Brachyury as a Therapeutic Target for Intervertebral Disc Degeneration Positively Regulates Extracellular Matrix Synthesis Via Directly Promoting Aggrecan Transcription

2022 ◽  
Author(s):  
Yinghui Wu ◽  
Qiang Wang ◽  
Hong Zhang ◽  
Bo Zheng ◽  
Cong Shen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Matrix Synthesis

scholarly journals JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Long ◽  
Xiaobo Wang ◽  
Xianfa Du ◽  
Hehai Pan ◽  
Jianru Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Intervertebral Disc ◽  
Notch Signaling ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Caspase 8 ◽  
Tnf Α ◽  
Intradiscal Injection

Abstract Background Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. Methods Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. Results Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Conclusions The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.

scholarly journals Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration

2018 ◽  
Vol 50 (11) ◽  
pp. 1-14 ◽  
Author(s):  
Jianle Wang ◽  
Majid Nisar ◽  
Chongan Huang ◽  
Xiangxiang Pan ◽  
Dongdong Lin ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Small Molecule ◽  
Therapeutic Target ◽  
Intervertebral Disc Degeneration ◽  
Natural Compound

scholarly journals Intervertebral Disc Degeneration and Low Back Pain: Molecular Mechanisms and Stem Cell Therapy

2018 ◽  
Vol 10 (1) ◽  
pp. 1 ◽  
Author(s):  
Anna Meiliana ◽  
Nurrani Mustika Dewi ◽  
Andi Wijaya
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Low Back Pain ◽  
Back Pain ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Low Back

BACKGROUND: Low back pain (LBP) mostly caused by disc degeneration, reflects to a tremendous of health care system and economy. More knowledge about these underlying pathologies will improve the opportunities that may represent critical therapeutic targets.CONTENT: Basic research is advancing the understanding of the pathogenesis and management of LBP at the molecular and genetic levels. Cytokines such as matrix metalloproteinases, phospholipase A2, nitric oxide, and tumor necrosis factor-α are thought to contribute to the development of LBP. Mesenchymal stem cells (MSCs) transplant to cartilage-like cells and secrete extracellular matrix and encourage nucleus pulposus (NP) cell activity inhibiting NP cell apoptosis, together with some chemical mediators such as cytokines and growth factors become a safe and effective new strategy for intervertebral disc degeneration (IDD) treatment and regeneration.SUMMARY: IDD occurs where there is a loss of homeostatic balance with a predominantly catabolic metabolic profile. A basic understanding of the molecular changes occurring in the degenerating disc is important for practicing clinicians to help them to inform patients to alter lifestyle choices, identify beneficial or harmful supplements, or offer new biologic, genetic, or stem cell therapies.KEYWORDS: low back pain (LBP), intervertebral disc (IVD), degeneration, nucleus pulposus (NP), annulus fibrosus (AF), extracellular matrix (ECM), genetic, stem cells

scholarly journals Effect of voluntary running activity on mRNA expression of extracellular matrix genes in a mouse model of intervertebral disc degeneration

JOR Spine ◽  
2021 ◽  
Author(s):  
Seon Ho Jang ◽  
Seunghwan Lee ◽  
Magali Millecamps ◽  
Alexander Danco ◽  
HyungMo Kang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Mouse Model ◽  
Intervertebral Disc ◽  
Mrna Expression ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Running Activity ◽  
Voluntary Running

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.

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