In-Vivo Nucleus Pulposus-Specific Regulation of Adult Murine Intervertebral Disc Degeneration via Wnt/Beta-Catenin Signaling

Chronic low back pain (CLBP) has been proved to be the dominating cause of disability in patients with lumbar degenerative diseases. Of the various etiological factors, intervertebral disc degeneration (IVDD) has been the dominating cause. In the past few decades, the role and changes of nerve systems, especially the peripheral sensory fibers and their neurotransmitters, in the induction and progression of IVDD have attracted growing concerns. The expression of many neuropeptides, such as SP, NPY, and CGRP, in the nociceptive pathways is increased during the progression of IVDD and responsible for the discogenic pain. Here, the role of CGRP in the progression of IVDD was firstly investigated both in vitro and in vivo. Firstly, we confirmed that human degenerated intervertebral disc tissue exhibited elevated expression of CGRP and its receptor. Secondly, in vitro experiments suggested that CGRP could inhibit the proliferation and induce apoptosis in human nucleus pulposus (NP) cells, as well as promote inflammation and degenerated phenotypes through activating NF-κB and MAPK signaling pathways. Thirdly, CGRP receptor antagonist, Rimegepant, can ameliorate the adverse effects of CGRP imposed on NP cells, which were confirmed in vitro and in vivo. Our results will bring about a brand-new insight into the roles of neuromodulation in IVDD and related therapeutic attempts.

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Apigenin Alleviates Intervertebral Disc Degeneration via Restoring Autophagy Flux in Nucleus Pulposus Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.787278 ◽

2022 ◽

Vol 9 ◽

Author(s):

Chenglong Xie ◽

Yifeng Shi ◽

Zuoxi Chen ◽

Xin Zhou ◽

Peng Luo ◽

...

Keyword(s):

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Nuclear Translocation ◽

Autophagic Flux ◽

Ecm Degradation ◽

Induced Apoptosis

Oxidative stress–induced apoptosis and senescence of nucleus pulposus (NP) cells play a crucial role in the progression of intervertebral disc degeneration (IVDD). Accumulation of studies has shown that activated autophagy and enhanced autophagic flux can alleviate IVDD. In this study, we explored the effects of apigenin on IVDD in vitro and in vivo. Apigenin was found to inhibit tert-butyl hydroperoxide (TBHP)–induced apoptosis, senescence, and ECM degradation in NP cells. In addition, apigenin treatment can restore the autophagic flux blockage caused by TBHP. Mechanistically, we found that TBHP may induce autophagosome and lysosome fusion interruption and lysosomal dysfunction, while apigenin alleviates these phenomena by promoting the nuclear translocation of TFEB via the AMPK/mTOR signaling pathway. Furthermore, apigenin also exerts a protective effect against the progression of IVDD in the puncture-induced rat model. Taken together, these findings indicate that apigenin protects NP cells against TBHP-induced apoptosis, senescence, and ECM degradation via restoration of autophagic flux in vitro, and it also ameliorates IVDD progression in rats in vivo, demonstrating its potential for serving as an effective therapeutic agent for IVDD.

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Urolithin A Inhibits the Catabolic Effect of TNFα on Nucleus Pulposus Cell and Alleviates Intervertebral Disc Degeneration in vivo

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01043 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 9

Author(s):

Huiyong Liu ◽

Honglei Kang ◽

Chao Song ◽

Zuowei Lei ◽

Li Li ◽

...

Keyword(s):

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Nucleus Pulposus Cell ◽

Urolithin A

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Celastrol reduces IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.04.093 ◽

2017 ◽

Vol 91 ◽

pp. 208-219 ◽

Cited By ~ 24

Author(s):

Jian Chen ◽

Jun Xuan ◽

Yun-Tao Gu ◽

Ke-Si Shi ◽

Jun-Jun Xie ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Nucleus Pulposus Cells

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Ligustilide alleviated IL-1β induced apoptosis and extracellular matrix degradation of nucleus pulposus cells and attenuates intervertebral disc degeneration in vivo

International Immunopharmacology ◽

10.1016/j.intimp.2019.01.004 ◽

2019 ◽

Vol 69 ◽

pp. 398-407 ◽

Cited By ~ 7

Author(s):

Ke Wang ◽

Tingting Chen ◽

Xiaozhou Ying ◽

Zengjie Zhang ◽

Zhenxuan Shao ◽

...

Keyword(s):

Extracellular Matrix ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Matrix Degradation ◽

Nucleus Pulposus Cells ◽

Extracellular Matrix Degradation ◽

Induced Apoptosis

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Autophagic Degradation of Gasdermin D Protects against Nucleus Pulposus Cell Pyroptosis and Retards Intervertebral Disc Degeneration In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5584447 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Zhiwei Liao ◽

Suyun Li ◽

Rong Liu ◽

Xiaobo Feng ◽

Yunsong Shi ◽

...

Keyword(s):

Cell Death ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Degradation Mechanism ◽

Nucleus Pulposus Cell ◽

Social Burden ◽

Related Proteins

Intervertebral disc degeneration (IDD) is the primary culprit of low back pain and renders heavy social burden worldwide. Pyroptosis is a newly discovered form of programmed cell death, which is also involved in nucleus pulposus (NP) cells during IDD progression. Moderate autophagy activity is critical for NP cell survival, but its relationship with pyroptosis remains unknown. This study is aimed at investigating the relationship between autophagy and pyroptotic cell death. The pyroptosis executor N-terminal domain of gasdermin D (GSDMD-N) and inflammation-related proteins were measured in lipopolysaccharide- (LPS-) treated human NP cells. Inhibition of autophagy by siRNA transfection and chemical drugs aggravated human NP cell pyroptosis. Importantly, we found that the autophagy-lysosome pathway and not the proteasome pathway mediated the degradation of GSDMD-N as lysosome dysfunction promoted the accumulation of cytoplasmic GSDMD-N. Besides, P62/SQSTM1 colocalized with GSDMD-N and mediated its degradation. The administration of the caspase-1 inhibitor VX-765 could reduce cell pyroptosis as confirmed in a rat disc IDD model in vivo, whereas ATG5 knockdown significantly accelerated the progression of IDD. In conclusion, our study indicated that autophagy protects against LPS-induced human NP cell pyroptosis via a P62/SQSTM1-mediated degradation mechanism and the inhibition of pyroptosis retards IDD progression in vivo. These findings deepen the understanding of IDD pathogenesis and hold implications in unraveling therapeutic targets for IDD treatment.

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Genipin Cross-Linked Decellularized Nucleus Pulposus Hydrogel-Like Cell Delivery System Induces Differentiation of ADSCs and Retards Intervertebral Disc Degeneration

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.807883 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lei Yu ◽

Yi Liu ◽

Jianxin Wu ◽

Shuang Wang ◽

Jiangming Yu ◽

...

Keyword(s):

Stem Cells ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Delivery System ◽

Intervertebral Disc Degeneration ◽

Therapeutic Potential ◽

Cell Delivery ◽

Intervertebral Disc Regeneration

Intervertebral disc degeneration (IDD) is the pathological basis of disc degenerative diseases (DDD). Reduction in the number of cells and degeneration of the extracellular matrix (ECM) in the nucleus pulposus (NP) are characteristics of IDD. Bio-hydrogel combined with stem cell transplantation is a promising treatment. Injectable ECM hydrogels have good biological activity and in-situ gelatinization. However, its biomechanics and stability are insufficient to provide adequate mechanical support for intervertebral discs and to maintain the long-term differential stimulus for seeded stem cells. In our study, we developed genipin cross-linked decellularized nucleus pulposus hydrogel (GDH) as delivery system. We evaluated the mechanical properties, stability, biocompatibility, and differentiation induction of GDH cross-linked with different concentrations of genipin in vitro. The GDH-loaded adipose-derived mesenchymal stem cells (ADSCs) (GDHA) were injected into the rat degenerated coccygeal intervertebral disc. The effect of intervertebral disc regeneration in vivo was evaluated. The results showed that GDH with 0.02% of genipin had similar elastic modulus to human nucleus pulposus, good biocompatibility, and inducibility of expressing NP-related genes. In vivo studies showed that GDHA improved the survival of ADSCs and improved the intervertebral height, MRI index, and histological grading score. In conclusion, GDH, as an outstanding bio-hydrogel cell delivery system, has the therapeutic potential for retarding IDD.

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Therapeutic Potential of Naringin for Intervertebral Disc Degeneration: Involvement of Autophagy Against Oxidative Stress-Induced Apoptosis in Nucleus Pulposus Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500805 ◽

2018 ◽

Vol 46 (07) ◽

pp. 1561-1580 ◽

Cited By ~ 4

Author(s):

Zengjie Zhang ◽

Chenggui Wang ◽

Jialiang Lin ◽

Haiming Jin ◽

Ke Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Therapeutic Potential ◽

Nucleus Pulposus Cells ◽

Induced Apoptosis

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but few efficacious medicines have been developed for IDD. Increased nucleus pulposus cells apoptosis is a dominant pathogenesis of IDD and is considered a therapeutic target. Previously, our group proved that autophagy may protect nucleus pulposus cells against apoptosis. As one of the major bioflavonoids of citrus, naringin activates autophagy. Therefore, we hypothesize that naringin may have therapeutic potential for IDD by activating autophagy in nucleus pulposus cells. In this study, we evaluated the effects of naringin on TBHP-induced oxidative stress in nucleus pulposus cells in vitro as well as in puncture-induced rat IDD model in vivo. Our results showed that naringin could reduce the incidence of oxidative stress-induced apoptosis in nucleus pulposus cells and promoted the expression of autophagy markers LC3-II/I and beclin-1. Meanwhile, inhibition of autophagy by 3-MA may partially reverse the anti-apoptotic effect of naringin, indicating that autophagy was involved in the protective effect of naringin in nucleus pulposus cells. Further study showed that autophagy regulation of naringin may be related to AMPK signaling. Also, we found that naringin treatment can regulate the expression of collagen II, aggrecan and Mmp13 to sustain the extracellular matrix. Furthermore, our in vivo study showed that naringin can ameliorate IDD in puncture-induced rat model. In conclusion, our study suggests that naringin can protect nucleus pulposus cells against apoptosis and ameliorate IDD in vivo, the mechanism may relate to its autophagy regulation.

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