Open Access

The role of miRNA, lncRNA and circRNA in the development of intervertebral disk degeneration (Review)

  • Authors:
    • Jian Jiang
    • Yuefeng Sun
    • Gaoran Xu
    • Hong Wang
    • Ling Wang
  • View Affiliations

  • Published online on: March 26, 2021     https://doi.org/10.3892/etm.2021.9987
  • Article Number: 555
  • Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Intervertebral disc degeneration (IVDD) is a degenerative musculoskeletal disorder with multiple causative factors, such as age, genetics, mechanics and life style. IVDD contributes to non‑specific lower back pain (NLBP), which is a globally prevalent and debilitating musculoskeletal disorder. NLBP has a substantial impact on medical resources and creates an economic burden for the public. Dysregulated phenotypes of nucleus pulposus (NP) cells and endplate chondrocytes, such as proliferation, senescence and apoptosis, along with aberrant expression of extracellular matrix components, including type II collagen and aggrecan, are involved in the pathological process of IVDD. Evidence indicates that non‑coding RNAs, mainly microRNAs (miRNAs), long non‑coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a vital role in the development of IVDD. In the present review, the potential molecular mechanisms of miRNAs, lncRNAs and circRNAs in the initiation and progression of IVDD were described based on the latest literature. Furthermore, ways to influence the functions of NP cells and endplate chondrocytes in IVDD were also summarized. The presented insights suggested that non‑coding RNAs may function as potential targets for the treatment of IVDD.

1. Introduction

Non-specific low back pain (NLBP) is a prevalent and debilitating musculoskeletal disorder that affects people globally (1). NLBP causes a substantial burden on medical resources and the economy (2-4). It is estimated that the medical costs of NLBP in the USA alone are ~$253 billion per year (5). Efforts have been made by clinicians and researchers to investigate the pathogenesis of NLBP and develop effective treatment strategies. Increasing evidence suggests that one of the major causes of NLBP is intervertebral disc degeneration (IVDD) (6), which can be caused by inflammatory factors (7), genetic factors (8), aging (9), intervertebral instability (10) and metabolic disorders (11). Currently, the underlying molecular mechanisms between these factors and IVDD have not yet been investigated. It is well known that the IVDD is composed of the inner nucleus pulposus (NP); a proteoglycan-rich gelatinous substance, the outer annulus fibrosus, as well as the upper and lower cartilage endplates (CEP) (12) (Fig. 1). NP cells play an important role in secreting extracellular matrix (ECM) components, such as type II collagen and aggrecan, in addition to retaining water (13). CEP, a crucial nutrition and metabolic exchange channel, maintains the balance between catabolism and anabolism within IVDD (14,15). Therefore, dysfunction of NP cells and CEP cells, including apoptosis, senescence and abnormal cell proliferation, may cause an imbalance between catabolism and anabolism, which is known to be involved in the pathology of IVDD (16,17).

Non-coding RNAs form a large segment of RNA molecules that are transcribed from DNA, but lack the potential to be translated into proteins or peptides (18). Non-coding RNAs include short hairpin RNA, small interfering RNA, antisense RNA, microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA) and extracellular RNAs (18-25). Increasing evidence suggests that miRNAs, lncRNAs and circRNAs have a vital regulatory function in the pathological process of several diseases, such as cancer (26-31), cardiac disease (32-35) and IVDD (36-41). The structures of miRNAs, lncRNAs and circRNAs are presented in Fig. 2 miRNAs, a class of small non-coding RNAs that are 19-25 nucleotides in length, suppress gene expression by directly binding to the 3'-untranslated regions (UTR), 5'-UTR and coding sequence regions of their target mRNAs, leading to translational repression and/or cleavage (42). This direct binding to 3'-UTR is the primary method by which miRNAs regulate target genes (43-49). Conversely, lncRNAs are the largest non-coding RNAs (>200 nucleotides in length) without an open reading frame (50). lncRNAs exert physiological functions by modulating gene expression at multiple levels, including DNA methylation, recruitment of transcriptional factors, miRNA sponges and protein-protein interactions (50-55). Unlike the linear structures of miRNAs and lncRNAs, circRNAs are characterized by covalently closed single-stranded loop structures without free 3' and 5' ends (56). This structure hinders the digestion by ribonucleases R and exonucleases (56-58). circRNAs are produced by a precursor mRNA back-splicing mechanism (59). Furthermore, they are widely expressed in eukaryotes with cell type- and tissue-specific patterns, acting as competing endogenous RNAs (ceRNAs) and transcriptional regulators (29,60,61). The present review article provides an overview of the role of miRNAs, lncRNAs and circRNAs in the pathological process of IVDD based on recent studies, in an attempt to clarify the diagnosis and treatment of IVDD.

2. miRNA in IVDD

Evidence indicates that abnormal proliferation of NP cells and formation of cell clusters are implicated in IVDD pathogenesis (45). Li et al (62) demonstrated that the expression of miR-184 was positively associated with Pfirrmann scores (63) and upregulated in degenerative NP samples compared with that in normal NP samples. Furthermore, luciferase assays from the same study indicated that growth arrest specific gene 1 (GAS1) is a target of miR-184, and degenerative NP tissues present low expression of GAS1 compared with normal NP samples (59). Functionally, overexpression of miR-184 can promote abnormal proliferation and cluster formation of NP cells by inducing AKT phosphorylation, which plays an important role in the development of IVDD (62). However, unequivocal evidence demonstrates that apoptosis exists in diverse biological processes, including IVDD (64). The expression levels of miR-138-5p and miR-494 in degenerated NP tissues compared with normal tissue controls, and their effects on apoptosis were investigated by Wang et al and Wang et al (43,65). The aim of their research was to identify the role of miRNAs in the pathogenesis of IVDD. A total of two signaling pathways (miR-138-5p/SIRT1/PTEN/PI3K/Akt and miR-494/JunD) were discovered through gain- and loss-of-function studies. The results demonstrated that miR-138-5p (43) and miR-494(65) promote tumor necrosis factor-α (TNF-α)-induced apoptosis of NP cells in IVDD by targeting silent mating type information regulation 2 homolog-1 and the transcription factor jun-D via the PTEN/PI3K/AKT signaling pathway and cytochrome c apoptotic signaling, respectively.

Recent studies have reported an imbalance between anabolism and catabolism of ECM in the development of IVDD, predominantly due to excessive ECM degradation. Wang et al and Wang et al (37,66) investigated whether miR-210 and miR-21 facilitate the degradation of ECM components, such as type II collagen and aggrecan within NP tissues. The results indicated that the expression levels of miR-210 and miR-21 are significantly upregulated in degenerated NP specimens compared with healthy controls. Furthermore, miR-210 and miR-21 expression exhibited a positive association with the grade of IVDD disease, using miRNA microarray and reverse transcription-quantitative (RT-q)PCR validation assays. Knockdown and overexpression of miR-210/miR-21 were followed by observation of downstream target genes and ECM-related gene expression compared with the control group. The aforementioned gain- and loss-of-function studies demonstrated that miR-210 and miR-21 promote ECM degradation by suppressing autophagy, targeting both the autophagy-related protein 7 and the PTEN/AKT/mTOR signaling pathway in human NP cells. Conversely, several miRNAs are downregulated in degenerative NP tissues, indicating that miRNAs may exert a protective effect on normal NP tissues against degeneration (45). Studies have indicated that 51 miRNAs are differentially expressed in degenerated intervertebral discs compared with normal intervertebral discs (67). Of these, downregulation of miR-127-5p, miR-193a-3p, miR-133a and miR-98 induce loss of ECM components by targeting matrix metalloproteinase (MMP)-13, MMP-14, MMP-9 and interleukin-6, respectively (68-71). Other miRNAs that have not been studied further may be found to have no differential expression using (RT-q)PCR.

The dysregulation of cell proliferation, matrix hardness and ECM degradation of CEP are also involved in the progression of IVDD (72). Chen et al (72) performed a RT-qPCR analysis, which verified that the expression of miR-34a is markedly elevated in the CEP samples obtained from patients with IVDD compared with samples of healthy donors. Functionally, apoptosis and proliferation of CEP cells are facilitated by upregulating miR-34a through targeting Bcl-2. Liu et al and Xiao et al (73,74) investigated the underlying molecular mechanisms of miR-20a and miR-455-5p in the pathogenesis of IVDD. The results demonstrated that matrix stiffness and ECM loss of CEP are positively associated with the degree of IVDD. Overexpression of miR-20a, which is upregulated in degenerative CEP tissues, accelerates the development of IVDD and facilitates calcification in CEP cells resulting in matrix stiffness by suppressing the expression of ankylosis protein homolog. Similarly, enforced expression of miR-455-5p, which is downregulated in degenerative CEP samples, promotes the progression of IVDD and increases ECM loss by targeting Runt-related transcription factor 2(73). Based on these findings, it is speculated that miRNA may serve as a potential novel therapeutic target for IVDD (Fig. 3).

Figure 3

Functional mechanism of upregulated and downregulated expression of lncRNAs in IVDD. Upregulated lncRNAs (SNHG1, RMRP, FAM83H-AS1, NEAT1, TUG1, H19, IncPolE, GAS5, LINC00969, HCG18 and LINC00641) and downregulated lncRNAs (HOTAIR and linc-ADAMTS5) in a degenerative IVD facilitate the development of IVDD by enhancing ECM degradation and proliferation, senescence, apoptosis and autophagy of NP cells by modulating different downstream targets. lncRNA, long non-coding RNA; IVDD, intervertebral disc degeneration; ECM, extracellular matrix; NP, nucleus pulposus; miR, microRNA; SNHG1, small nucleolar RNA host gene 1; RMRP, RNA component of mitochondrial RNA processing endoribonuclease; FAM83H-AS1, IQ motif and ankyrin repeat containing; NEAT1, nuclear paraspeckle assembly transcript 1; TUG1, taurine upregulated gene 1; H19, H19 imprinted maternally expressed transcript; LINC00969, long intergenic non-protein coding RNA 969; HCG18, HLA complex group 18; LINC00641, long intergenic non-protein coding RNA 641; HOTAIR, homeobox transcript antisense intergenic RNA; GAS5, growth arrest specific 5; linc, long intergenic non-protein coding RNA; ADAMTS5, A disintegrin and metalloproteinase with thrombospondin motif 5; PCNA, proliferating cell nuclear antigen; MAPK, mitogen-activated protein kinase; LEF1, lymphoid enhancer binding factor 1; PolE1, DNA polymerase Ε catalytic subunit A; TRAF6, TNF receptor-associated factor 6; RREB1, ras-responsive element-binding protein 1; TXNIP, thioredoxin interacting protein; NLRP3, NLR family pyrin domain containing 3.

3. lncRNAs in IVDD

Evidence indicates that lncRNAs are involved in the pathological process of IVDD and play a key role in relevant signaling axes (75). Previous studies have demonstrated that the ectopic expression of homeobox transcript antisense intergenic RNA (HOTAIR), lncPolE, growth arrest specific 5, long intergenic non-protein coding RNA 969 and HLA complex group 18 (HCG18) contributes to initiation of IVDD by inducing apoptosis of NP cells through diverse signaling pathways (76-80). Of these lncRNAs, HOTAIR is downregulated in degenerative NP samples and inhibits TNF-α-induced apoptosis of NP cells by regulating Bcl-2 through sponging miR-34a (76). However, the other aforementioned lncRNAs are markedly upregulated in degenerative NP tissues and promote apoptosis of NP cells by targeting DNA polymerase Ε catalytic subunit A, miR-155, miR-335-3p and miR-146a-5p, respectively (77-80). HCG18 increases the rate of apoptosis of NP cells and inhibits the proliferation of NP cells through the miR-146a-5p/TNF receptor-associated factor 6/NFκB axis (80). Tan et al, Wang et al and Wei et al (39,81,82) first demonstrated that ectopic expression of small nucleolar RNA host gene 1, RNA component of mitochondrial RNA processing endoribonuclease (RMRP) and IQ motif and ankyrin repeat containing (FAM83H-AS1), which are substantially upregulated in IVDD samples compared with control samples, promote the progression of IVDD by enhancing NP cell proliferation. Mechanistically, they suppress the expression of miR-326, miR-206 and Notch1 to promote NP cell proliferation. Furthermore, RMRP and FAM83H-AS1 also demonstrate the ability to modulate the expression of ECM components, including type II collagen and aggrecan (39,81,82). Ruan et al and Wang et al (83,84) confirmed that nuclear paraspeckle assembly transcript 1 (NEAT1) and long intergenic non-protein coding RNA (linc)-A disintegrin and MMP with thrombospondin motifs (ADAMTS)5 play crucial roles in the progression of IVDD by regulating the balance between synthesis and degradation of the ECM. However, the expression levels of NEAT1 and linc-ADAMTS5 are different in NP tissues isolated from patients with IVDD. In IVDD, NEAT1 and linc-ADAMTS5 are notably upregulated and downregulated, respectively. Functionally, NEAT1 promotes ECM degradation by upregulating MMP-13 and ADAMTS4 (genes encoding ECM-associated enzymes), and downregulating collagen II and aggrecan through the ERK/mitogen-activated protein kinase signaling pathway. Linc-ADAMTS5 interacts with Ras-responsive element-binding protein 1 to suppress the degradation of ECM and inhibit the expression of ADAMTS5 (83,84). Notably, it was identified that two different lncRNAs, taurine upregulated gene 1 (TUG1) and H19 imprint maternally expressed transcript (H19), modulate NP cell senescence, apoptosis and ECM synthesis through the Wnt/β-catenin signaling pathway (85,86). Functionally, TUG1 and H19, which are both upregulated in degenerative NP tissues, promote NP cell senescence, apoptosis and ECM degradation by targeting Wnt/β-catenin and miR-22, respectively (85,86). A recent study by Wang et al (87) focused on the role of autophagy in the pathogenesis of IVDD and demonstrated that the long intergenic non-protein coding RNA 641, which is markedly upregulated in NP samples obtained from patients with IVDD compared with controls, regulate the development of IVDD by inducing autophagic cell death through targeting miR-153-3p and autophagy-related gene 5. In addition, some treatments can be used to target lncRNAs in IVDD, such as silencing of lncRNAs, locked nucleic acid GapmeRs, small molecule inhibitors, antisense nucleotides and zinc-finger nucleases (88). lncRNAs may represent potential effective novel targets for the treatment of IVDD (Fig. 4).

4. circRNAs in IVDD

circRNAs are involved in the regulation of manifold diseases as a novel subtype of non-coding RNAs. Cheng et al (40) were the first to demonstrate that circVMA21 derived from vacuolar ATPase assembly factor gene is markedly decreased in the degenerative NP specimens compared with the normal NP tissues based on RT-qPCR analyses. Functionally, circVMA21 is able to protect against IVDD by suppressing inflammatory cytokine-induced NP cell apoptosis, downregulating the expression of catabolic enzymes (MMP-3, MMP-13, ADAMTS4 and ADAMTS5) and promoting synthesis of ECM. Mechanistically, circVMA21 is expected to function as ceRNAs to modulate the pathological process of IVDD through sponging miR-200c and targeting X-linked inhibitor-of-apoptosis protein. Recently, Wang et al (89) analyzed the expression profiling of human lumbar disc circRNAs based on an online database and reported that circSEMA4B is substantially downregulated in degenerative lumbar disc tissues. Functionally, circSEMA4B can inhibit the development of IVDD by enhancing NP cell proliferation and alleviating cell senescence and ECM degradation. Mechanistically, circSEMA4B is a potential therapeutic target for IVDD as it represses miR-431 via the Wnt/β-catenin signaling pathway (89). However, circRNA_104670 and circRNA_0058097 are upregulated in degenerative NP tissues and tension-induced degenerative endplate chondrocytes, and it has been reported that they promote the progression of IVDD by acting as ceRNAs (41,90). Furthermore, Song et al (41) confirmed via the dual-luciferase and EGFP/RFP reporter assays that circRNA_104670 directly binds to miR-17-3p, while MMP-2 is the direct target of miR-17-3p. Knockdown and overexpression of circRNA 104670 was followed by the observation of proliferation and apoptosis of NP cells and the expression of miR-17-3p and ECM-related gene compared with the control group. Functionally, through gain- and loss-of-function studies, circRNA_104670 was demonstrated to inhibit proliferation of NP cells and expression of collagen II, and promote apoptosis and the expression of MMP-2 by targeting miR-17-3p and MMP-2. Xiao et al (90) reported that circRNA_0058097 may promote morphological changes of endplate chondrocytes and enhance ECM degradation and degeneration of IVDs by upregulating the expression of histone deacetylase 4 through sponging miR-365a-5p. Thus, circRNA_0058097 promotes the pathological process of IVDD by regulating tension-induced degeneration of endplate chondrocytes. CircRNAs modulate the development of IVDD by functioning as ceRNAs (90) and may serve as a potential novel therapeutic target of IVDD, similar to miRNAs and lncRNAs (Fig. 5).

5. Conclusions

As one of the most prevalent diseases among the elderly population, NLBP has caused tremendous pressure on medical resources and the economy. Several studies have demonstrated that IVDD is responsible for the pathogenesis of NLBP; however, its underlying molecular and cellular mechanisms remain unclear. Recently, the role of non-coding RNAs in several diseases emerged, including IVDD.

In the present review, the role of miRNAs, lncRNAs and circRNAs in the progression of IVDD is summarized. Furthermore, it presents a summary of how to modulate the proliferation, senescence, apoptosis and ECM degradation of NP and CEP by regulating downstream target genes (Tables I-III). The data presented in the current review provide novel insights into the etiology of IVDD and identifies non-coding RNAs as a potential novel target for the treatment of IVDD. However, there is still a lack of relevant studies on miRNAs and circRNAs as therapeutic targets for IVDD. With the development of nanoparticle technology and an in-depth understanding of the pathogenesis of IVDD, research on non-coding RNAs, particularly miRNAs, lncRNAs and circRNAs as therapeutic targets for the treatment of IVDD have potential to become a novel research focus.

Acknowledgements

Not applicable.

Availability of data and materials

Not applicable.

Authors' contributions

HW and LW designed the present review. JJ, YS and GX performed the literature review and drafted the initial manuscript. HW and LW critically revised the manuscript for important intellectual content. All authors have read and approved the manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Maher C, Underwood M and Buchbinder R: Non-specific low back pain. Lancet. 389:736–747. 2017.PubMed/NCBI View Article : Google Scholar

2 

Dudli S, Fields AJ, Samartzis D, Karppinen J and Lotz JC: Pathobiology of modic changes. Eur Spine J. 25:3723–3734. 2016.PubMed/NCBI View Article : Google Scholar

3 

Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, Shibuya K, Salomon JA, Abdalla S, Aboyans V, et al: Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: A systematic analysis for the global burden of disease study 2010. Lancet. 380:2163–2196. 2012.PubMed/NCBI View Article : Google Scholar

4 

Hartvigsen J, Hancock MJ, Kongsted A, Louw Q, Ferreira ML, Genevay S, Hoy D, Karppinen J, Pransky G, Sieper J, et al: What low back pain is and why we need to pay attention. Lancet. 391:2356–2367. 2018.PubMed/NCBI View Article : Google Scholar

5 

Yelin E, Weinstein S and King T: The burden of musculoskeletal diseases in the United States. Semin Arthritis Rheum. 46:259–260. 2016.PubMed/NCBI View Article : Google Scholar

6 

Foster NE, Anema JR, Cherkin D, Chou R, Cohen SP, Gross DP, Ferreira PH, Fritz JM, Koes BW, Peul W, et al: Prevention and treatment of low back pain: Evidence, challenges, and promising directions. Lancet. 391:2368–2383. 2018.PubMed/NCBI View Article : Google Scholar

7 

Risbud MV and Shapiro IM: Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nat Rev Rheumatol. 10:44–56. 2014.PubMed/NCBI View Article : Google Scholar

8 

Adams MA and Roughley PJ: What is intervertebral disc degeneration, and what causes it? Spine (Phila Pa 1976). 31:2151–2161. 2006.PubMed/NCBI View Article : Google Scholar

9 

Vo NV, Hartman RA, Patil PR, Risbud MV, Kletsas D, Iatridis JC, Hoyland JA, Le Maitre CL, Sowa GA and Kang JD: Molecular mechanisms of biological aging in intervertebral discs. J Orthop Res. 34:1289–1306. 2016.PubMed/NCBI View Article : Google Scholar

10 

Bian Q, Jain A, Xu X, Kebaish K, Crane JL, Zhang Z, Wan M, Ma L, Riley LH, Sponseller PD, et al: Excessive activation of TGFβ by spinal instability causes vertebral endplate sclerosis. Sci Rep. 6(27093)2016.PubMed/NCBI View Article : Google Scholar

11 

Huang YC, Urban JP and Luk KD: Intervertebral disc regeneration: Do nutrients lead the way? Nat Rev Rheumatol. 10:561–566. 2014.PubMed/NCBI View Article : Google Scholar

12 

Liao Z, Wu X, Song Y, Luo R, Yin H, Zhan S, Li S, Wang K, Zhang Y and Yang C: Angiopoietin-like protein 8 expression and association with extracellular matrix metabolism and inflammation during intervertebral disc degeneration. J Cell Mol Med. 23:5737–5750. 2019.PubMed/NCBI View Article : Google Scholar

13 

Liu X, Zhuang J, Wang D, Lv L, Zhu F, Yao A and Xu T: Glycyrrhizin suppresses inflammation and cell apoptosis by inhibition of HMGB1 via p38/p-JUK signaling pathway in attenuating intervertebral disc degeneration. Am J Transl Res. 11:5105–5113. 2019.PubMed/NCBI

14 

Grant MP, Epure LM, Bokhari R, Roughley P, Antoniou J and Mwale F: Human cartilaginous endplate degeneration is induced by calcium and the extracellular calcium-sensing receptor in the intervertebral disc. Eur Cell Mater. 32:137–151. 2016.PubMed/NCBI View Article : Google Scholar

15 

Yao Y, Deng Q, Song W, Zhang H, Li Y, Yang Y, Fan X, Liu M, Shang J, Sun C, et al: MIF plays a key role in regulating tissue-specific chondro-osteogenic differentiation fate of human cartilage endplate stem cells under hypoxia. Stem Cell Reports. 7:249–262. 2016.PubMed/NCBI View Article : Google Scholar

16 

Tang Z, Hu B, Zang F, Wang J, Zhang X and Chen H: Nrf2 drives oxidative stress-induced autophagy in nucleus pulposus cells via a Keap1/Nrf2/p62 feedback loop to protect intervertebral disc from degeneration. Cell Death Dis. 10(510)2019.PubMed/NCBI View Article : Google Scholar

17 

Wang G, Huang K, Dong Y, Chen S, Zhang J, Wang J, Xie Z, Lin X, Fang X and Fan S: Lycorine suppresses endplate-chondrocyte degeneration and prevents intervertebral disc degeneration by inhibiting NF-κB signalling pathway. Cell Physiol Biochem. 45:1252–1269. 2018.PubMed/NCBI View Article : Google Scholar

18 

Matsui M and Corey DR: Non-coding RNAs as drug targets. Nat Rev Drug Discov. 16:167–179. 2017.PubMed/NCBI View Article : Google Scholar

19 

Ning B, Yu D and Yu AM: Advances and challenges in studying noncoding RNA regulation of drug metabolism and development of RNA therapeutics. Biochem Pharmacol. 169(113638)2019.PubMed/NCBI View Article : Google Scholar

20 

Wang WT, Han C, Sun YM, Chen TQ and Chen YQ: Noncoding RNAs in cancer therapy resistance and targeted drug development. J Hematol Oncol. 12(55)2019.PubMed/NCBI View Article : Google Scholar

21 

Guttman M and Rinn JL: Modular regulatory principles of large non-coding RNAs. Nature. 482:339–346. 2012.PubMed/NCBI View Article : Google Scholar

22 

Sato-Kuwabara Y, Melo SA, Soares FA and Calin GA: The fusion of two worlds: Non-coding RNAs and extracellular vesicles-diagnostic and therapeutic implications (Review). Int J Oncol. 46:17–27. 2015.PubMed/NCBI View Article : Google Scholar

23 

Zhou X, Chen L, Grad S, Alini M, Pan H, Yang D, Zhen W, Li Z, Huang S and Peng S: The roles and perspectives of microRNAs as biomarkers for intervertebral disc degeneration. J Tissue Eng Regen Med. 11:3481–3487. 2017.PubMed/NCBI View Article : Google Scholar

24 

St Laurent G, Wahlestedt C and Kapranov P: The Landscape of long noncoding RNA classification. Trends Genet. 31:239–251. 2015.PubMed/NCBI View Article : Google Scholar

25 

Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013.PubMed/NCBI View Article : Google Scholar

26 

Zhou L, Dong S, Deng Y, Yang P, Zheng Y, Yao L, Zhang M, Yang S, Wu Y, Zhai Z, et al: GOLGA7 rs11337, a polymorphism at the MicroRNA binding site, is associated with glioma prognosis. Mol Ther Nucleic Acids. 18:56–65. 2019.PubMed/NCBI View Article : Google Scholar

27 

Bhan A, Soleimani M and Mandal SS: Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77:3965–3981. 2017.PubMed/NCBI View Article : Google Scholar

28 

Wei Y, Chen X, Liang C, Ling Y, Yang X, Ye X, Zhang H, Yang P, Cui X, Ren Y, et al: A noncoding regulatory RNAs network driven by Circ-CDYL acts specifically in the early stages hepatocellular carcinoma. Hepatology. 71:130–147. 2020.PubMed/NCBI View Article : Google Scholar

29 

Shang Q, Yang Z, Jia R and Ge S: The novel roles of circRNAs in human cancer. Mol Cancer. 18(6)2019.PubMed/NCBI View Article : Google Scholar

30 

Wu K, Liao X, Gong Y, He J, Zhou JK, Tan S, Pu W, Huang C, Wei YQ and Peng Y: Circular RNA F-circSR derived from SLC34A2-ROS1 fusion gene promotes cell migration in non-small cell lung cancer. Mol Cancer. 18(98)2019.PubMed/NCBI View Article : Google Scholar

31 

Wu Y, Xie Z, Chen J, Chen J, Ni W, Ma Y, Huang K, Wang G, Wang J, Ma J, et al: Circular RNA circTADA2A promotes osteosarcoma progression and metastasis by sponging miR-203a-3p and regulating CREB3 expression. Mol Cancer. 18(73)2019.PubMed/NCBI View Article : Google Scholar

32 

Lange S, Banerjee I, Carrion K, Serrano R, Habich L, Kameny R, Lengenfelder L, Dalton N, Meili R, Börgeson E, et al: miR-486 is modulated by stretch and increases ventricular growth. JCI Insight. 4(e125507)2019.PubMed/NCBI View Article : Google Scholar

33 

Calderon-Dominguez M, Belmonte T, Quezada-Feijoo M, Ramos-Sánchez M, Fernández-Armenta J, Pérez-Navarro A, Cesar S, Peña-Peña L, Vea À, Llorente-Cortés V, et al: Emerging role of microRNAs in dilated cardiomyopathy: Evidence regarding etiology. Transl Res. 215:86–101. 2020.PubMed/NCBI View Article : Google Scholar

34 

Cai B, Zhang Y, Zhao Y, Wang J, Li T, Zhang Y, Jiang Y, Jin X, Xue G, Li P, et al: Long noncoding RNA-DACH1 (Dachshund Homolog 1) regulates cardiac function by inhibiting SERCA2a (Sarcoplasmic Reticulum Calcium ATPase 2a). Hypertension. 74:833–842. 2019.PubMed/NCBI View Article : Google Scholar

35 

Huang S, Li X, Zheng H, Si X, Li B, Wei G, Li C, Chen Y, Chen Y, Liao W, et al: Loss of super-enhancer-regulated circRNA Nfix induces cardiac regeneration after myocardial infarction in adult mice. Circulation. 139:2857–2876. 2019.PubMed/NCBI View Article : Google Scholar

36 

Hasvik E, Schjølberg T, Jacobsen DP, Haugen AJ, Grøvle L, Schistad EI and Gjerstad J: Up-regulation of circulating microRNA-17 is associated with lumbar radicular pain following disc herniation. Arthritis Res Ther. 21(186)2019.PubMed/NCBI View Article : Google Scholar

37 

Wang C, Zhang ZZ, Yang W, Ouyang ZH, Xue JB, Li XL, Zhang J, Chen WK, Yan YG and Wang WJ: MiR-210 facilitates ECM degradation by suppressing autophagy via silencing of ATG7 in human degenerated NP cells. Biomed Pharmacother. 93:470–479. 2017.PubMed/NCBI View Article : Google Scholar

38 

Shao T, Hu Y, Tang W, Shen H, Yu Z and Gu J: The long noncoding RNA HOTAIR serves as a microRNA-34a-5p sponge to reduce nucleus pulposus cell apoptosis via a NOTCH1-mediated mechanism. Gene. 715(144029)2019.PubMed/NCBI View Article : Google Scholar

39 

Tan H, Zhao L, Song R, Liu Y and Wang L: The long noncoding RNA SNHG1 promotes nucleus pulposus cell proliferation through regulating miR-326 and CCND1. Am J Physiol Cell Physiol. 315:C21–C27. 2018.PubMed/NCBI View Article : Google Scholar

40 

Cheng X, Zhang L, Zhang K, Zhang G, Hu Y, Sun X, Zhao C, Li H, Li YM and Zhao J: Circular RNA VMA21 protects against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein. Ann Rheum Dis. 77:770–779. 2018.PubMed/NCBI View Article : Google Scholar

41 

Song J, Wang HL, Song KH, Ding ZW, Wang HL, Ma XS, Lu FZ, Xia XL, Wang YW, Fei-Zou   and Jiang JY: CircularRNA_104670 plays a critical role in intervertebral disc degeneration by functioning as a ceRNA. Exp Mol Med. 50(94)2018.PubMed/NCBI View Article : Google Scholar

42 

Lu TX and Rothenberg ME: MicroRNA. J Allergy Clin Immunol. 141:1202–1207. 2018.PubMed/NCBI View Article : Google Scholar

43 

Wang B, Wang D, Yan T and Yuan H: miR-138-5p promotes TNF-α-induced apoptosis in human intervertebral disc degeneration by targeting SIRT1 through PTEN/PI3K/Akt signaling. Exp Cell Res. 345:199–205. 2016.PubMed/NCBI View Article : Google Scholar

44 

Hayes J, Peruzzi PP and Lawler S: MicroRNAs in cancer: Biomarkers, functions and therapy. Trends Mol Med. 20:460–469. 2014.PubMed/NCBI View Article : Google Scholar

45 

Wang C, Wang WJ, Yan YG, Xiang YX, Zhang J, Tang ZH and Jiang ZS: MicroRNAs: New players in intervertebral disc degeneration. Clin Chim Acta. 450:333–341. 2015.PubMed/NCBI View Article : Google Scholar

46 

Mo YY: MicroRNA regulatory networks and human disease. Cell Mol Life Sci. 69:3529–3531. 2012.PubMed/NCBI View Article : Google Scholar

47 

Ivey KN and Srivastava D: microRNAs as developmental regulators. Cold Spring Harb Perspect Biol. 7(a008144)2015.PubMed/NCBI View Article : Google Scholar

48 

Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009.PubMed/NCBI View Article : Google Scholar

49 

Liu B, Li J and Cairns MJ: Identifying miRNAs, targets and functions. Brief Bioinform. 15:1–19. 2014.PubMed/NCBI View Article : Google Scholar

50 

Chi Y, Wang D, Wang J, Yu W and Yang J: Long non-coding RNA in the pathogenesis of cancers. Cells. 8(1015)2019.PubMed/NCBI View Article : Google Scholar

51 

Robinson EK, Covarrubias S and Carpenter S: The how and why of lncRNA function: An innate immune perspective. Biochim Biophys Acta Gene Regul Mech. 1863(194419)2019.PubMed/NCBI View Article : Google Scholar

52 

Ji E, Kim C, Kim W and Lee EK: Role of long non-coding RNAs in metabolic control. Biochim Biophys Acta Gene Regul Mech. 1863(194348)2020.PubMed/NCBI View Article : Google Scholar

53 

Chen WK, Yu XH, Yang W, Wang C, He WS, Yan YG, Zhang J and Wang WJ: lncRNAs: Novel players in intervertebral disc degeneration and osteoarthritis. Cell Prolif. 50(e12313)2017.PubMed/NCBI View Article : Google Scholar

54 

Ulitsky I and Bartel DP: lincRNAs: Genomics, evolution, and mechanisms. Cell. 154:26–46. 2013.PubMed/NCBI View Article : Google Scholar

55 

Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W, Merkurjev D, Ohgi KA, Meng D, Zhang J, et al: lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature. 500:598–602. 2013.PubMed/NCBI View Article : Google Scholar

56 

Santer L, Bär C and Thum T: Circular RNAs: A novel class of functional RNA molecules with a therapeutic perspective. Mol Ther. 27:1350–1363. 2019.PubMed/NCBI View Article : Google Scholar

57 

Suzuki H, Zuo Y, Wang J, Zhang MQ, Malhotra A and Mayeda A: Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing. Nucleic Acids Res. 34(e63)2006.PubMed/NCBI View Article : Google Scholar

58 

Jeck WR and Sharpless NE: Detecting and characterizing circular RNAs. Nat Biotechnol. 32:453–461. 2014.PubMed/NCBI View Article : Google Scholar

59 

Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB and Kjems J: The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 20:675–691. 2019.PubMed/NCBI View Article : Google Scholar

60 

Li X, Yang L and Chen LL: The biogenesis, functions, and challenges of circular RNAs. Mol Cell. 71:428–442. 2018.PubMed/NCBI View Article : Google Scholar

61 

Szabo L and Salzman J: Detecting circular RNAs: Bioinformatic and experimental challenges. Nat Rev Genet. 17:679–692. 2016.PubMed/NCBI View Article : Google Scholar

62 

Li W, Wang P, Zhang Z, Wang W, Liu Y and Qi Q: miR-184 regulates proliferation in nucleus pulposus cells by targeting GAS1. World Neurosurg. 97:710–715.e1. 2017.PubMed/NCBI View Article : Google Scholar

63 

Che YJ, Guo JB, Liang T, Chen X, Zhang W, Yang HL and Luo ZP: Assessment of changes in the micro-nano environment of intervertebral disc degeneration based on Pfirrmann grade. Spine J. 19:1242–1253. 2019.PubMed/NCBI View Article : Google Scholar

64 

Yang SD, Yang DL, Sun YP, Wang BL, Ma L, Feng SQ and Ding WY: 17β-estradiol protects against apoptosis induced by interleukin-1β in rat nucleus pulposus cells by down-regulating MMP-3 and MMP-13. Apoptosis. 20:348–357. 2015.PubMed/NCBI View Article : Google Scholar

65 

Wang T, Li P, Ma X, Tian P, Han C, Zang J, Kong J and Yan H: MicroRNA-494 inhibition protects nucleus pulposus cells from TNF-α-induced apoptosis by targeting JunD. Biochimie. 115:1–7. 2015.PubMed/NCBI View Article : Google Scholar

66 

Wang WJ, Yang W, Ouyang ZH, Xue JB, Li XL, Zhang J, He WS, Chen WK, Yan YG and Wang C: MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. Biomed Pharmacother. 99:725–734. 2018.PubMed/NCBI View Article : Google Scholar

67 

Zhao B, Yu Q, Li H, Guo X and He X: Characterization of microRNA expression profiles in patients with intervertebral disc degeneration. Int J Mol Med. 33:43–50. 2014.PubMed/NCBI View Article : Google Scholar

68 

Ji ML, Zhang XJ, Shi PL, Lu J, Wang SZ, Chang Q, Chen H and Wang C: Downregulation of microRNA-193a-3p is involved in invertebral disc degeneration by targeting MMP14. J Mol Med (Berl). 94:457–468. 2016.PubMed/NCBI View Article : Google Scholar

69 

Xu YQ, Zhang ZH, Zheng YF and Feng SQ: Dysregulated miR-133a mediates loss of type II collagen by directly targeting matrix metalloproteinase 9 (MMP9) in human intervertebral disc degeneration. Spine (Phila Pa 1976). 41:E717–E724. 2016.PubMed/NCBI View Article : Google Scholar

70 

Hua WB, Wu XH, Zhang YK, Song Y, Tu J, Kang L, Zhao KC, Li S, Wang K, Liu W, et al: Dysregulated miR-127-5p contributes to type II collagen degradation by targeting matrix metalloproteinase-13 in human intervertebral disc degeneration. Biochimie. 139:74–80. 2017.PubMed/NCBI View Article : Google Scholar

71 

Ji ML, Lu J, Shi PL, Zhang XJ, Wang SZ, Chang Q, Chen H and Wang C: Dysregulated miR-98 contributes to extracellular matrix degradation by targeting IL-6/STAT3 signaling pathway in human intervertebral disc degeneration. J Bone Miner Res. 31:900–909. 2016.PubMed/NCBI View Article : Google Scholar

72 

Chen H, Wang J, Hu B, Wu X, Chen Y, Li R and Yuan W: miR-34a promotes Fas-mediated cartilage endplate chondrocyte apoptosis by targeting Bcl-2. Mol Cell Biochem. 406:21–30. 2015.PubMed/NCBI View Article : Google Scholar

73 

Liu MH, Sun C, Yao Y, Fan X, Liu H, Cui YH, Bian XW, Huang B and Zhou Y: Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression. Sci Rep. 6(25401)2016.PubMed/NCBI View Article : Google Scholar

74 

Xiao L, Xu S, Xu Y, Liu C, Yang B, Wang J and Xu H: TGF-β/SMAD signaling inhibits intermittent cyclic mechanical tension-induced degeneration of endplate chondrocytes by regulating the miR-455-5p/RUNX2 axis. J Cell Biochem. 119:10415–10425. 2018.PubMed/NCBI View Article : Google Scholar

75 

Li Z, Li X, Chen C, Li S, Shen J, Tse G, Chan MTV and Wu WKK: Long non-coding RNAs in nucleus pulposus cell function and intervertebral disc degeneration. Cell Prolif. 51(e12483)2018.PubMed/NCBI View Article : Google Scholar

76 

Yu Y, Zhang X, Li Z, Kong L and Huang Y: LncRNA HOTAIR suppresses TNF-α induced apoptosis of nucleus pulposus cells by regulating miR-34a/Bcl-2 axis. Biomed Pharmacother. 107:729–737. 2018.PubMed/NCBI View Article : Google Scholar

77 

Li X, Lou Z, Liu J, Li H, Lei Y, Zhao X and Zhang F: Upregulation of the long noncoding RNA lncPolE contributes to intervertebral disc degeneration by negatively regulating DNA polymerase epsilon. Am J Transl Res. 11:2843–2854. 2019.PubMed/NCBI

78 

Wang Y, Song Q, Huang X, Chen Z, Zhang F, Wang K, Huang G and Shen H: Long noncoding RNA GAS5 promotes apoptosis in primary nucleus pulposus cells derived from the human intervertebral disc via Bcl-2 downregulation and caspase3 upregulation. Mol Med Rep. 19:2164–2172. 2019.PubMed/NCBI View Article : Google Scholar

79 

Yu L, Hao Y, Xu C, Zhu G and Cai Y: LINC00969 promotes the degeneration of intervertebral disk by sponging miR-335-3p and regulating NLRP3 inflammasome activation. IUBMB life. 71:611–618. 2019.PubMed/NCBI View Article : Google Scholar

80 

Xi Y, Jiang T, Wang W, Yu J, Wang Y, Wu X and He Y: Long non-coding HCG18 promotes intervertebral disc degeneration by sponging miR-146a-5p and regulating TRAF6 expression. Sci Rep. 7(13234)2017.PubMed/NCBI View Article : Google Scholar

81 

Wang X, Peng L, Gong X, Zhang X, Sun R and Du J: lncRNA-RMRP promotes nucleus pulposus cell proliferation through regulating miR-206 expression. J Cell Mol Med. 22:5468–5476. 2018.PubMed/NCBI View Article : Google Scholar

82 

Wei R, Chen Y, Zhao Z, Gu Q and Wu J: LncRNA FAM83H-AS1 induces nucleus pulposus cell growth via targeting the Notch signaling pathway. J Cell Physiol. 234:22163–22171. 2019.PubMed/NCBI View Article : Google Scholar

83 

Ruan Z, Ma H, Li J, Liu H, Jia H and Li F: The long non-coding RNA NEAT1 contributes to extracellular matrix degradation in degenerative human nucleus pulposus cells. Exp Biol Med (Maywood). 243:595–600. 2018.PubMed/NCBI View Article : Google Scholar

84 

Wang K, Song Y, Liu W, Wu X, Zhang Y, Li S, Kang L, Tu J, Zhao K, Hua W and Yang C: The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression. Clin Sci (Lond). 131:965–979. 2017.PubMed/NCBI View Article : Google Scholar

85 

Chen J, Jia YS, Liu GZ, Sun Q, Zhang F, Ma S and Wang YJ: Role of LncRNA TUG1 in intervertebral disc degeneration and nucleus pulposus cells via regulating Wnt/β-catenin signaling pathway. Biochem Biophys Res Commun. 491:668–674. 2017.PubMed/NCBI View Article : Google Scholar

86 

Wang X, Zou M, Li J, Wang B, Zhang Q, Liu F and Lü G: lncRNA H19 targets miR-22 to modulate H2 O2-induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling. J Cell Biochem. 119:4990–5002. 2018.PubMed/NCBI View Article : Google Scholar

87 

Wang XB, Wang H, Long HQ, Li DY and Zheng X: LINC00641 regulates autophagy and intervertebral disc degeneration by acting as a competitive endogenous RNA of miR-153-3p under nutrition deprivation stress. J Cell Physiol. 234:7115–7127. 2019.PubMed/NCBI View Article : Google Scholar

88 

Sampara P, Banala RR, Vemuri SK, Av GR and Gpv S: Understanding the molecular biology of intervertebral disc degeneration and potential gene therapy strategies for regeneration: A review. Gene Ther. 25:67–82. 2018.PubMed/NCBI View Article : Google Scholar

89 

Wang X, Wang B, Zou M, Li J, Lü G, Zhang Q, Liu F and Lu C: CircSEMA4B targets miR-431 modulating IL-1β-induced degradative changes in nucleus pulposus cells in intervertebral disc degeneration via Wnt pathway. Biochim Biophys Acta Mol Basis Dis. 1864:3754–3768. 2018.PubMed/NCBI View Article : Google Scholar

90 

Xiao L, Ding B, Xu S, Gao J, Yang B, Wang J and Xu H: circRNA_0058097 promotes tension-induced degeneration of endplate chondrocytes by regulating HDAC4 expression through sponge adsorption of miR-365a-5p. J Cell Biochem. 121:418–429. 2019.PubMed/NCBI View Article : Google Scholar

Related Articles

Journal Cover

June-2021
Volume 21 Issue 6

Print ISSN: 1792-0981
Online ISSN:1792-1015

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Jiang J, Sun Y, Xu G, Wang H and Wang L: The role of miRNA, lncRNA and circRNA in the development of intervertebral disk degeneration (Review). Exp Ther Med 21: 555, 2021
APA
Jiang, J., Sun, Y., Xu, G., Wang, H., & Wang, L. (2021). The role of miRNA, lncRNA and circRNA in the development of intervertebral disk degeneration (Review). Experimental and Therapeutic Medicine, 21, 555. https://doi.org/10.3892/etm.2021.9987
MLA
Jiang, J., Sun, Y., Xu, G., Wang, H., Wang, L."The role of miRNA, lncRNA and circRNA in the development of intervertebral disk degeneration (Review)". Experimental and Therapeutic Medicine 21.6 (2021): 555.
Chicago
Jiang, J., Sun, Y., Xu, G., Wang, H., Wang, L."The role of miRNA, lncRNA and circRNA in the development of intervertebral disk degeneration (Review)". Experimental and Therapeutic Medicine 21, no. 6 (2021): 555. https://doi.org/10.3892/etm.2021.9987