scholarly journals Phlpp1 is associated with human intervertebral disc degeneration and its deficiency promotes healing after needle puncture injury in mice

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Changli Zhang ◽  
Madeline P. Smith ◽  
George K. Zhou ◽  
Alon Lai ◽  
Robert C. Hoy ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Cell Loss ◽  
Akt Signaling ◽  
Protective Effects ◽  
Needle Puncture ◽  
Matrix Degradation ◽  
Ph Domain ◽  
Matrix Deposition ◽  
Matrix Production

Abstract Back pain is a leading cause of global disability and is strongly associated with intervertebral disc (IVD) degeneration (IDD). Hallmarks of IDD include progressive cell loss and matrix degradation. The Akt signaling pathway regulates cellularity and matrix production in IVDs and its inactivation is known to contribute to a catabolic shift and increased cell loss via apoptosis. The PH domain leucine-rich repeat protein phosphatase (Phlpp1) directly regulates Akt signaling and therefore may play a role in regulating IDD, yet this has not been investigated. The aim of this study was to investigate if Phlpp1 has a role in Akt dysregulation during IDD. In human IVDs, Phlpp1 expression was positively correlated with IDD and the apoptosis marker cleaved Caspase-3, suggesting a key role of Phlpp1 in the progression of IDD. In mice, 3 days after IVD needle puncture injury, Phlpp1 knockout (KO) promoted Akt phosphorylation and cell proliferation, with less apoptosis. At 2 and 8 months after injury, Phlpp1 deficiency also had protective effects on IVD cellularity, matrix production, and collagen structure as measured with histological and immunohistochemical analyses. Specifically, Phlpp1-deletion resulted in enhanced nucleus pulposus matrix production and more chondrocytic cells at 2 months, and increased IVD height, nucleus pulposus cellularity, and extracellular matrix deposition 8 months after injury. In conclusion, Phlpp1 has a role in limiting cell survival and matrix degradation in IDD and research targeting its suppression could identify a potential therapeutic target for IDD.

scholarly journals Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

2020 ◽  
Vol 21 (8) ◽  
pp. 2720 ◽  
Author(s):  
Anita Krouwels ◽  
Juvita D. Iljas ◽  
Angela H. M. Kragten ◽  
Wouter J. A. Dhert ◽  
F. Cumhur Öner ◽  
...  
Keyword(s):  
Growth Factors ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Bone Morphogenetic Proteins ◽  
High Potential ◽  
Added Value ◽  
Great Promise ◽  
Matrix Deposition ◽  
Matrix Production ◽  
Incorporation Efficiency

Matrix production by nucleus pulposus (NP) cells, the cells residing in the center of the intervertebral disc, can be stimulated by growth factors. Bone morphogenetic proteins (BMPs) hold great promise. Although BMP2 and BMP7 have been used most frequently, other BMPs have also shown potential for NP regeneration. Heterodimers may be more potent than single homodimers, but it is not known whether combinations of homodimers would perform equally well. In this study, we compared BMP2, BMP4, BMP6, and BMP7, their combinations and heterodimers, for regeneration by human NP cells. The BMPs investigated induced variable matrix deposition by NP cells. BMP4 was the most potent, both in the final neotissue glysosaminoglycan content and incorporation efficiency. Heterodimers BMP2/6H and BMP2/7H were more potent than their respective homodimer combinations, but not the BMP4/7H heterodimer. The current results indicate that BMP4 might have a high potential for regeneration of the intervertebral disc. Moreover, the added value of BMP heterodimers over their respective homodimer BMP combinations depends on the BMP combination applied.

scholarly journals Icariin Prevents H2O2-Induced Apoptosis via the PI3K/Akt Pathway in Rat Nucleus Pulposus Intervertebral Disc Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Xiangyu Deng ◽  
Sheng Chen ◽  
Dong Zheng ◽  
Zengwu Shao ◽  
Hang Liang ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Caspase 3 ◽  
Chinese Herb ◽  
Akt Pathway ◽  
Control Group ◽  
Protective Effects ◽  
Nucleus Pulposus Cells ◽  
Intracellular Ros ◽  
Induced Apoptosis

Icariin is a prenylated flavonol glycoside derived from the Chinese herb Epimedium sagittatum. This study investigated the mechanism by which icariin prevents H2O2-induced apoptosis in rat nucleus pulposus (NP) cells. NP cells were isolated from the rat intervertebral disc and they were divided into five groups after 3 passages: (A) blank control; (B) 200 μM H2O2; (C) 200 μM H2O2 + 20 μM icariin; (D) 20 μM icariin + 200 μM H2O2 + 25 μM LY294002; (E) 200 μM H2O2 + 25 μM LY294002. LY294002 is a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. NP cell viability, apoptosis rate, intracellular reactive oxygen species levels, and the expression of AKT, p-AKT, p53, Bcl-2, Bax, caspase-3 were estimated. The results show that, compared with the control group, H2O2 significantly increased NP cell apoptosis and the level of intracellular ROS. Icariin pretreatment significantly decreased H2O2-induced apoptosis and intracellular ROS and upregulated p-Akt and BCL-2 and downregulated caspase-3 and Bax. LY294002 abolished the protective effects of icariin. Our results show that icariin can attenuate H2O2-induced apoptosis in rat nucleus pulposus cells and PI3K/AKT pathway is at least partly included in this protection effect.

scholarly journals Moracin attenuates LPS-induced inflammation in nucleus pulposus cells via Nrf2/HO-1 and NF-κB/TGF-β pathway

2019 ◽  
Vol 39 (12) ◽  
Author(s):  
Ronghe Gu ◽  
Zonggui Huang ◽  
Huijiang Liu ◽  
Qiwen Qing ◽  
Zou Zhuan ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Primary Culture ◽  
Nucleus Pulposus ◽  
Underlying Mechanism ◽  
Pcr Analysis ◽  
Protective Effects ◽  
Nucleus Pulposus Cells ◽  
Protein Levels ◽  
Lps Challenge ◽  
Smad 3

Abstract The present study was designed to investigate the protective effect of moracin on primary culture of nucleus pulposus cells in intervertebral disc and explore the underlying mechanism. Moracin treatment significantly inhibited the LPS-induced inflammatory cytokine accumulation (IL-1β, IL-6 and TNF-α) in nucleus pulposus cells. And moracin also dramatically decreased MDA activity, and increased the levels of SOD and CAT induced by LPS challenge. Moreover, the expressions of Nrf-2 and HO-1 were decreased and the protein levels of p-NF-κBp65, p-IκBα, p-smad-3 and TGF-β were increased by LPS challenge, which were significantly reversed after moracin treatments. Moracin treatments also decreased the levels of matrix degradation enzymes (MMP-3, MMP-13) as indicated by RT-PCR analysis. However, Nrf-2 knockdown abolished these protective effects of moracin. Together, our results demonstrated the ability of moracin to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc by partly regulating the Nrf2/HO-1 and NF-κB/TGF-β pathway in nucleus pulposus cells.

scholarly journals Resveratrol enhances matrix biosynthesis of nucleus pulposus cells through activating autophagy via the PI3K/Akt pathway under oxidative damage

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Jinlou Gao ◽  
Qingyun Zhang ◽  
Lin Song
Keyword(s):  
Oxidative Damage ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Akt Pathway ◽  
Control Group ◽  
Protective Effects ◽  
Nucleus Pulposus Cells ◽  
Matrix Synthesis ◽  
Cellular Autophagy ◽  
Matrix Production

The decrease in nucleus pulposus (NP) matrix production is a classic feature during disc degeneration. Resveratrol (RSV) is reported to play protective effects under many pathological factors.The present study aims to study the effects of RSV on NP matrix homeostasis under oxidative damage and the potential mechanism. Rat NP cells were exposed to H2O2 solution to create an oxidative damage. RSV and the 3-methyladenine (3-MA) were added along with the culture medium to respectively investigate the role of RSV and cellular autophagy. NP matrix synthesis was evaluated by the expression of macromolecules (aggrecan and collagen II) and glycosaminoglycan (GAG) content. Activation of cellular autophagy was assessed by the expression of several molecular markers. Additionally, activity of the PI3K/Akt pathway was also evaluated to study its potential role. Compared with the control group (NP cells treated with H2O2), RSV significantly up-regulated expression of matrix macromolecules (aggrecan and collagen), promoted GAG production, and increased the expression of autophagy-related markers (Beclin-1 and LC-3). Further analysis showed that inhibition of autophagy by 3-MA partly attenuated NP matrix production. Additionally, RSV increased activity of the PI3K/Akt pathway compared with the control NP cells, but it was not affected by the addition of 3-MA. RSV plays a protective role in enhancing NP matrix synthesis under oxidative damage. Mechanistically, activation of the cellular autophagy via the PI3K/Akt pathway may participate in this process. RSV may be an effective drug to attenuate oxidative stress-induced disc degeneration.

scholarly journals Oxymatrine suppresses IL-1β-induced degradation of the nucleus pulposus cell and extracellular matrix through the TLR4/NF-κB signaling pathway

2020 ◽  
Vol 245 (6) ◽  
pp. 532-541
Author(s):  
Kang Wei ◽  
Jun Dai ◽  
Zhenggang Wang ◽  
Yaping Pei ◽  
Yan Chen ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Intervertebral Disc ◽  
Nucleus Pulposus ◽  
Disc Degeneration ◽  
Interleukin 6 ◽  
Intervertebral Disc Degeneration ◽  
Interleukin 1 ◽  
Interleukin 1 Beta ◽  
Matrix Degradation ◽  
Nucleus Pulposus Cells

Intervertebral disc degeneration is the main cause of low back pain. However, its pathomechanism has not been fully clarified yet. Previous studies have indicated that inflammation may lead to apoptosis of nucleus pulposus cells and break the balance between anabolism and catabolism of the nucleus pulposus extracellular matrix. The purpose of this study is to explore the mitigative effect of oxymatrine on extracellular matrix degradation and apoptosis of nucleus pulposus cells after interleukin-1 beta-induced inflammation, and its possible signaling pathway. We examined the gene and protein levels of collagen II, aggrecan, and MMPs (MMP2/3/9/13) and interleukin 6 in nucleus pulposus cells. The results demonstrated that oxymatrine could reduce extracellular matrix degradation and apoptosis of nucleus pulposus cells; interleukin-1 beta prompted the expression of MMPs and interleukin 6 through TLR4/NF-κB axis, while oxymatrine reduced the expression of MMPs and TNF-α induced by interleukin-1 beta. Moreover, TAK 242, as a small molecule inhibitor of TLR4 signaling, was used to detect the effect of oxymatrine on the TLR4/NF-κB signaling. The final experimental results show that oxymatrine could reduce the inflammatory response of nucleus pulposus cells and degradation of nucleus pulposus tissue. Oxymatrine may be a potential medicine to reduce disc inflammation and relieve intervertebral disc degeneration by inhibiting the TLR4/NF-κB signal pathway. Impact statement Currently, drug therapy is a potential treatment for patients with intervertebral disc degeneration. In the present research, oxymatrine intervenes in intervertebral disc degeneration effectively via regulating inflammation in intervertebral disc degeneration rats. Our research highlights the therapeutic potential of oxymatrine in the treatment of intervertebral disc degeneration.

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