A positive feedback loop between EZH2 and NOX4 regulates nucleus pulposus cell senescence in age-related intervertebral disc degeneration

Liu, Chang; Liu, Libangxi; Yang, Minghui; Li, Bin; Yi, Jinyao; Ai, Xuezheng; Zhang, Yang; Huang, Bo; Li, Changqing; Feng, Chencheng; Zhou, Yue

doi:10.1186/s13008-020-0060-x

Cited by 24 publications

(14 citation statements)

References 56 publications

(72 reference statements)

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“…In agreement with this finding, previous work showed that silencing of EZH2 could, by demethylating Sox‐9, result in attenuation of cartilage endplate degeneration and alleviation of IVDD progression 6 . However, others reported that EZH2 was underexpressed in the degenerative discs of aging rats, which could mediate NP cell senescence via H3K27me3 in NOX4 promoter 18 . Furthermore, we demonstrated in the current study that EZH2 can mediate H3K27me3 modification of the miR‐129‐5p promoter, thereby decreasing miR‐129‐5p expression.…”

Section: Discussionsupporting

confidence: 69%

EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR‐129‐5p

Zhou

Liu

et al. 2022

The Journal of Gene Medicine

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Background This study was designed to verify whether enhancer of zeste homolog 2 (EZH2) affects intervertebral disc degeneration (IVDD) development through regulation of microRNA (miR)‐129‐5p/MAPK1. Methods Initially, we collected lumbar nucleus pulposus (NP) tissue samples from patients with juvenile idiopathic scoliosis (n = 14) and IVDD (n = 34). We measured the expression of related genes in clinical IVDD tissues and a lipopolysaccharide (LPS)‐induced NP cell model. After loss‐ and gain‐of‐function assays, NP cell proliferation and senescence were examined. The targeting relationship between miR‐129‐5p and MAPK1 was explored by dual luciferase reporter gene and RNA immunoprecipitation (RIP) assays. The enrichment of EZH2 and H3K27me3 in miR‐129‐5p promoter was verified by chromatin immunoprecipitation (ChIP). Finally, an IVDD rat model was established to test the effects of transduction with lentiviral vector carrying miR‐129‐5p agomir and/or oe‐EZH2 in vivo. Results miR‐129‐5p was underexpressed, and EZH2 and MAPK1 levels were overexpressed in lumbar nucleus pulposus from human IVDD patients and in LPS‐induced NP cells. miR‐129‐5p overexpression or silencing of MAPK1 promoted proliferation of NP cells, while inhibiting their senescence. EZH2 inhibited miR‐129‐5p through H3K27me3 modification in the miR‐129‐5p promoter. miR‐129‐5p could target the downregulation of MAPK1 expression. EZH2 overexpression increased the release of inflammatory factors and cell senescence factors, which was reversed by miR‐129‐5p agomir in vivo. Conclusions Taken together, EZH2 inhibits miR‐129‐5p through H3K27me3 modification, which upregulates MAPK1, thereby promoting the development of IVDD.

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Section: Discussionsupporting

confidence: 69%

EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR‐129‐5p

Zhou

Liu

et al. 2022

The Journal of Gene Medicine

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“…Cellular senescence of IVD cells is the most important pathophysiological mechanism underlying IVD degeneration leading to IDH, and the antisenescence-based pharmacological strategies may be effective in preventing or attenuating the disease onset and progression. [123][124][125][126][127][128][129][130][131][132][133][134] The chemokine pathway is an inflammatory pathomechanism associated with IDH development and its activity is related to the generation, persistence, and severity of neuropathic and radicular pain induced by IDH; additionally, targeting this pathway may hold therapeutic potential. 122,[135][136][137][138][139] The Fork head box O (FoxO) pathway has an antioxidant effect that can protect IVDs against their degeneration induced by oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacological Dissection of the Mechanisms of Eucommiae Cortex-Achyranthis Radix Combination for Intervertebral Disc Herniation Treatment

Lee¹,

Kang

Jung

et al. 2021

Natural Product Communications

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Eucommiae cortex (EC) and Achyranthis radix (AR) are herbal medicines widely used in combination for the treatment of intervertebral disc herniation (IDH). The mechanisms of action of the herbal combination have not been understood from integrative and comprehensive points of view. By adopting network pharmacological methodology, we aimed to investigate the pharmacological properties of the EC-AR combination as a therapeutic agent for IDH at a systematic molecular level. Using the pharmacokinetic information for the chemical ingredients of the EC-AR combination obtained from the comprehensive herbal drug-associated databases, we determined its 31 bioactive ingredients and 68 IDH-related therapeutic targets. By analyzing their enrichment for biological functions, we observed that the targets of the EC-AR combination were associated with the regulation of angiogenesis; cytokine and chemokine activity; oxidative and inflammatory stress responses; extracellular matrix organization; immune response; and cellular processes such as proliferation, apoptosis, autophagy, differentiation, migration, and activation. Pathway enrichment investigation revealed that the EC-AR combination may target IDH-pathology-associated signaling pathways, such as those of cellular senescence and chemokine, neurotrophin, TNF, MAPK, toll-like receptor, and VEGF signaling, to exhibit its therapeutic effects. Collectively, these data provide mechanistic insights into the pharmacological activity of herbal medicines for the treatment of musculoskeletal diseases such as IDH.

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“…Modifications are principally ensured by two cooperating Polycomb group (PcG) complexes: PRC1 (formed by BMI-1, CBX, HPH, RING1) and PRC2 (composed of EED, SUZ12, EZH2, the methyltransferase) [26,162]. ROS/RNS are implicated in a senescence-driving circuit involving EZH2 downregulation and NOX4 increase through a positive feedback [163]. In line with this, EZH2 and BMI-1, as well as other components of the PcG pathway become downregulated in senescence prompting changes in chromatin landscape, increased p16 INK4a expression, and establishment of the SASP [164,165] (Figure 4A).…”

Section: Ros/rns and Histone Modificationsmentioning

confidence: 99%

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence

et al. 2022

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Cell senescence is critical in diverse aspects of organism life. It is involved in tissue development and homeostasis, as well as in tumor suppression. Consequently, it is tightly integrated with basic physiological processes during life. On the other hand, senescence is gradually being considered as a major contributor of organismal aging and age-related diseases. Increased oxidative stress is one of the main risk factors for cellular damages, and thus a driver of senescence. In fact, there is an intimate link between cell senescence and response to different types of cellular stress. Oxidative stress occurs when the production of reactive oxygen species/reactive nitrogen species (ROS/RNS) is not adequately detoxified by the antioxidant defense systems. Non-coding RNAs are endogenous transcripts that govern gene regulatory networks, thus impacting both physiological and pathological events. Among these molecules, microRNAs, long non-coding RNAs, and more recently circular RNAs are considered crucial mediators of almost all cellular processes, including those implicated in oxidative stress responses. Here, we will describe recent data on the link between ROS/RNS-induced senescence and the current knowledge on the role of non-coding RNAs in the senescence program.

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A positive feedback loop between EZH2 and NOX4 regulates nucleus pulposus cell senescence in age-related intervertebral disc degeneration

Cited by 24 publications

References 56 publications

EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR‐129‐5p

EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR‐129‐5p

Network Pharmacological Dissection of the Mechanisms of Eucommiae Cortex-Achyranthis Radix Combination for Intervertebral Disc Herniation Treatment

MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Redox Control of Cell Senescence

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