Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Bian, Qin; Ma, Lei; Jain, Amit; Crane, Janet L.; Kebaish, Khaled M.; Wan, Mei; Zhang, Zhengdong; Guo, X. Edward; Sponseller, Paul D.; Séguin, Cheryle A.; Riley, Lee H.; Wang, Yongjun; Cao, Xu

doi:10.1038/boneres.2017.8

Cited by 101 publications

(98 citation statements)

References 68 publications

(81 reference statements)

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“…These alternations can cause a deficiency in important cellular defense mechanisms, which contributes to the initiation and progression of tissue damage [15, 16]. Recently, such dysfunction of intervertebral disc homeostasis has been proposed as one of the main mechanisms in IDD [17-19]. In particular, the activation of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling has been demonstrated to mediate these defective intracellular functions [20, 21].…”

Section: Introductionmentioning

confidence: 99%

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

et al. 2018

Cell Physiol Biochem

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Background/Aims: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (NP) cells and its potential roles during IDD pathogenesis. Methods: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation. Results: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. Conclusions: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD.

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Section: Introductionmentioning

confidence: 99%

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

et al. 2018

Cell Physiol Biochem

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“…Due to its adverse impulsion on either individuals or society, IDD has been a highlighted research field, and many factors have been found to contribute to the development of IDD, including age, metabolism, nutrition, and mechanical loading [37]. Among those damaging factors, excessive/abnormal mechanical loading on IVD has been determined to be a primary incentive [38].…”

Section: Discussionmentioning

confidence: 99%

“…Among those damaging factors, excessive/abnormal mechanical loading on IVD has been determined to be a primary incentive [38]. Moreover, the underlying mechanism of pressure-induced IDD has now been clarified to a great extent, and many singling pathways have been demonstrated to be involved in the progress, such as TGF-β, PI3K/Akt pathway, and p38-MAPK pathway [37,38].…”

Section: Discussionmentioning

confidence: 99%

Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

Huang

Peng

et al. 2020

Stem Cells International

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Puerarin (PUR), an 8-C-glucoside of daidzein extracted from Pueraria plants, is closely related to autophagy, reduced reactive oxygen species (ROS) production, and anti-inflammatory effects, but its effects on human nucleus pulposus mesenchymal stem cells (NPMSCs) have not yet been identified. In this study, NPMSCs were cultured in a compression apparatus to simulate the microenvironment of the intervertebral disc under controlled pressure (1.0 MPa), and we found that cell viability was decreased and apoptosis level was gradually increased as compression duration was prolonged. After PUR administration, apoptosis level evaluated by flow cytometry and caspase-3 activity was remitted, and protein levels of Bas as well as cleaved caspase-3 were decreased, while elevated Bcl-2 level was identified. Moreover, ATP production detection, ROS, and JC-1 fluorography as well as quantitative analysis suggested that PUR could attenuate intercellular ROS accumulation and mitochondrial dysfunction. Besides, the rat tail compression model was utilized, which indicated that PUR could restore impaired nucleus pulposus degeneration induced by compression. The PI3K/Akt pathway was identified to be deactivated after compression stimulation by western blot, and PUR could rescue the phosphorylation of Akt, thus reactivating the pathway. The effects of PUR, such as antiapoptosis, cell viability restoration, antioxidation, and mitochondrial maintenance, were all counteracted by application of the PI3K/Akt pathway inhibitor (LY294002). Summarily, PUR could alleviate compression-induced apoptosis and cell death of human NPMSCs in vitro as well as on the rat compression model and maintain intracellular homeostasis by stabilizing mitochondrial membrane potential and attenuating ROS accumulation through activating the PI3K/Akt pathway.

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“…The physiological homeostasis of NP tissue relies on the balance of ECM, which is determined by anabolic and catabolic activities. 36 As the disk degenerates, cell properties of NPCs, responsible for producing NP extracellular matrix components such as proteoglycans and collagens, are inhibited accordingly. 37 The inflammatory cytokine TNF-a significantly suppresses ECM gene expression and promotes expression of ECM-degrading enzymes.…”

Section: Discussionmentioning

confidence: 99%

Functional self‐assembled peptide scaffold inhibits tumor necrosis factor‐alpha‐induced inflammation and apoptosis in nucleus pulposus cells by suppressing nuclear factor‐κB signaling

Cheng

et al. 2017

J Biomedical Materials Res

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Although nucleus pulposus (NP) tissue engineering has achieved tremendous success, researches still face the huge obstacles in maintaining cell survival and function. A novel functional self-assembled peptide RADA-KPSS was constructed by conjugating BMP-7 short active fragment (KPSS) to the C-terminus of RADA16-I that displays anti-inflammatory and anti-apoptosis effects. However, whether this functional self-assembled RADA-KPSS peptide can alleviate inflammation and NPC apoptosis induced by tumor necrosis factor-alpha (TNF-α) has not been studied. Therefore, we cultured NPCs treated with TNF-α for 48 h with the RADA-KPSS peptide, and compared the results to those with RADA16-I peptide. The cell apoptosis rate, inflammatory mediator secretion, expression of matrix-degrading enzymes, and extracellular matrix (ECM) protein levels were evaluated. The expression of nuclear factor-κB-p65 (NF-κB-p65) protein was also tested. TNF-α-treated NPCs cultured with the RADA16-I peptide showed up-regulated gene expression for matrix-degrading enzymes, such as matrix metalloproteinases-3 (MMP-3), MMP-9, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4), and down-regulated gene expression for ECM proteins such as aggrecan, collagen II, and Sox-9. The RADA-KPSS peptide could attenuate the expression of MMP-3, MMP-9, and ADAMTS-4, promote accumulation of ECM proteins, and increase secretion of glycosaminoglycan as compared with the RADA16-I peptide. Moreover, the TNF-α-damaged NPCs was further demonstrated to inhibit NF-κB-p65, IL-1, IL-6, and prostaglandin E-2 proteins and decrease cell apoptosis in RADA-KPSS peptide. In conclusion, the functional self-assembled RADA-KPSS peptides have anti-inflammatory and anti-apoptotic effects by promoting anabolic processes and inhibiting catabolic processes in intervertebral disk degeneration. These peptides may be feasible for clinical applications in NP tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1082-1091, 2018.

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Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Cited by 101 publications

References 68 publications

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

Functional self‐assembled peptide scaffold inhibits tumor necrosis factor‐alpha‐induced inflammation and apoptosis in nucleus pulposus cells by suppressing nuclear factor‐κB signaling

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