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The role of lncRNA MALAT1 in intervertebral degenerative disc disease.

ABSTRACT: Intervertebral degenerative disc disease (IDDD) is a common disease in clinic that causes pain and heavy financial burden on patients with poor prognosis. However, the pathogenesis of IDDD is not clear. Long non-coding RNA (LncRNA) is involved in regulating various body growth and pathological processes by affecting cell proliferation, differentiation, and apoptosis. However, the role of lncRNAs in IDDD is rarely reported. This study aims to investigate the role and mechanism of lncRNA MALAT1 in the development of IDDD. The nucleus pulposus of the intervertebral disc were collected and the primary nucleus pulposus cells were isolated and cultured. The cells were divided into three groups, including IDDD group, empty plasmid group transfected by pcDNA3.1, or MALAT1 group transfected by pcDNA3.1-MALAT1. MALAT1 expression was detected by real-time PCR. Cell proliferation was assessed by MTT assay. Caspase 3 activity was tested by the activity detection kit. IL-1 and IL-6 levels were analyzed by ELISA. The expression of MALAT1 in IDDD nucleus pulposus cells was significantly lower than that in control group (P < 0.05). The expression of MALAT1 was significantly increased after transfection with pcDNA3.1-MALAT1 plasmid in IDDD nucleus pulposus cells, which obviously inhibited cell proliferation, enhanced Caspase 3 activity, and promoted the secretion of IL-1 and IL-6 compared with IDDD group (P < 0.05). MALAT1 level decreased in IDDD nucleus pulposus cells. Upregulation of MALAT1 expression restrained IDDD through suppressing inflammation; inhibiting nucleus pulposus cell apoptosis, and promoting cell proliferation.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6965762 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The role of lncRNA MALAT1 in intervertebral degenerative disc disease.

Zhang Hui H Li Jinde J Duan Dapeng D She Wei W Wang Liguo L Zhang Fuqiang F

International journal of clinical and experimental pathology 20171001 10

Intervertebral degenerative disc disease (IDDD) is a common disease in clinic that causes pain and heavy financial burden on patients with poor prognosis. However, the pathogenesis of IDDD is not clear. Long non-coding RNA (LncRNA) is involved in regulating various body growth and pathological processes by affecting cell proliferation, differentiation, and apoptosis. However, the role of lncRNAs in IDDD is rarely reported. This study aims to investigate the role and mechanism of lncRNA MALAT1 in ...[more]

PMID: 31966403

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Project description:IntroductionThe avascular nature of the human intervertebral disc (IVD) is thought to play a major role in disc pathophysiology by limiting nutrient supply to resident IVD cells. In the human IVD, the central IVD cells at maturity are normally chondrocytic in phenotype. However, abnormal cell phenotypes have been associated with degenerative disc diseases, including cell proliferation and cluster formation, cell death, stellate morphologies, and cell senescence. Therefore, we have examined the relative influence of possible blood-borne factors on the growth characteristics of IVD cells in vitro.MethodsBovine IVD cells were cultured either in monolayer to encourage cell proliferation or in alginate to induce chondrocytic differentiation. In both culture systems, cells were maintained with or without 20% serum, with or without 320 mg/dL glucose, and in atmospheric levels (~21%) of oxygen or 1% oxygen. Cell proliferation and viability, cell senescence, and collagen immunopositivity were assessed after 7 days. Statistical differences in these growth characteristics were tested using nonparametric analyses (n = 4 samples).ResultsIn both culture systems, serum deprivation significantly inhibited IVD cell proliferation and increased cell positivity for senescence-associated beta-galactosidase (SA-beta-gal), a marker of cell senescence. Conversely, IVD cells cultured in the presence of serum, but deprived of glucose, proliferated significantly more rapidly. In alginate cultures, this enhanced cell proliferation (through glucose deprivation) led to the formation of IVD cell clusters. Serum-deprived cells in monolayer, but not in alginate, adopted a stellate appearance. Oxygen deprivation alone had little effect on IVD cell proliferation or survival. Oxygen and glucose deprivation also had no significant effect on SA-beta-gal positivity. IVD cell viability was markedly and significantly decreased in serum-deprived alginate cultures, but in all other conditions remained at or greater than approximately 95%. Glucose deprivation, but not serum or oxygen deprivation, inhibited synthesis of type I and type II collagen, both in monolayer and alginate cultures.ConclusionThis study demonstrates that factors present in serum interact with other nutrients, notably glucose, to play a major role in regulating the behaviour of IVD cells. These findings suggest that IVD cell phenotypes seen in degenerative disc disease may arise through the cells' response to altered vascularisation and nutrient supply.

Project description:Study designIn vivo patient biomechanical study.ObjectiveTo investigate the dimensions of lumbar intervertebral foramen (LIVF) of patients with degenerative disc disease (DDD) during a flexion-extension motion of the body.Summary of background dataLIVF narrowing may result in nerve root compression. The area changes of degenerated and adjacent nondegenerated LIVFs in DDD patients under physiologic loading conditions are unknown.MethodsNine symptomatic low back pain patients with radiological evidence of L4-S1 DDD were recruited. Each subject was magnetic resonance imaging scanned for construction of three-dimensional lumbar vertebral models, and fluoroscopically imaged when the body extended from 45 flexion to full extension for reconstruction of LIVF dimensions. The data of the adjacent segment L3/4 and diseased segments L4/5 and L5/S1 were compared with a normal control group at 45 flexion, upright, and full extension of the body.ResultsThe mean LIVF areas of DDD segments were significantly smaller than those of the normal subjects in all positions (P <0.05). In upright position, the LIVF areas of the DDD patients were 32.8% and 33.6% smaller than the normal subjects for L4/5 and L5/S1, respectively. For the adjacent L3/4, the LIVF area of the DDD patients was 32.3% smaller than that of the normal controls (P <0.05). The total change of L3/4 LIVF area in DDD patients from flexion to extension was significantly smaller than that of the normal subjects, but the changes in L4/5 and L5/S1 LIVF areas were similar between the two groups (P >0.05).ConclusionSimilar reductions of the LIVF dimensions were observed at the adjacent and the involved levels of the DDD patients, implying that biomechanical changes might have already occurred at the adjacent segment despite the lack of radiographic evidence of degeneration. Subsequent research should focus on the effects of surgical fusion on the biomechanical features of the adjacent segment.Level of evidenceN/A.

Project description:BackgroundIntervertebral disc degeneration (IVDD) is considered a multifactorial disease that is influenced by both environmental and genetic factors. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single-nucleotide polymorphisms (SNPs) that are associated with IVDD.AimThis review presents comprehensive and updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD. An organized collection of information is provided regarding genetic polymorphisms that have been identified to influence the risk of developing IVDD. Understanding the proteins and signaling systems involved in IVDD can lead to improved understanding and targeting of therapeutics.Materials and methodsAn electronic literature search was performed using the National Library of Medicine for publications using the keywords genetics of IVDD, lumbar disc degeneration, degenerative disc disease, polymorphisms, SNPs, and disc disease. The articles were then screened based on inclusion criteria that included topics that covered the correlation of SNPs with developing IVDD. Sixty-five articles were identified as containing relevant information. Articles were excluded if they investigated lower back pain or just disc herniation without an analysis of disc degeneration. This study focuses on the chronic degeneration of IVDs.ResultsVarious genes were identified to contain SNPs that influenced the risk of developing IVDD. Among these are genes contributing to structural proteins, such as COL1A1, COL9A3, COL9A3, COL11A1, and COL11A2, ACAN, and CHST3. Furthermore, various SNPs found in the vitamin-D receptor gene are also associated with IVDD. SNPs related to inflammatory cytokine imbalance are associated with IVDD, although some effects are limited by sex and certain populations. SNPs in genes that code for extracellular matrix-degrading enzymes, such as MMP-1, MMP-2, MMP-3, MMP-9, MMP-14, ADAMTS-4, and ADAMTS-5 are also associated with IVDD. Apoptosis-mediating genes, such as caspase 9 gene (CASP9), TRAIL, and death receptor 4 (DR4), as well as those for growth factors, such as growth differentiation factor 5 and VEGF, are identified to have polymorphisms that influence the risk of developing IVDD.ConclusionWithin the last 10 years, countless new SNPs have been identified in genes previously unknown to be associated with IVDD. Furthermore, the last decade has also revealed new SNPs identified in genes already known to be involved with increased risk of developing IVDD. Improved understanding of the numerous genetic variants behind various pathophysiological elements of IVDD could help advance personalized care and pharmacotherapeutic strategies for patients suffering from IVDD in the future.

Project description:Accumulating evidence has indicated that noncoding RNAs are involved in intervertebral disc degeneration (IDD); however, the competing endogenous RNA (ceRNA)‑mediated regulatory mechanisms in IDD remain rarely reported. The present study aimed to comprehensively investigate the alterations in expression levels of circular RNA (circRNA), long noncoding RNA (lncRNA), microRNA (miRNA/miR) and mRNA in the nucleus pulposus (NP) of patients with IDD. In addition, crucial lncRNA/circRNA‑miRNA‑mRNA ceRNA interaction axes were screened using the GSE67567 microarray dataset obtained from the Gene Expression Omnibus database. After data preprocessing, differentially expressed circRNAs (DECs), lncRNAs (DELs), miRNAs (DEMs) or genes (DEGs) between IDD and normal controls were identified using the Linear Models for Microarray data method. A protein‑protein interaction (PPI) network was constructed for DEGs based on protein databases, followed by module analysis. The ceRNA network was constructed based on the interaction between miRNAs and mRNAs, and lncRNAs/circRNAs and miRNAs. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery database. The present study identified 636 DECs, 115 DELs, 84 DEMs and 1,040 DEGs between patients with IDD and control individuals. PPI network analysis demonstrated that Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), mitogen‑activated protein kinase 1 (MAPK1), hypoxia inducible factor 1 subunit α (HIF1A) and transforming growth factor β1 (TGFB1) were hub genes and enriched in modules. Metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1)/hsa_circRNA_102348‑hsa‑miR‑185‑5p‑TGFB1/FOS, MALAT1‑hsa‑miR‑155‑5p‑HIF1A, hsa_circRNA_102399‑hsa‑miR‑302a‑3p‑HIF1A, MALAT1‑hsa‑miR‑519d‑3p‑MAPK1 and hsa_circRNA_100086‑hsa‑miR‑509‑3p‑MAPK1 ceRNA axes were obtained by constructing the ceRNA networks. In conclusion, these identified ceRNA interaction axes may be crucial targets for the treatment of IDD.

Dataset Information

The role of lncRNA MALAT1 in intervertebral degenerative disc disease.

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The role of lncRNA MALAT1 in intervertebral degenerative disc disease.

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