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CircSPG21 protects against intervertebral disc disease by targeting miR-1197/ATP1B3.

ABSTRACT: The abnormal expression of circular RNAs (circRNAs) is associated with numerous human diseases. This study investigated the mechanism by which circRNA acts as competitive endogenous RNA in the regulation of degenerative intervertebral disc disease (IVDD). Decreased expression of circSPG21 was detected in degenerated nucleus pulposus cells (NPCs), the function of circSPG21 in NPCs was explored and verified, and the downstream target of circSPG21 was investigated. The interaction between circSPG21 and miR-1197 and its target gene (ATP1B3) was studied by online database prediction and molecular biological verification. Finally, the circSPG21/miR-1197/ATP1B3 axis was verified in the mouse tail-looping model. The expression of circSPG21 in the nucleus pulposus in IVDD was directly related to an imbalance of anabolic and catabolic factors, which affected cell senescence. circSPG21 was found to play a role in human NPCs by acting as a sponge of miR-1197 and thereby affecting ATP1B3. The regulation of circSPG21 provides a potentially effective therapeutic strategy for IVDD.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8568895 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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circSPG21 protects against intervertebral disc disease by targeting miR-1197/ATP1B3.

Huang Yizhen Y Zhang Zhenlei Z Wang Jianle J Shen Shuying S Yao Teng T Xu Yining Y Chen Zizheng Z Fang Bin B Ma Jianjun J

Experimental & molecular medicine 20211006 10

The abnormal expression of circular RNAs (circRNAs) is associated with numerous human diseases. This study investigated the mechanism by which circRNA acts as competitive endogenous RNA in the regulation of degenerative intervertebral disc disease (IVDD). Decreased expression of circSPG21 was detected in degenerated nucleus pulposus cells (NPCs), the function of circSPG21 in NPCs was explored and verified, and the downstream target of circSPG21 was investigated. The interaction between circSPG21 ...[more]

PMID: 34611269

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Project description:BackgroundIntervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects.ObjectiveThis study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein.MethodsWe exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin.ResultsDigoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells.ConclusionThese findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Dataset Information

CircSPG21 protects against intervertebral disc disease by targeting miR-1197/ATP1B3.

Publications

circSPG21 protects against intervertebral disc disease by targeting miR-1197/ATP1B3.

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