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Circular RNA derived from TIMP2 functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR?185?5p and matrix metalloproteinase 2.

ABSTRACT: Intervertebral disc degeneration (IDD) is an important cause of lower back pain, although the underlying mechanisms remain poorly understood. The present study aimed to examine the role of a circular RNA derived from tissue inhibitor of metallopeptidases 2 (circ?TIMP2) in degenerative nucleus pulposus (NP) tissues, and to validate its function in cultured human NP cells. Overexpression of miR?185?5p in NP cells markedly inhibited the enhanced extracellular matrix (ECM) catabolism induced by tumor necrosis factor?? (TNF??) and interleukin?1? (IL?1?) treatment. Bioinformatics analysis demonstrated that matrix metalloproteinase 2 (MMP2) was a potential target of miR?185?5p. MMP2 protein expression levels were increased following treatment with TNF?? and IL?1? in NP cells compared with those in untreated cells, and this effect was attenuated by transfection with miR?185?5p. Compared with normal NP tissues, IDD samples exhibited higher circ?TIMP2 expression levels. In addition, overexpression of circ?TIMP2 promoted ECM catabolism and suppressed ECM anabolism. Furthermore, circ?TIMP2 sequestered miR?185?5p, which may potentially upregulate the target genes associated with ECM degradation. In conclusion, the results of the present study revealed that circ?TIMP2 promoted TNF??? and IL?1??induced NP cell imbalance between ECM anabolism and catabolism via miR?185?5p?MMP2 signaling. These findings provide a potential therapeutic option for the treatment of IDD.

SUBMITTER: Guo W

PROVIDER: S-EPMC7307854 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Circular RNA derived from TIMP2 functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR‑185‑5p and matrix metalloproteinase 2.

Guo Wei W Zhang Bin B Sun Chao C Duan Hui-Quan HQ Liu Wei-Xiao WX Mu Kun K Zhao Ling L Li Hao-Ran HR Dong Zhan-Yin ZY Cui Qing Q

International journal of molecular medicine 20200529 2

Intervertebral disc degeneration (IDD) is an important cause of lower back pain, although the underlying mechanisms remain poorly understood. The present study aimed to examine the role of a circular RNA derived from tissue inhibitor of metallopeptidases 2 (circ‑TIMP2) in degenerative nucleus pulposus (NP) tissues, and to validate its function in cultured human NP cells. Overexpression of miR‑185‑5p in NP cells markedly inhibited the enhanced extracellular matrix (ECM) catabolism induced by tumo ...[more]

PMID: 32626912

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Project description:BackgroundIntervertebral disc degeneration (IDD) is a leading cause of disability with limited treatment strategies. A better understanding of the mechanism of IDD might enable less invasive and more targeted treatments. This study aimed to identify the circular RNA (circRNA)-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) regulatory mechanisms in IDD. METHODS : The GSE67567 microarray dataset was downloaded from the Gene Expression Omnibus database. After data preprocessing, differentially expressed circRNAs, miRNAs and mRNAs between IDD and controls were identified. A ceRNA network was constructed on the basis of the interaction between circRNAs and miRNAs, and miRNAs and mRNAs. Pathway enrichment analysis was performed on the mRNAs in the ceRNA network. Then, with 'intervertebral disc degeneration' as keywords, IDD-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were searched for in the Comparative Toxicogenomics Database.ResultsA total of 105 differentially expressed circRNAs, 84 miRNAs and 967 mRNAs were identified. After analysis, 86 circRNA-miRNA, and 126 miRNA-mRNA regulatory relationship pairs were obtained to construct a ceRNA network. The mRNAs were enriched in six KEGG signalling pathways, and four were associated with IDD: the hsa04350: TGF-beta signalling pathway, hsa04068: FoxO signalling pathway, hsa05142: Chagas disease (American trypanosomiasis) and hsa04380: Osteoclast differentiation. An IDD-related ceRNA network was constructed involving four circRNAs, three miRNAs and 11 mRNAs. Auxiliary validation showed that the expression levels of miR-185-5p, miR-486-5p, ACVR1B, FOXO1, SMAD2 and TGFB1 were consistent in different databases.ConclusionsOur study identified some circRNA-miRNA-mRNA interaction axes potentially associated with the progression of IDD, viz.: circRNA_100086-miR-509-3p-MAPK1, circRNA_000200-miR-185-5p-TGFB1, circRNA_104308-miR-185-5p-TGFB1, circRNA_400090-miR-486-5p-FOXO1 and circRNA_400090-miR-486-5p-SMAD2.

Dataset Information

Circular RNA derived from TIMP2 functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR?185?5p and matrix metalloproteinase 2.

Publications

Circular RNA derived from TIMP2 functions as a competitive endogenous RNA and regulates intervertebral disc degeneration by targeting miR‑185‑5p and matrix metalloproteinase 2.

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