scholarly journals Analysis of key genes and pathways associated with pathogenesis of intervertebral disc degeneration

2020 ◽  
Author(s):  
Shiyu Hu ◽  
Yucheng Fu ◽  
Bin Yan ◽  
Zhe Shen ◽  
Tao Lan
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Matrix Organization ◽  
Underlying Mechanisms ◽  
Upregulated Genes

Abstract Background: Intervertebral disc degeneration (IDD) is widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. The aim of this study is to analyze the dataset GSE23130 using bioinformatics methods to identify the pivotal genes and pathways associated with IDD. Material/Methods: The gene expression data of GSE23130 was downloaded and differentially expressed genes (DEGs) were extracted from 8 samples and 15 controls. GO and KEGG pathway enrichment analyses were performed. In addition, Protein–protein interaction (PPI) network was constructed and visualized, followed by identification of hub genes and key module. Results: A total of 30 downregulated and 79 upregulated genes were identified. The DEGs mainly enriched in regulation of protein catabolic process, extracellular matrix organization, collagen fibril organization, and extracellular structure organization. Meanwhile, we found that most of DEGs were primarily enriched in PI3K-Akt signaling pathway. The top 10 hub genes were FN1, COL1A2, SPARC, COL3A1, CTGF, LUM, TIMP1, THBS2, COL5A2, and TGFB1. Conclusions: In summary, key candidate genes and pathway were identified by using integrated bioinformatics analysis, which may provide insights into underlying mechanisms and offer potential target genes for the treatment of IDD.

scholarly journals Analysis of key genes and pathways associated with the pathogenesis of intervertebral disc degeneration

2020 ◽  
Author(s):  
Shiyu Hu ◽  
Yucheng Fu ◽  
Bin Yan ◽  
Zhe Shen ◽  
Tao Lan
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Underlying Mechanism ◽  
Hub Genes ◽  
Protein Protein Interaction ◽  
Matrix Organization ◽  
Underlying Mechanisms ◽  
Upregulated Genes

Abstract Background: Intervertebral disc degeneration (IDD) is widely known as a main contributor to low back pain which has a negative socioeconomic impact worldwide. However, the underlying mechanism remains unclear. This study aims to analyze the dataset GSE23130 using bioinformatics methods to identify the pivotal genes and pathways associated with IDD.Material/Methods: The gene expression data of GSE23130 was downloaded and differentially expressed genes (DEGs) were extracted from 8 samples and 15 controls. GO and KEGG pathway enrichment analyses were performed. Also, Protein–protein interaction (PPI) network was constructed and visualized, followed by identification of hub genes and key module.Results: A total of 30 downregulated and 79 upregulated genes were identified. The DEGs mainly enriched in regulation of protein catabolic process, extracellular matrix organization, collagen fibril organization, and extracellular structure organization. Meanwhile, we found that most of DEGs were primarily enriched in PI3K-Akt signaling pathway. The top 10 hub genes were FN1, COL1A2, SPARC, COL3A1, CTGF, LUM, TIMP1, THBS2, COL5A2, and TGFB1.Conclusions: In summary, key candidate genes and pathway were identified by using integrated bioinformatics analysis, which may provide insights into underlying mechanisms and offer potential target genes for the treatment of IDD.

scholarly journals Identification of microRNAs and target genes associated with the development of human intervertebral disc degeneration by bioinformatic analysis and verification

2019 ◽  
Author(s):  
Hongze Chang ◽  
Xiaolong Yang ◽  
Kemin You ◽  
Mingwei Jiang ◽  
Feng Cai ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Intervertebral Disc ◽  
Wnt Signaling ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Cell Development ◽  
Functional Enrichment ◽  
Hub Genes ◽  
Micro Rnas

Abstract Micro RNAs (miRNAs) are widely recognized to play an essential role via target genes in the development of intervertebral disc degeneration( IDD), but the molecular mechanisms remain unclear. To identify the key microRNAs and potential targets during IDD, the Gene Expression Omnibus datasets (GSE19943, GSE63492, and GSE116726) were downloaded.An R package was used to identify differentially expressed miRNAs (DEMs) and four online tools(TargetScan, miRDB, miRTarBase, and DIANA-TarBase) were performed to predict their target genes. Functional enrichment analysis revealed that DEMs gene targets were highly enriched in cell development, cell differentiation, and the p53 and Wnt signaling pathways. we identified 13 hub genes with node degree≥10 through established a protein-protein interaction (PPI) network. Among them,MAPK8, BMP4, and GSK3B were top 3 highest degree. After constructing the miRNA-target gene-functional analysis network, we found that most hub genes could be regulated by miR-557 and were mainly enriched in cell development, cell differentiation, and Wnt signaling pathway. Further in vitro experiment by qRT-PCR confirmed that miR-577 was significantly downregulated than the control,whereas miR-516-3p was significantly upregulated. Together, the key microRNA and their target genes identified in this study help us understand the underlying pathogenesis mechanisms in the development of IDD, and provide diagnostic biomarkers and new therapeutic strategies for the treatment of IDD.

scholarly journals Identification of Key Genes and Pathways Associated With Pathogenesis of Intervertebral Disc Degeneration by Integrated miRNA-mRNA Network Analysis

2021 ◽  
Author(s):  
Tao Lan ◽  
Ning-dao Li ◽  
Zhe Shen ◽  
Xiao-sheng Chen ◽  
Shi-yu Hu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Intervertebral Disc ◽  
Signaling Pathway ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Critical Pathways ◽  
Underlying Mechanisms

Abstract Background: Intervertebral disc degeneration (IDD) is one of the most common cause of low back pain. Previous studies have suggested that miRNAs are associated with the pathogenesis of IDD. However, the underlying mechanisms remain unclear based on inconsistent results of available literatures. In addition, integrated miRNA-mRNA comprehensive analysis is limited. Material/Methods: In this study, we investigated the profiles of differentially expressed miRNAs (DEMIs) and mRNAs (DEGs) and constructed a miRNA-mRNA regulatory network. First, transcription factors and target genes of DEMIs were predicted. Then, an intersection between DEMIs predicted genes and DEGs were performed to screen out the most significant differential expressed common genes. Results: A total of 65 DEMIs and 61 common target genes were identified from datasets. Functional enrichment analysis showed that most genes were mainly involved in extracellular matrix organization and extracellular structure organization. Furthermore, DEGs were primarily enriched in PI3K−Akt signaling pathway, ECM−receptor interaction, focal adhesion and p53 signaling pathway, indicating that these pathways may be the critical pathways.Conclusions: In summary, several important miRNAs, as well as their related target genes and transcription factors in the pathogenesis of IDD were identified from our bioinformatic analysis, which may provide insights into underlying mechanisms and offer potential target genes for the treatment of IDD.

scholarly journals Emerging evidence on noncoding-RNA regulatory machinery in intervertebral disc degeneration: a narrative review

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Hao-Yu Guo ◽  
Ming-Ke Guo ◽  
Zhong-Yuan Wan ◽  
Fang Song ◽  
Hai-Qiang Wang
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Noncoding Rna ◽  
Regulatory Networks ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Noncoding Rnas ◽  
Circular Rnas ◽  
Form Complex ◽  
Underlying Mechanisms

AbstractIntervertebral disc degeneration (IDD) is the most common cause of low-back pain. Accumulating evidence indicates that the expression profiling of noncoding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), are different between intervertebral disc tissues obtained from healthy individuals and patients with IDD. However, the roles of ncRNAs in IDD are still unclear until now. In this review, we summarize the studies concerning ncRNA interactions and regulatory functions in IDD. Apoptosis, aberrant proliferation, extracellular matrix degradation, and inflammatory abnormality are tetrad fundamental pathologic phenotypes in IDD. We demonstrated that ncRNAs are playing vital roles in apoptosis, proliferation, ECM degeneration, and inflammation process of IDD. The ncRNAs participate in underlying mechanisms of IDD in different ways. MiRNAs downregulate target genes’ expression by directly binding to the 3′-untranslated region of mRNAs. CircRNAs and lncRNAs act as sponges or competing endogenous RNAs by competitively binding to miRNAs and regulating the expression of mRNAs. The lncRNAs, circRNAs, miRNAs, and mRNAs widely crosstalk and form complex regulatory networks in the degenerative processes. The current review presents novel insights into the pathogenesis of IDD and potentially sheds light on the therapeutics in the future.

scholarly journals The Role of Unfolded Protein Response in Human Intervertebral Disc Degeneration: Perk and IRE1-α as Two Potential Therapeutic Targets

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Tianyong Wen ◽  
Peng Xue ◽  
Jinwei Ying ◽  
Shi Cheng ◽  
Yue Liu ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Underlying Mechanism ◽  
Nucleus Pulposus Cells ◽  
Unfolded Protein ◽  
Underlying Mechanisms ◽  
Protein Response

Inflammation plays a key role in intervertebral disc degeneration (IDD). The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, whether ER stress plays an important role in IDD remains unclear. Therefore, this study is aimed at investigating the expression of ER stress in IDD and at exploring the underlying mechanisms of IDD, ER stress, and inflammation. The expression of ER stress was activated in nucleus pulposus cells from patients who had IDD (D-NPCs) compared with patients without IDD (N-NPCs); and both the proliferation and synthesis capacity were decreased by inducer tunicamycin (Tm) and proinflammatory cytokines. Pretreatment of NPCs with 4-phenyl butyric acid (4-PBA) prevented the inflammatory cytokine-induced upregulation of unfolded protein response- (UPR-) related proteins and recovered cell synthetic ability. Furthermore, proinflammatory cytokine treatment significantly upregulated the expression of inositol-requiring protein 1 (IRE1-α) and protein kinase RNA-like ER kinase (PERK), but not activating transcription factor 6 (ATF6). Finally, knockdown of IRE1-α and PERK also restored the biological activity of NPCs. Our findings identified that IRE1-α and PERK might be the potential targets for IDD treatment, which may help illustrate the underlying mechanism of ER stress in IDD.

A Bioinformatic Analysis of MicroRNAs’ Role in Human Intervertebral Disc Degeneration

Pain Medicine ◽  
2019 ◽  
Vol 20 (12) ◽  
pp. 2459-2471 ◽  
Author(s):  
Xue-Qiang Wang ◽  
Wen-Zhan Tu ◽  
Jia-Bao Guo ◽  
Ge Song ◽  
Juan Zhang ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Health Care Policy ◽  
Target Genes ◽  
Biological Process ◽  
Regulation Of Gene Expression ◽  
Bioinformatic Analysis ◽  
Nervous System Development ◽  
Negative Regulation

AbstractObjectives The aim of our study was to ascertain the underlying role of microRNAs (miRNAs) in human intervertebral disc degeneration (IDD).Design Bioinformatic analysis from multiple databases.Methods Studies of the association of miRNAs and IDD were identified in multiple electronic databases. All potential studies were assessed by the same inclusion and exclusion criteria. We recorded whether miRNA expression was commonly increased or suppressed in the intervertebral disc tissues and cells of IDD subjects. We used String to identify biological process and cellular component pathways of differentially expressed genes.Results We included fifty-seven articles from 1,277 records in this study. This report identified 40 different dysregulated miRNAs in 53 studies, including studies examining cell apoptosis (26 studies, 49.06%), cell proliferation (15 studies, 28.3%), extracellular matrix (ECM) degradation (10 studies, 18.86%), and inflammation (five studies, 9.43%) in IDD patients. Three upregulated miRNAs (miR-19b, miR-32, miR-130b) and three downregulated miRNAs (miR-31, miR-124a, miR-127-5p) were considered common miRNAs in IDD tissues. The top three biological process pathways for upregulated miRNAs were positive regulation of biological process, nervous system development, and negative regulation of biological process, and the top three biological process pathways for downregulated miRNAs were negative regulation of gene expression, intracellular signal transduction, and negative regulation of biological process.Conclusions This study revealed that miRNAs could be novel targets for preventing IDD and treating patients with IDD by regulating their target genes. These results provide valuable information for medical professionals, IDD patients, and health care policy makers.

scholarly journals Propionibacterium acnes Induces Intervertebral Disc Degeneration by Promoting iNOS/NO and COX-2/PGE2 Activation via the ROS-Dependent NF-κB Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yazhou Lin ◽  
Guoqing Tang ◽  
Yucheng Jiao ◽  
Ye Yuan ◽  
Yuehuan Zheng ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Propionibacterium Acnes ◽  
Intervertebral Discs ◽  
Cox 2 ◽  
Underlying Mechanisms

Accumulating evidence suggests that Propionibacterium acnes (P. acnes) is a novel pathogenic factor promoting intervertebral disc degeneration (IVDD). However, the underlying mechanisms by which P. acnes induces IVDD have been unclear. In this study, we quantified the severity of IVDD, as well as the expressions of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase (COX-2)/prostaglandin (PGE2) in human intervertebral discs (IVDs) infected with P. acnes. Compared with P. acnes-negative IVDs, P. acnes-positive IVDs showed increased iNOS/NO and COX-2/PGE2 activity concomitant with more severe IVDD. In order to detect the potential correlation between iNOS/NO expression, COX-2/PGE2 expression, and IVDD, we developed a P. acnes-induced IVDD rat model and found that the upregulation of iNOS/NO and COX-2/PGE2 was essential to the occurrence of P. acnes-induced IVDD. This finding was supported by the fact that the inhibition of iNOS/NO and COX-2/PGE2 activity ameliorated IVDD significantly, as evidenced by restored aggrecan and collagen II expression both in vivo and in vitro. Mechanistically, we found that P. acnes induced iNOS/NO and COX-2/PGE2 expressions via a reactive oxygen species- (ROS-) dependent NF-κB cascade. Furthermore, NADPH oxidase participated in P. acnes-induced ROS, iNOS/NO, and COX-2/PGE2 expressions. Overall, these findings further validated the involvement of P. acnes in the pathology of IVDD and provided evidence that P. acnes-induced iNOS/NO and COX-2/PGE2 activation via the ROS-dependent NF-κB pathway is likely responsible for the pathology of IVDD.

scholarly journals Integrated Analysis of a circRNA-miRNA-mRNA Axis in Intervertebral Disc Degeneration

2020 ◽  
Author(s):  
Laifu Wei ◽  
Bizhi Tu ◽  
Fei Gao ◽  
Jun Qian
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Underlying Mechanism ◽  
Differentially Expressed ◽  
Circular Rnas ◽  
Integrated Analysis ◽  
Control Group ◽  
Common Symptom ◽  
Sequencing Data

Abstract Background: Low back pain (LBP) is a common symptom in daily life and one of the primary causes is intervertebral disc degeneration (IDD). Growing studies have indicated that circular RNAs (circRNAs) are intimately associated with IDD; however, the underlying mechanism has not yet been elucidated. We aimed to explore how circRNAs regulate IDD in an effort to provide novel insight for clinical diagnosis and treatment. Methods: The sequencing data of circRNAs, microRNAs (miRNAs), and mRNA were acquired from Gene Expression Omnibus (GEO) datasets. By analyzing the dataset consisting of a control group and degenerated group, differentially expressed circRNAs, miRNAs, and mRNAs were collected, and then the intersection of circRNAs, miRNAs, and mRNAs was screened. According to these intersectional RNAs, we constructed an integrally circRNA-miRNA-mRNA network. Finally, using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, we further clarified functions of the intersectional mRNA in IDD. Results: we obtained 620 differentially expressed circRNAs(DEcircRNAs), 13 miRNA (DEmiRNA), 273 mRNAs(DEmRNAs), 12 intersectional miRNAs, and 47 intersectional mRNAs. Finally, based on interactional 8 circRNA, 5 miRNAs and 15 mRNAs, an integrally circRNA-miRNA-mRNA network was constructed. Eight circRNAs, contained hsa_circ_0032254, hsa_circ_0003183, hsa_circ_0032253, hsa_circ_0001293, hsa_circ_0004565, hsa_circ_0091570, hsa_circ_0077526, and hsa_circ_0057552, may regulate IDD onset and progression by acting as competing endogenous RNAs. The results of GO and KEGG analyses implied that the targeted genes might significantly correlate to IDD.Conclusion: our findings improved a better understanding of the circRNA-related ceRNA regulatory mechanism in IDD and offered possible targets for IDD treatment.

scholarly journals Suramin attenuates intervertebral disc degeneration by inhibiting NF-κB signalling pathway

2021 ◽  
Vol 10 (8) ◽  
pp. 498-513
Author(s):  
Zi-Miao Liu ◽  
Cheng-Chang Lu ◽  
Po-Chih Shen ◽  
Shih-Hsiang Chou ◽  
Chia-Lung Shih ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Treatment Options ◽  
Underlying Mechanism ◽  
Mitogen Activated Protein Kinase ◽  
Blue Staining ◽  
Alcian Blue Staining

Aims Interleukin (IL)-1β is one of the major pathogenic regulators during the pathological development of intervertebral disc degeneration (IDD). However, effective treatment options for IDD are limited. Suramin is used to treat African sleeping sickness. This study aimed to investigate the pharmacological effects of suramin on mitigating IDD and to characterize the underlying mechanism. Methods Porcine nucleus pulposus (NP) cells were treated with vehicle, 10 ng/ml IL-1β, 10 μM suramin, or 10 μM suramin plus IL-1β. The expression levels of catabolic and anabolic proteins, proinflammatory cytokines, mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-κB-related signalling molecules were assessed by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence analysis. Flow cytometry was applied to detect apoptotic cells. The ex vivo effects of suramin were examined using IDD organ culture and differentiation was analyzed by Safranin O-Fast green and Alcian blue staining. Results Suramin inhibited IL-1β-induced apoptosis, downregulated matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5, and upregulated collagen 2A (Col2a1) and aggrecan in IL-1β-treated NP cells. IL-1β-induced inflammation, assessed by IL-1β, IL-8, and tumour necrosis factor α (TNF-α) upregulation, was alleviated by suramin treatment. Suramin suppressed IL-1β-mediated proteoglycan depletion and the induction of MMP-3, ADAMTS-4, and pro-inflammatory gene expression in ex vivo experiments. Conclusion Suramin administration represents a novel and effectively therapeutic approach, which could potentially alleviate IDD by reducing extracellular matrix (ECM) deposition and inhibiting apoptosis and inflammatory responses in the NP cells. Cite this article: Bone Joint Res 2021;10(8):498–513.

scholarly journals A novel circRNA–miRNA–mRNA network reveals hsa-circ-0040039 as a biomarker for intervertebral disc degeneration

2021 ◽  
Vol 49 (12) ◽  
pp. 030006052096098
Author(s):  
Jianhua Tang ◽  
Chenlin Zhang ◽  
Shengru Wang ◽  
Jianfeng Chen
Keyword(s):  
Intervertebral Disc ◽  
Disc Degeneration ◽  
Intervertebral Disc Degeneration ◽  
Target Genes ◽  
Coagulation Factor ◽  
Circular Rna ◽  
Change Score ◽  
Intervertebral Discs ◽  
Gene Expression Omnibus ◽  
And Function

Objective Alterations in the structure and function of intervertebral discs by multifaceted chronic processes can result in intervertebral disc degeneration (IDD). The mechanisms involved in IDD are still unknown. Methods We investigated the possible mechanisms underlying IDD using a bioinformatics analysis of publicly available microarray expression datasets and built a circular RNA–microRNA–mRNA (circRNA–miRNA–mRNA) network based on the results. Datasets GSE67566 and GSE116726 were downloaded from the Gene Expression Omnibus (GEO) and analyzed using the limma package in R. The CircInteractome database was used to detect miRNAs related to circRNA, and TargetScan, miRDB, and miRTarBase were used to predict target mRNAs. Key target genes were annotated using Gene Ontology terms. Results The circRNA hsa-circ-0040039 was found to have the top log fold-change score. Analysis using Metascape showed that the associated genes were enriched mainly in the cell cycle. The Cytoscape plugin MCODE predicted that two members of the RAS oncogene family—RAB1A and RAB1B—and multiple coagulation factor deficiency (MCFD2) may play key roles in IDD. Conclusion Our results suggested that hsa-circ-0040039 and the related network may be potential biomarkers for IDD.

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