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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.
Exp Mol Med. 2018 04 13; 50(4):27.EM

Abstract

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.

Authors+Show Affiliations

Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China. wangxucheng@gmail.com.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China.Department of Medical Genetics, Zhongshan School of Medicine and Center for Genome Research, Sun Yat-Sen University, 74 Zhongshan Second Road, Guangzhou, China. Jiangwy@mail.sysu.edu.cn.Department of Orthopedics, First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Second Road, Guangzhou, China. zhengzm1@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29651107

Citation

Wang, Hua, et al. "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." Experimental & Molecular Medicine, vol. 50, no. 4, 2018, p. 27.
Wang H, He P, Pan H, et al. 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. Exp Mol Med. 2018;50(4):27.
Wang, H., He, P., Pan, H., Long, J., Wang, J., Li, Z., Liu, H., Jiang, W., & Zheng, Z. (2018). 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. Experimental & Molecular Medicine, 50(4), 27. https://doi.org/10.1038/s12276-018-0056-7
Wang H, et al. 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. Exp Mol Med. 2018 04 13;50(4):27. PubMed PMID: 29651107.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Wang,Hua, AU - He,Peiheng, AU - Pan,Hehai, AU - Long,Jun, AU - Wang,Jianru, AU - Li,Zemin, AU - Liu,Hui, AU - Jiang,Weiying, AU - Zheng,Zhaomin, Y1 - 2018/04/13/ PY - 2017/09/26/received PY - 2017/12/25/accepted PY - 2018/4/14/entrez PY - 2018/4/14/pubmed PY - 2019/2/12/medline SP - 27 EP - 27 JF - Experimental & molecular medicine JO - Exp. Mol. Med. VL - 50 IS - 4 N2 - 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. SN - 2092-6413 UR - https://www.unboundmedicine.com/medline/citation/29651107/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_ L2 - http://dx.doi.org/10.1038/s12276-018-0056-7 DB - PRIME DP - Unbound Medicine ER -