scholarly journals Caspase 3 as a therapeutic target for regulation of intervertebral disc degeneration in rabbits

2011 ◽  
Vol 63 (6) ◽  
pp. 1648-1657 ◽  
Author(s):  
Hideki Sudo ◽  
Akio Minami
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3

The Caspase-3 Knockout Inhibits Intervertebral Disc Degeneration Related to Injury But Accelerates Degeneration Related to Aging

2019 ◽  
Author(s):  
Takashi Ohnishi ◽  
Katsuhisa Yamada ◽  
Koji Iwasaki ◽  
Takeru Tsujimoto ◽  
Hideaki Higashi ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3

scholarly journals Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhu Guo ◽  
Chensheng Qiu ◽  
Christina Mecca ◽  
Yang Zhang ◽  
Jiang Bian ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Cell Viability ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3 ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Optimal Conditions ◽  
Cell Degeneration ◽  
Lymphotoxin Α

Abstract Background Intervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive. Methods Real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB. Results The levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels. Conclusions This study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined.

scholarly journals AMPK as a Potential Therapeutic Target for Intervertebral Disc Degeneration

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhen Wang ◽  
Jianxiong Shen ◽  
Erwei Feng ◽  
Yang Jiao
Keyword(s):  
Protein Kinase ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Cell Metabolism ◽  
Activation Process ◽  
Cellular Processes ◽  
Disc Cells ◽  
Remodeling Of Extracellular Matrix

As the principal reason for low back pain, intervertebral disc degeneration (IDD) affects the health of people around the world regardless of race or region. Degenerative discs display a series of characteristic pathological changes, including cell apoptosis, senescence, remodeling of extracellular matrix, oxidative stress and inflammatory local microenvironment. As a serine/threonine-protein kinase in eukaryocytes, AMP-activated protein kinase (AMPK) is involved in various cellular processes through the modulation of cell metabolism and energy balance. Recent studies have shown the abnormal activity of AMPK in degenerative disc cells. Besides, AMPK regulates multiple crucial biological behaviors in IDD. In this review, we summarize the pathophysiologic changes of IDD and activation process of AMPK. We also attempt to generalize the role of AMPK in the pathogenesis of IDD. Moreover, therapies targeting AMPK in alleviating IDD are analyzed, for better insight into the potential of AMPK as a therapeutic target.

scholarly journals Acidic pH promotes intervertebral disc degeneration: Acid-sensing ion channel -3 as a potential therapeutic target

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Hamish T. J. Gilbert ◽  
Nathan Hodson ◽  
Pauline Baird ◽  
Stephen M. Richardson ◽  
Judith A. Hoyland
Keyword(s):  
Intervertebral Disc ◽  
Ion Channel ◽  
Disc Degeneration ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Acidic Ph ◽  
Potential Therapeutic Target

scholarly journals Tension induces intervertebral disc degeneration via endoplasmic reticulum stress-mediated autophagy

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Jiangwei Chen ◽  
Zunwen Lin ◽  
Kui Deng ◽  
Bin Shao ◽  
Dong Yang
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Cyclic Deformation ◽  
Annulus Fibrosus ◽  
Intervertebral Disc Degeneration ◽  
Caspase 3 ◽  
Beclin 1 ◽  
Caspase 12

Abstract Background: Intervertebral disc degeneration is a common degenerative disease. The present study aimed to explore the role and mechanism of tension-induced endoplasmic reticulum stress in intervertebral disc degeneration. Methods: Intervertebral disc degeneration models of SD rat were analyzed for apoptosis, the expression of Poly(ADP-ribose) polymerase (PARP), Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP using immunohistochemistry, qPCR and Western blot analysis. Annulus fibrosus cells of intervertebral disc were isolated, subjected to cyclic deformation stress and analyzed for ROS and apoptosis, lysosome activity and expression of genes. The cells were knockdown with siRNA or treated with endoplasmic reticulum stress inhibitor 4-PBA and assayed for ROS, apoptosis, lysosome activity and gene expression. Results: Compared with the controls, intervertebral disc degeneration was observed through X-rays examinations and HS staining. Apoptosis and expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP were significantly increased in the intervertebral disc tissue of the models. In mechanic mimic experiments, the primary annulus fibrosus cells were subjected to 18% cyclic deformation, ROS and apoptosis as well as the activity of lysosome were increased. Similarly, the expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP was also increased significantly after deformation treatment. On other hand, when the cells were treated with 9 mM 4-PBA and/or CHOP-siRNA4, the apoptosis rate, ROS level, lysosome activity and expression of PARP, Caspase-12, Caspase-3, LC3, Beclin-1 and CHOP were significantly reduced. Conclusions: Autophagy reaction mediated by endoplasmic reticulum stress plays important rale in tension-induced intervertebral disc degeneration. Intervertebral disc degeneration likely results from interactions between autophagy, apoptosis and reticulum stress, and is ROS-dependent.

scholarly journals LDHA-Mediated Glycolytic Metabolism in Nucleus Pulposus Cells Is a Potential Therapeutic Target for Intervertebral Disc Degeneration

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Longxi Wu ◽  
Jieliang Shen ◽  
Xiaojun Zhang ◽  
Zhenming Hu
Keyword(s):  
Energy Metabolism ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Control Group ◽  
Potential Therapeutic Target ◽  
Strong Activity ◽  
Upstream Gene

The intervertebral disc degeneration (IDD) is considered to be an initiator of a series of spinal diseases, among which changes in the nucleus pulposus (NP) are the most significant. NP cells reside in a microenvironment with a lack of blood vessels, hypoxia, and low glucose within the intervertebral disc. Due to the strong activity of HIF-1α, glycolysis is the main pathway for energy metabolism in NP cells. Our previous study found that higher SIRT1 expression is beneficial to delay the degeneration of NP cells. In order to find the downstream genes by which SIRT1 acts on NP cells, we used iTRAQ sequencing to detect the differences between degenerated NP cells overexpressing SIRT1 and a control group (human NP cells were derived from surgery) and found that the expression of LDHA changed in the same direction with SIRT1. This suggests that SIRT1 may delay the degeneration of NP cells by regulating glycolysis. We then used a Seahorse XFe24 analyzer to measure the bioenergetic parameters of NP cells and obtained three findings: (a) glycolysis is the main energy metabolism pathway in NP cells, (b) there is a large difference in ATP production between senescent cells and young cells, and (c) SIRT1 can regulate the production of ATP from glycolysis by regulating LDHA. We also found that SIRT1 in NP cells has a positive regulatory effect on c-Myc which is an upstream gene of LDHA. Through observing IDD-related indicators such as apoptosis, proliferation, senescence, and extracellular matrix, we found that SIRT1 can delay degeneration, and interference with c-Myc and LDHA, respectively, weakens the protective effect of SIRT1. Interfering with LDHA alone can also inhibit glycolysis and accelerate degeneration. Overall, we found that the inhibition of glycolysis in Np cells significantly affects their normal physiological functions and determined that LDHA is a potential therapeutic target for the treatment of IDD.

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