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Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration

Circular RNAs (circRNAs) play important roles in the initiation and development of different diseases. Here, we detected their role in intervertebral disc (IVD) degeneration. An Arraystar human circular RNA microarray assay was used to detect circRNAs in normal and degenerated human IVD nucleus pulp...

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Autores principales: Wang, Hua, He, Peiheng, Pan, Hehai, long, Jun, Wang, Jianru, Li, Zemin, Liu, Hui, Jiang, Weiying, Zheng, Zhaomin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938034/
https://www.ncbi.nlm.nih.gov/pubmed/29651107
http://dx.doi.org/10.1038/s12276-018-0056-7
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author Wang, Hua
He, Peiheng
Pan, Hehai
long, Jun
Wang, Jianru
Li, Zemin
Liu, Hui
Jiang, Weiying
Zheng, Zhaomin
author_facet Wang, Hua
He, Peiheng
Pan, Hehai
long, Jun
Wang, Jianru
Li, Zemin
Liu, Hui
Jiang, Weiying
Zheng, Zhaomin
author_sort Wang, Hua
collection PubMed
description Circular RNAs (circRNAs) play important roles in the initiation and development of different diseases. Here, we detected their role in intervertebral disc (IVD) degeneration. An Arraystar human circular RNA microarray assay was used to detect circRNAs in normal and degenerated human IVD nucleus pulposus (NP) tissues. The role of circ-4099 in IVDD and its mechanism were evaluated by qRT-PCR and gain-of-function/loss-of-function studies. Interaction networks for competing endogenous RNAs (ceRNAs), miRNAs, and miRNA target gene were detected by bioinformatics analysis, RNA immunoprecipitation and luciferase assay. Expression of seventy-two circRNAs were increased by more than twofold in degenerated NP tissues. qRT-PCR showed that the expression of circ-4099 in NP tissues was consistent with that of the array screening. Over-expression of circ-4099 increased the expression of Collagen II and Aggrecan and decreased the secretion of the pro-inflammatory factors IL-1β, TNF-α, and PGE2. TNF-α treatment increased circ-4099 expression in NP cells. NF-κB/MAPK inhibitors or shRNAs abolished the inductive effects of TNF-α on circ-4099 expression. We further demonstrated that circ-4099 was able to function as a “sponge” by competitively binding miR-616-5p, which reversed the suppression of Sox9 by miR-616-5p. We used DNA pull-down and spectrometry experiments to show that TNF-α can promote circ-4099 transcription through upregulation of GRP78. We provide the first evidence that shows circRNAs are differentially expressed in degenerated and normal NP tissues. Circ-4099 may play a role in a protective mechanism and be part of a compensatory response that maintains the synthesis and secretion of the extracellular matrix in NP cells and might be a protective factor in IVD degeneration as well as restore NP cell function.
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spelling pubmed-59380342018-05-15 Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration Wang, Hua He, Peiheng Pan, Hehai long, Jun Wang, Jianru Li, Zemin Liu, Hui Jiang, Weiying Zheng, Zhaomin Exp Mol Med Article Circular RNAs (circRNAs) play important roles in the initiation and development of different diseases. Here, we detected their role in intervertebral disc (IVD) degeneration. An Arraystar human circular RNA microarray assay was used to detect circRNAs in normal and degenerated human IVD nucleus pulposus (NP) tissues. The role of circ-4099 in IVDD and its mechanism were evaluated by qRT-PCR and gain-of-function/loss-of-function studies. Interaction networks for competing endogenous RNAs (ceRNAs), miRNAs, and miRNA target gene were detected by bioinformatics analysis, RNA immunoprecipitation and luciferase assay. Expression of seventy-two circRNAs were increased by more than twofold in degenerated NP tissues. qRT-PCR showed that the expression of circ-4099 in NP tissues was consistent with that of the array screening. Over-expression of circ-4099 increased the expression of Collagen II and Aggrecan and decreased the secretion of the pro-inflammatory factors IL-1β, TNF-α, and PGE2. TNF-α treatment increased circ-4099 expression in NP cells. NF-κB/MAPK inhibitors or shRNAs abolished the inductive effects of TNF-α on circ-4099 expression. We further demonstrated that circ-4099 was able to function as a “sponge” by competitively binding miR-616-5p, which reversed the suppression of Sox9 by miR-616-5p. We used DNA pull-down and spectrometry experiments to show that TNF-α can promote circ-4099 transcription through upregulation of GRP78. We provide the first evidence that shows circRNAs are differentially expressed in degenerated and normal NP tissues. Circ-4099 may play a role in a protective mechanism and be part of a compensatory response that maintains the synthesis and secretion of the extracellular matrix in NP cells and might be a protective factor in IVD degeneration as well as restore NP cell function. Nature Publishing Group UK 2018-04-13 /pmc/articles/PMC5938034/ /pubmed/29651107 http://dx.doi.org/10.1038/s12276-018-0056-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, http://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Article
Wang, Hua
He, Peiheng
Pan, Hehai
long, Jun
Wang, Jianru
Li, Zemin
Liu, Hui
Jiang, Weiying
Zheng, Zhaomin
Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title_full Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title_fullStr Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title_full_unstemmed Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title_short Circular RNA circ-4099 is induced by TNF-α and regulates ECM synthesis by blocking miR-616-5p inhibition of Sox9 in intervertebral disc degeneration
title_sort circular rna circ-4099 is induced by tnf-α and regulates ecm synthesis by blocking mir-616-5p inhibition of sox9 in intervertebral disc degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938034/
https://www.ncbi.nlm.nih.gov/pubmed/29651107
http://dx.doi.org/10.1038/s12276-018-0056-7
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