scholarly journals MicroRNA-338-3p as a novel therapeutic target for intervertebral disc degeneration

2021 ◽  
Author(s):  
Hua Jiang ◽  
Abu Moro ◽  
Jiaqi Wang ◽  
Dihua Meng ◽  
Xinli Zhan ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Negative Regulator ◽  
Erk Pathway ◽  
Matrix Synthesis ◽  
Functional Studies ◽  
Promising Target ◽  
Proliferation And Apoptosis ◽  
Intradiscal Injection

AbstractRecent studies have demonstrated the pivotal role played by microRNAs (miRNAs) in the etiopathogenesis of intervertebral disc degeneration (IDD). The study of miRNA intervention in IDD models may promote the advancement of miRNA-based therapeutic strategies. The aim of the current study was to investigate whether intradiscal delivery of miRNA can attenuate IDD development. Our results showed that miR-338-3p expression was significantly increased in the nucleus pulposus (NP) of patients with IDD. Moreover, there was a statistically significant positive correlation between the expression level of miR-338-3p and the severity of IDD. Our functional studies showed that miR-338-3p significantly influenced the expression of extracellular matrix synthesis genes, as well as the proliferation and apoptosis of NP cells. Mechanistically, miR-338-3p aggravated IDD progression by directly targeting SIRT6, a negative regulator of the MAPK/ERK pathway. Intradiscal injection of antagomir-338-3p significantly decelerated IDD development in mouse models. Our study is the first to identify miR-338-3p as a mediator of IDD and thus may be a promising target for rescuing IDD.

scholarly journals MicroRNA-338-3p as A Novel Therapeutic Target for Intervertebral Disc Degeneration

2020 ◽  
Author(s):  
Hua Jiang ◽  
Abu Moro ◽  
Jiaqi Wang ◽  
Dihua Meng ◽  
Xinli Zhan ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Significant Positive Correlation ◽  
Negative Regulator ◽  
Erk Pathway ◽  
Matrix Synthesis ◽  
Functional Studies ◽  
Promising Target ◽  
Proliferation And Apoptosis

Abstract Background: Recent studies have demonstrated the pivotal role played by microRNA (miRNA) in the etiopathogenesis of intervertebral disc degeneration (IDD). The aim of this current study is to investigate whether intra-discal delivery of miRNA can attenuate IDD development.Results: miR-338-3p expression was significantly increased in the nucleus pulposus (NP) of patients with IDD. Moreover, there was a statistically significant positive correlation between the level of expression of miR-338-3p and the severity of IDD. Our functional studies showed that miR-338-3p significantly influenced the expression of extracellular matrix synthesis of genes, as well as the proliferation and apoptosis of NP cells. Mechanistically, miR-338-3p aggravated IDD progression by directly targeting SIRT6, a negative regulator of MAPK/ERK pathway. Intra-discal injection of antagomir-338-3p significantly decelerated IDD development in mice models.Conclusions: miR-338-3p is identified as a mediator of IDD, and thus may be a promising target for rescuing IDD.

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.

MicroRNA‐181a exerts anti‐inflammatory effects via inhibition of the ERK pathway in mice with intervertebral disc degeneration

2019 ◽  
Vol 235 (3) ◽  
pp. 2676-2686 ◽  
Author(s):  
Yanpeng Sun ◽  
Xiangqin Shi ◽  
Xiaodong Peng ◽  
Yanzhou Li ◽  
Husheng Ma ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Erk Pathway ◽  
Anti Inflammatory

scholarly journals Circular RNA hsa_circ_0001658 Inhibits Intervertebral Disc Degeneration Development by Regulating hsa-miR-181c-5p/FAS

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Ge-dong Meng ◽  
Bao-shan Xu
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Noncoding Rna ◽  
Intervertebral Disc Degeneration ◽  
Neural Progenitor Cells ◽  
Death Receptor ◽  
Circular Rna ◽  
Gene Expression Omnibus ◽  
Proliferation And Apoptosis ◽  
Human Neural Progenitor Cells

Background and Purpose. Intervertebral disc degeneration (IDD) is the main cause of low back pain, but its pathogenesis has not been studied clearly. Circular RNA is a type of noncoding RNA (ncRNA). In this study, we studied the potential role of circular RNA in the pathogenesis of IDD. Methods. We obtained microarray data (GSE116726, GSE67566) from Gene Expression Omnibus database, and differential expression level of ncRNA in nucleus pulposus (NP) tissues of IDD patients was analyzed. The potential circRNA-miRNA-mRNA regulatory network was analyzed by starBase. The effect of the interaction between hsa_circ_0001658, hsa-miR-181c-5p, and FAS on the proliferation and apoptosis of human neural progenitor cells (hNPCs) was studied. Results. hsa_circ_0001658 was significantly upregulated ( logFC > 2.0 and adj . P . Val < 0.01 ) in the NP tissues of IDD patients, and hsa-miR-181c-5p expression was downregulated ( logFC < − 2.0 and adj . P . Val < 0.01 ). Silencing of hsa-miR-181c-5p or overexpression of hsa_circ_0001658 inhibited the proliferation of hNPCs and promoted their apoptosis. hsa_circ_0001658 acted as a sponge of hsa-miR-181c-5p. hsa-miR-181c-5p downregulated the expression of Fas cell surface death receptor (FAS), promoted the proliferation, and inhibited the apoptosis of hNPCs. hsa_circ_0001658 functioned in hNPCs through targeting hsa-miR-181c-5p/FAS. Conclusion. Circular RNA hsa_circ_0001658 inhibits IDD development by regulating hsa-miR-181c-5p/FAS. It is expected to be a potential target for the therapy of IDD.

scholarly journals LncRNA OIP5-AS1 targets miR-25-3p to accelerate intervertebral disc degeneration

2021 ◽  
Author(s):  
Jie Xu ◽  
Zongyu Zhang ◽  
Zhaoping Che
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Immunofluorescence Assay ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Proliferation And Apoptosis ◽  
Ecm Degradation ◽  
Collagen Ii

Abstract Background Long noncoding RNAs (lncRNAs) have been validated to exert vital roles in intervertebral disc degeneration (IDD). However, the effect of OIP5-AS1 on IDD is unknown. This research intends to explore the function of OIP5-AS1 in IDD. Methods RT-PCR was utilized to detect levels of OIP5-AS1, miR-25-3p, Collagen II and Aggrecan in IDD tissues and NPCs. Immunofluorescence assay measured Collagen II expression. CCK-8, EdU, and flow cytometry estimated the levels of proliferation and apoptosis. Collagen II and Aggrecan proteins were assessed via western blot. The binding affinity of OIP5-AS1 with miR-25-3p was investigated by luciferase reporter assay. Enzyme-linked immunosorbent assay (ELISA) dissected the levels of inflammatory factors such as IL-6, TNF-α, IL-10 and IL-1β. Results OIP5-AS1 was high expressed in IDD tissues and its expression gradually promoted with the increasing of Pfirrmann scores. The cell morphology of NPCs changed into spindle-shaped, and Collagen II expression was low. After OIP5-AS1 was silenced, cell proliferation was boosted whereas both apoptosis and extracellular matrix (ECM) degradation were restrained. In LPS-activated NPCs, OIP5-AS1 depletion also suppressed inflammation response. Further, miR-25-3p was a target of OIP5-AS1. The effects of OIP5-AS1 silence on proliferation, apoptosis and ECM degradation were reversed upon miR-25-3p downregulation. Moreover, the inhibitory impact of OIP5-AS1 knockdown on the inflammation of LPS-treated NPCs was rescued with miR-25-3p inference. Conclusion Totally, lncRNA OIP5-AS1 targeting miR-25-3p exerted promoting effects in IDD due to its high expression, implying the usage of OIP5-AS1/miR-25-3p as a novel regulatory axis for the molecular targets of IDD therapy.

scholarly journals Effects of Intradiscal Injection of Local Anesthetics on Intervertebral Disc Degeneration in Rabbit Degenerated Intervertebral Disc

2019 ◽  
Vol 37 (9) ◽  
pp. 1963-1971 ◽  
Author(s):  
Katsuro Ura ◽  
Hideki Sudo ◽  
Koji Iwasaki ◽  
Takeru Tsujimoto ◽  
Daisuke Ukeba ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Local Anesthetics ◽  
Intervertebral Disc Degeneration ◽  
Intradiscal Injection

scholarly journals Intradiscal injection of simvastatin retards progression of intervertebral disc degeneration induced by stab injury

2009 ◽  
Vol 11 (6) ◽  
pp. R172 ◽  
Author(s):  
Huina Zhang ◽  
Lin Wang ◽  
Jun Beom Park ◽  
Paul Park ◽  
Victor C Yang ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Stab Injury ◽  
Intradiscal Injection

scholarly journals M2 Macrophage-Conditioned Medium Inhibits Intervertebral Disc Degeneration in a Tumor Necrosis Factor-α-rich Environment

2021 ◽  
Author(s):  
Xiao-Chuan Li ◽  
Shao-Jian Luo ◽  
Wu Fan ◽  
Tian-Li Zhou ◽  
Chun-Ming Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Western Blotting ◽  
Intervertebral Disc Degeneration ◽  
M2 Macrophages ◽  
Matrix Synthesis ◽  
Culture Model ◽  
Tnf Α ◽  
Necrosis Factor

Abstract BackgroundInflammation is the primary pathological phenomenon associated with disc degeneration; accordingly, the inflammatory cytokine tumor necrosis factor (TNF-α) plays a crucial role in disc degeneration. M1 macrophages produce proinflammatory cytokines that facilitate the progression of intervertebral disc degeneration (IDD).However, the anti-inflammatory and regenerative effects of M2 macrophages on nucleus pulposus cells (NPCs) in IDD progression remain unknown. Here, we aimed to determine the role of M2 macrophages in IDD progression. MethodsM2 conditioned medium (M2CM) was harvested and purified from THP-1 cells; it was then used for culturing human NPCs and a mouse intervertebral disc (IVD) organ culture model. NPCs and IVD organ models were divided into the following three groups: group 1 was treated with 10% fetal bovine serum to actas the control, group 2 was treated with 10 ng/ml TNF-α, and group 3 was treated with 10 ng/ml TNF-α and M2CMto act as the co-culture group. After 3 to 14 days, cell proliferation (CCK-8 assay and western blotting for proliferation markers), extracellular matrix synthesis (quantitative polymerase chain reaction, western blotting, and immunofluorescence), apoptosis (TUNEL staining and western blotting), and NPC senescence (senescence-associated beta-galactosidase staining and western blotting) were assessed.ResultsCD206 and interleukin (IL)-10 levels were increased after 48 h of induction for M2 macrophages (both p<0.01). Cell proliferation was decreased in TNF-α-treated NPCs and was inhibited by M2CM co-culture. Moreover, TNF-α treatment enhanced the apoptosis, senescence, and expression of inflammatory factor-related genes, including IL-6, MMP-13, ADAMTS-4, and ADAMTS-5, whereas M2CM co-culture significantly reversed these effects. M2CM promoted aggrecan and collagen II synthesis but reduced collagen Iα1 levels in TNF-α treatment groups. Using our established three-dimensional murine IVD organ culture model, M2CM suppressed the inhibitory effect of TNF-α of the TNF-α-rich environment. ConclusionsCollectively, these results indicate that M2CM promotes cell proliferation and extracellular matrix synthesis and inhibits inflammation, apoptosis, and NPC senescence. This study therefore highlights the therapeutic potential of M2CM for IDD.

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