Dataset Information

The Regulatory Effect of MicroRNA-101-3p on Disc Degeneration by the STC1/VEGF/MAPK Pathway.

ABSTRACT: Aims. Accumulating evidence reported that the microRNA (miRNA) took an important role in intervertebral disc degeneration (IDD). In this study, we revealed a novel miRNA regulatory mechanism in IDD. Main Methods. The miRNA microarray analyses of human degenerated and normal disc samples were employed to screen out the target miRNA. In vitro and in vivo experiments were conducted to verify the regulatory effect of miR-101-3p. Key Findings. The expression level of miR-101-3p was significantly decreased in the degenerated disc samples which were confirmed by qRT-PCR. Moreover, the miR-101-3p expression level was changed dynamically according to the disc degeneration grade. Upregulation of miR-101-3p expression level inhibited cell apoptosis. Furthermore, stanniocalcin-1 (STC1) was selected to be the target gene of miR-101-3p according to the bioinformatic algorithms. Mechanically, upregulation of miR-101-3p significantly decreased the expression of STC1, vascular endothelial growth factor (VEGF), and MAPK pathway expression levels. Therapeutically, in vivo experiment on IDD rat model illustrated that agomir-101-3p could effectively suspend IDD. Significance. Our findings demonstrated that miR-101-3p alleviated IDD process through the STC1/VEGF/MAPK pathway.

SUBMITTER: Wang J

PROVIDER: S-EPMC8510813 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The Regulatory Effect of MicroRNA-101-3p on Disc Degeneration by the STC1/VEGF/MAPK Pathway.

Wang Juehan J Huang Leizhen L Yang Xi X Zhu Ce C Huang Yong Y He Xin X Shi Kun K Wang Jingcheng J Feng Ganjun G Liu Limin L Song Yueming Y

Oxidative medicine and cellular longevity 20211005

Aims. Accumulating evidence reported that the microRNA (miRNA) took an important role in intervertebral disc degeneration (IDD). In this study, we revealed a novel miRNA regulatory mechanism in IDD. Main Methods. The miRNA microarray analyses of human degenerated and normal disc samples were employed to screen out the target miRNA. In vitro and in vivo experiments were conducted to verify the regulatory effect of miR-101-3p. Key Findings. The expression level of miR-101-3p w ...[more]

PMID: 34650661

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Project description:Intervertebral disc degeneration (IVDD) remains a clinical challenge and requires more effective therapeutic targets. Long noncoding RNAs (lncRNAs) have emerged as critical modulators of multiple biological processes, such as cell proliferation and extracellular matrix (ECM) remodeling. Accordingly, the current study sets out to explore the influence of the lncRNA growth arrest-specific 5 (GAS5) on IVDD and investigate the possible involvement of microRNA-17-3p (miR-17-3p)/Angiopoietin-2 (Ang-2) axis. Firstly, the expression patterns of GAS5, miR-17-3p, and Ang-2 were characterized by RNA quantification from the isolated human degenerative nucleus pulposus (NP) tissues. miR-17-3p was found to express at an abnormal low level while GAS5 and Ang-2 expressed at aberrant high level in the human degenerative NP tissues. Utilizing dual-luciferase reporter, RNA immunoprecipitation, and pull-down assays, GAS5 was found to competitively bound to miR-17-3p and further upregulate the expression of Ang-2, a target gene of miR-17-3p. Employing gain- and loss-of-function approaches, their expressions were altered in human degenerative nucleus pulposus cells (NPCs), followed by IL-1β treatment, in order to identify their roles in NP cell proliferation, apoptosis, and ECM metabolism. Silencing of GAS5 expression restrained the levels of cleaved caspase-3, cleaved caspase-7, cleaved caspase-9, MMP3, MMP13, ADAMTS4, and ADAMTS5 and increased collagen II and aggrecan levels. In vitro experiments also revealed that GAS5 depletion inhibited apoptosis and ECM degradation in HDNPCs, while elevating the proliferation through downregulation of Ang-2 by increasing miR-17-3p. Furthermore, in vivo data further validated that either GAS5 silencing or miR-17-3p reexpression alleviated IVDD degree with the help of IVDD mouse models. Altogether, our findings substantiated that downregulation of GAS5 reduced NPC apoptosis and promoted ECM remodeling, ultimately ameliorating the IVDD via miR-17-3p-dependent inhibition of Ang-2. We hope our discoveries offer a fresh molecular insight that can aid the development of novel therapies against IVDD.

Project description:MicroRNAs (miRNAs) are associated with healing or deteriorating degenerated intervertebral disc (IVD) tissues in spinal cord diseases, including intervertebral disc degeneration (IDD). IDD represents a chronic process of extracellular matrix destruction, but the relevant molecular mechanisms implicated in the regenerative effects of miRNAs are unclear. Here, we investigated the regenerative effects of microRNA-140 (miR-140-3p) in an IDD model induced by annulus needle puncture. Bioinformatics analysis was conducted to identify regulatory factors (KLF5/N-cadherin/MDM2/Slug) linked to miR-140-3p effects in IDD. Mesenchymal stem cells (MSCs) were extracted from degenerated IVD nucleus pulposus (NP), and the expression of miR-140-3p/KLF5/N-cadherin/MDM2/Slug was manipulated to explore their effects on cell proliferation, migration, apoptosis and differentiation. The results showed that miR-140-3p was under-expressed in the degenerated IVD NP, whereas its overexpression alleviated IDD. Mechanistic studies suggested that miR-140-3p targeted KLF5 expression, and high KLF5 expression impeded the migration and differentiation of MSCs. In degenerated IVD NP-derived MSCs, MiR-140-3p-mediated KLF5 downregulation simultaneously elevated N-cadherin expression and transcriptionally inhibited MDM2, thus upregulating Slug expression. The experimental data indicated that miR-140-3p enhanced the proliferation, migration and differentiation of degenerated IVD NP-derived MSCs and repressed their apoptosis. The in vivo validation experiment also demonstrated that miR-140-3p inhibited IDD by modulating the KLF5/N-cadherin/MDM2/Slug axis. Collectively, our results uncovered the regenerative role of miR-140-3p in IDD via regulation of the KLF5/N-cadherin/MDM2/Slug axis, which could be a potential therapeutic target for IDD.Abbreviations: miR-140-3p: microRNA-140-3p; IDD: intervertebral disc degeneration; MSCs: Mesenchymal stem cells; IVD: intervertebral disc; MSCs: mesenchymal stem cells; KLF5: Kruppel-like factor 5; MDM2: mouse double minute 2; NC: negative control; DHI: disc height index.

Dataset Information

The Regulatory Effect of MicroRNA-101-3p on Disc Degeneration by the STC1/VEGF/MAPK Pathway.

Publications

The Regulatory Effect of MicroRNA-101-3p on Disc Degeneration by the STC1/VEGF/MAPK Pathway.

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