differentiation factor; GSK3b, glycogen synthase kinase-3b; hESC, human embryonic stem cell; KO, knockout; LEF, lymphoid enhancer factor; MMP, matrix metalloproteinase; NAM, nicotinamide adenine mononucleotide; OA, osteoarthritis; Res, resveratrol; qPCR, quantitative PCR; siRNA, small interfering RNA; SIRT1, silent mating type information regulation 2 homolog 1 (sirtuin-1); SOX9, sex-determining-region-on-the-Y-chromosome-relate...

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SIRT1 inhibits apoptosis of degenerative human disc nucleus pulposus cells through activation of Akt pathway

Cited by 65 publications

References 43 publications

Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro

Resveratrol could reverse the expression of SIRT1 and MMP-1 in vitro

FOXO are required for intervertebral disk homeostasis during aging and their deficiency promotes disk degeneration

LEF1‐mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes

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