circARL15 Plays a Critical Role in Intervertebral Disc Degeneration by Modulating miR-431-5p/DISC1

Wang, Hanbang; Zhu, Yakun; Cao, Le; Guo, Ziming; Sun, Kai; Qiu, Wangbao; Fan, Haitao

doi:10.3389/fgene.2021.669598

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…The binding between circRNAs and miRNAs regulates cell proliferation, mitophagy, and apoptosis in IDD [ 10 ]. Of note, miR-431-5p has been documented to be upregulated in IDD and circARL15 acts as a ceRNA to reduce miR-431-5p expression, thus inhibiting NPC apoptosis but inducing NPC proliferation to alleviate IDD [ 35 ], providing validation of our finding.…”

Section: Discussionsupporting

confidence: 78%

circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Ferroptosis, as an iron-dependent form of necrotic cell death, has been reported to affect activities of nucleus pulposus cells (NPCs). However, its role in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. Notably, our bioinformatics analysis predicted that circ_0072464 was downregulated in nucleus pulposus of IDD mice. Therefore, this study is aimed at clarifying the mechanisms of extracellular vesicle- (EV-) encapsulated circ_0072464 derived from bone marrow mesenchymal stem cells (BMSCs) in NPC ferroptosis in IDD. EVs were extracted from mouse BMSCs (BMSC-EVs) and then cocultured with IL-1β-induced NPCs, followed by detection of matrix synthesis, proliferation, and ferroptosis of NPCs based on gain- or loss-of-function experiments. It was found that the uptake of BMSC-EVs by NPCs alleviated IDD. circ_0072464 and NRF2 were downregulated, and miR-431 was upregulated in IDD. Mechanistically, circ_0072464 competitively bound to miR-431, which targeted and inhibited NRF2 expression. BMSC-derived EVs carrying circ_0072464 inhibited NPC ferroptosis to promote matrix synthesis and proliferation of NPCs by inhibiting miR-431 and upregulating NRF2. Besides, in vivo experiments also confirmed that BMSC-EVs alleviated intervertebral disc lesions in mice with IDD through the circ_0072464/miR-431/NRF2 axis. Collectively, BMSC-EV-loaded circ_0072464 inhibited NPC ferroptosis to relieve IDD via upregulation of miR-431-mediated NRF2, therefore providing a potential therapeutic target against IDD.

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Section: Discussionsupporting

confidence: 78%

circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Hydrogen peroxide can activate the senescence signal transduction pathway and induce cell cycle stagnation in G0/ G1 phase of nucleus pulposus cells. These studies indicate that oxidative stress is an important inducement of intervertebral disc degeneration (Yudoh et al, 2005;Wang et al, 2021a).…”

Section: Introductionmentioning

confidence: 79%

Key LncRNAs Associated With Oxidative Stress Were Identified by GEO Database Data and Whole Blood Analysis of Intervertebral Disc Degeneration Patients

Jiang

Guo

et al. 2022

Front. Genet.

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Background: Intervertebral disc degeneration (IDD) is a major cause of low back pain, but the onset and progression of IDD are unknown. Long non-coding RNA (lncRNA) has been validated to play a critical role in IDD, while an increasing number of studies have linked oxidative stress (OS) to the initiation and progression of IDD. We aim to investigate key lncRNAs in IDD through a comprehensive network of competing endogenous RNA (ceRNA) and to identify possible underlying mechanisms.Methods: We downloaded IDD-related gene expression data from the Gene Expression Omnibus (GEO) database and obtained differentially expressed-lncRNAs (DE-lncRNA), -microRNAs (DE-miRNA), and -messenger RNAs (DE-mRNA) by bioinformatics analysis. The OS-related lncRNA-miRNA-mRNA ceRNA interaction axis was constructed and key lncRNAs were identified based on ceRNA theory. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses on mRNAs regulated by lncRNAs in the ceRNA network. Single sample gene set enrichment analysis (ssGSEA) was used to reveal the immune landscape. Expression of key lncRNAs in IDD was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR).Results: In this study, 111 DE-mRNAs, 20 DE-lncRNAs, and 502 DE-miRNAs were identified between IDD patients and controls, and 16 OS-related DE-lncRNAs were also identified. The resulting lncRNA-miRNA-mRNA network consisted of eight OS-related DE-lncRNA nodes, 24 DE-miRNA nodes, 70 DE-mRNA nodes, and 183 edges. Functional enrichment analysis suggested that the ceRNA network may be involved in regulating biological processes related to cytokine secretion, lipid, and angiogenesis. We also identified four key lncRNAs, namely lncRNA GNAS-AS1, lncRNA MIR100HG, lncRNA LINC01359, and lncRNA LUCAT1, which were also found to be significantly associated with immune cells.Conclusion: These results provide novel insights into the potential applications of OS-related lncRNAs in patients with IDD.

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“…Zhang et al [ 36 ] also demonstrated that circSNHG5 inhibited cartilage endplate degradation through sponging mir-495-3p to derepress CITED2. Wang et al [ 37 ] reported that circARL15 modulated IDD progression via regulating the miR-431-5p/DISC1 axis. Zhang et al [ 38 ] demonstrated that circ_ITCH induced ECM degradation through regulating Wnt/β-catenin signaling in IDD.…”

Section: Discussionmentioning

confidence: 99%

Hsa_circ_0134111 promotes intervertebral disc degeneration via sponging miR-578

et al. 2022

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Intervertebral disc degeneration (IDD) is a chronic degenerative and age-dependent process characterized by aberrant apoptosis, proliferation, synthesis, and catabolism of the extracellular matrix of the nucleus pulposus (NP) cells. Recently, studies showed that circular RNAs play important roles in the development of many diseases. However, the role of circRNAs in IDD development remains unknown. We showed that circ_0134111 level was overexpressed in IDD tissue samples as compar-ed to control tissues. The upregulation of circ_0134111 was more drastic in the moderate and severe IDD cases than in those with mild IDD. In addition, we showed that interleukin-1β and tumor necrosis factor-α exposure significantly enhanced circ_0134111 expression in NP cells. Furthermore, ectopic expression of circ_0134111 induced proliferation, pro-inflammatory cytokine secretion, and ECM degradation in the NP cells. We also showed that circ_0134111 directly interacted with microRNA (miR)-578 in NP cells where elevated expression of circ_0134111 enhanced the ADAMTS-5 and MMP-9 expression. Moreover, miR-578 expression was significantly decreased in IDD patients and the miR-578 expression was negatively correlated with circ_0134111 expression in the IDD samples. Interleukin-1β and tumor necrosis factor-α exposure significantly decreased miR-578 levels in NP cells, in which ectopic miR-578 expression inhibited cell growth, pro-inflammatory cytokine expression, and ECM degradation. Finally, we showed that circ_0134111 overexpression induced the IDD-related phenotypic changes through inhibiting miR-578. These data suggested that circ_0134111 could promote the progression of IDD through enhancing aberrant NP cell growth, inflammation, and ECM degradation partly via regulating miR-578.

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circARL15 Plays a Critical Role in Intervertebral Disc Degeneration by Modulating miR-431-5p/DISC1

Cited by 14 publications

References 30 publications

circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration

circ_0072464 Shuttled by Bone Mesenchymal Stem Cell-Secreted Extracellular Vesicles Inhibits Nucleus Pulposus Cell Ferroptosis to Relieve Intervertebral Disc Degeneration

Key LncRNAs Associated With Oxidative Stress Were Identified by GEO Database Data and Whole Blood Analysis of Intervertebral Disc Degeneration Patients

Hsa_circ_0134111 promotes intervertebral disc degeneration via sponging miR-578

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