Previously, it has been determined that miRNAs play a critical role in complex gene regulatory networks (70). According to statistics, >1,500 miRNAs have been found in the human genome, and each miRNA can target multiple mRNAs; in addition, each mRNA can also be regulated by several miRNAs (71-73). Short RNA molecules of 19-25 nucleotides in size are a class of ncRNAs that regulate the post-transcriptional silencing of target genes by directly binding to the 3'-untranslated region (UTR), 5'-UTR and coding sequence regions of their target mRNAs (74). The majority of miRNA sequences are conserved across species (75). However, miRNA expression varies depending on the time and period examined and tissue type, which indicates that changes in miRNA expression may reflect different cellular composition or activation states (76,77). There is evidence to indicate that miRNAs participate in diverse chondrocyte processes, such as cell proliferation (78), apoptosis (79) and differentiation (80). They are therefore involved in a wider range of processes, such as cartilaginous development, degeneration (81) and regeneration (82). Consequently, CEP degeneration is the primary factor leading to IDD and maintaining the physiological function of CEP is essential for prevention and treatment of IDD (46).

Previous studies have demonstrated that intermittent cyclic mechanical tension (ICMT) can lead to CEP degeneration (83,84). However, the role of miRNAs in regulating chondrocyte responses to ICMT needs to be elucidated. In the study by Feng et al (85), CEP chondrocytes from patients without ICMT stimulation were used as controls and specimens were obtained from patients who underwent posterior discectomy and a fusion procedure for IDD. They identified a total of 21 significantly upregulated and 62 downregulated identified compared with the control.

The biological potency of miRNAs has been well-established, with their regulatory effects primarily exerted through sponge target genes, as depicted in Fig. 2, which illustrates the underlying molecular mechanisms.

miRNAs are involved in the regulation of multiple mechanisms as a novel subtype ncRNAs. There is evidence to indicate that the apoptosis of chondrocytes in the CEP is implicated in the pathogenesis IDD. Chen et al (86) demonstrated that the expression of miR-34a is markedly elevated in human degenerated CEP chondrocytes compared with normal CEP chondrocytes. Furthermore, luciferase assays from the same study indicated that Bcl-2 is a target of miR-34a, while miR-34a represses the expression of Bcl-2. Functionally, the inhibition of miR-34a rescues the fas-induced apoptosis of CEP chondrocytes by releasing Bcl-2, which plays an important role in the development of IDD.

It has been shown that miRNAs are involved in the tension-induced degeneration of endplate chondrocytes by regulating the miR-455-5p/runt-related transcription factor 2 (RUNX2) axis. In the majority of cases, more tension is borne by endplate chondrocytes compared with other cells in human body (87), which is responsible for chondrocyte degeneration (88,89). In chondrocytes, the aberrantly low-expression of miR-455-5p increases the degeneration level of chondrocytes by upregulating RUNX2 expression using ICMT. Furthermore, Xiao et al (90) revealed that the up- or downregulation of miR-455-5p does not affect the proliferation or apoptosis of endplate chondrocytes, while RUNX2 expression also exhibits a down- and upregulation, respectively. Therefore, these findings result indicate that miR-455-5p is a therapeutic target for tension-induced degeneration. There is previous evidence to indicate that miRNAs are involved in the calcification of CEP chondrocytes induced by matrix stiffness. For example, it has been shown that the inhibition of miR-20a attenuates calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhances the calcification of CEP chondrocytes on a stiff matrix, which is positively associated with the degree of IDD (91).

The role of CEP chondrocytes in ECM synthesis and catabolism, such as collagens and proteoglycans, plays an important role in maintaining the structural stability of the IVD and in resisting mechanical loads (92,93). In patients with IDD, an imbalance in matrix synthesis and breakdown in the CEP is observed, as shown by the increased expression of breakdown proteins, such as MMP-3 and MMP-9, and a corresponding reduction in the expression of synthetic proteins. Sheng et al (94) found that the overexpression of miR-221 in degenerative CEP tissue accelerates apoptosis by downregulating the level of estrogen receptor α. Furthermore, the increased level of miR-221 deteriorates the degradation of the ECM by disrupting the balance in the expression of ECM-degrading and anti-ECM-degrading genes.

Recent studies have demonstrated that cartilage endplate stem cells (CESCs) can maintain the normal function of the NP and CEP through miRNAs. Chen et al (95) revealed that miR-637 is expressed in low levels in the degenerative CEP, and the inhibition of miR-637 promotes the osteogenic differentiation ability of degenerative CESCs. However, the upregulation of Wnt family member 5A partially annuls the inhibitory effects of miR-637 overexpression on the osteogenic differentiation of degenerative CESCs. In addition, Chen and Jiang (96) examined the effects of normal CESC-derived exosomes on autophagy, apoptosis and ECM metabolism in the NP. Bioinformatics analysis was used to analyze differences in miRNA expression, and dual-luciferase reporter assays were used to detect target associations. They confirmed that exosomes-derived miR-125-5p from CESCs regulate autophagy and ECM metabolism in the NP by targeting SUV38H1.

There is evidence to indicate that the reduction of the proliferation of CEP chondrocytes is implicated in the pathogenesis of IDD. Using a double luciferase assay, Wang et al (97) indicated that the target gene of miR-142-3p is high mobility group box 1 (HMGB1), the expression of which is significantly increased during the process of IDD. Functionally, the inhibition of chondrocytes proliferation ability follows the addition of a HMGB1 inhibitor.

In conclusion, the aberrant expression of seven miRNAs has been discovered to be involved in various cellular processes, such as proliferation, apoptosis and calcification-induced apoptosis, with their specific regulatory mechanisms and expressions documented in Table I.

From the discovery of the first ncRNA in bacteria in 1980(98) to a few long-stranded ncRNAs, such as H19 and Xist characterized in the pre-genomic era, to the entry of the genomic era in the 21st century, immense progress has been made in the depth and breadth of research into lncRNAs (99). Previously, lncRNAs were considered as biologically non-functional transcriptional ‘noise’ (100). However, at present, lncRNAs are considered important regulatory factors with multiple biological functions (99,101), which cannot be translated into protein. The expression patterns of various lncRNAs regulate the different phenotypes of cells (102). In addition, lncRNAs function through a variety of mechanisms, such as acting as a scaffold, bait, signal and guide (103). Of note, lncRNAs play the role of competitive endogenous RNAs (ceRNAs) or small interfering RNA and participate in the lncRNA/circRNA/miRNA/mRNA network as transcriptional regulators (104), which mainly regulate gene expression or control signaling pathways by competitively inhibiting or destroying specific miRNAs (105,106). LncRNAs play an important role in various life processes of organisms, including the cell cycle (101,107-109), differentiation (110-112), and metabolism (57). Furthermore, they participate in the occurrence and development of diseases by affecting gene expression (113), chromatin structure (114) and cell signaling pathways (115).

It has been shown that there is a clear difference in lncRNA expression between degenerated endplate chondrocytes and normal endplate chondrocytes (116). In 2020, the expression profile of lncRNAs was reported for the first time in the endplate of degenerated cartilage. In degenerated chondrocytes, 369 lncRNAs exhibited a differential expression, including 316 upregulated and 53 downregulated lncRNAs, contrasting with the non-degenerated CEP of cervical fractures. In addition, Li et al (117) identified the highly selective expression of 34 lncRNAs in human fetal growth plate chondrocytes by employing RNA sequencing. A total of eight lncRNAs were adjacent to the loci of protein coding genes that participate in skeletal development, suggesting that cartilage-selective lncRNAs may be involved in chondrogenesis is through the regulation of protein coding genes.

In summary, the biological functions of lncRNA in chondrocytes can be mediated by various mechanisms, including miRNA sponging, protein scaffolding and translational regulation. Additionally, specific expression patterns of lncRNAs in degenerated endplate chondrocytes have been demonstrated.

Evidence suggests that diabetes causes CEP degeneration by altering endplate thickening and reducing porosity (118-121). Furthermore, chondrocyte apoptosis, characterized by various signaling molecules, is involved in the degeneration of CEPs (122,123). Based on these findings, Jiang et al (124) induced CEP cell degeneration with high-glucose medium and revealed that the knockdown of lncRNA MALAT1 reduces the apoptosis of chondrocytes. Furthermore, they demonstrated that lncRNA MALAT1 promotes high glucose-induced rat CEP apoptosis via the p38/MAPK signaling pathway. lncRNAs, as gene expression modulators, are expected to be a novel target for the treatment of disc degeneration; however, to the best of our knowledge, studies on lncRNAs in CEP degeneration are limited and, thus, further studies on their mechanism of action in CEP degeneration are warranted.

circRNAs, which are single-stranded and covalently closed, were first reported as viroids (125), which are pathogens of certain plants in 1976 and were first detected in human HeLa cells by electron microscopy in 1979(126). Later on, with the development of high-throughput RNA sequencing and bioinformatics tools, circRNAs began to be considered as a general feature of the human transcriptome and are ubiquitous in numerous other metazoans, including mammals (127), unicellular eukaryotes (128), prokaryotes (129) and viruses (130). Previous studies have identified multiple functions of circRNAs, including serving as protein scaffolds or miRNA sponges and being translated into polypeptides (131,132). In addition, the unique covalently closed structure of circRNAs that provides them with a longer half-life and greater resistance to RNase R compared with linear RNAs (133), renders them as potential candidates for use as diagnostic biomarkers and therapeutic targets.

We previously conducted a study to compare degenerative CEP to healthy CEP using a human ceRNA microarray (134). It was revealed that 578 circRNAs were differentially regulated in degenerative CEP samples compared with healthy tissues. Of these, 435 circRNAs were highly expressed, while 143 were significantly repressed. In addition, it has been indicated that biomechanical stimulation is essential for the growth and maintenance of endplate cartilage function (102). Excessive mechanical loading, on the other hand, alters the distribution of the ECM in the CEP, ultimately leading to the destruction of normal cartilage structure and the interruption of nutrient supply (135). By applying an ICMT of 0.5 Hz and an extension of 10% to primitive human endplate chondrocytes, Xiao et al (136) verified upregulated expression levels of 17circRNAs and the downregulated expression of another 12 with fold changes 1.5 by using a circRNA microarray technique.

Compared with miRNAs and lncRNAs, circRNAs exhibit an enhanced richness, stability and specific expression (137). Furthermore, various mechanisms such as miRNA sponging, protein scaffolding and translational regulation can be utilized to regulate the chondrocyte process by circRNAs (138) (Fig. 2).

Specific circRNAs regulate the ECM and proliferation via a ceRNA mechanism, which contributes to the development of IDD (139). Specifically, circRNA_0058097 and circ small nucleolar RNA host gene 5 (SNHG5) are involved in ECM regulation (136,140). circSNHG5 is related to CEP cell proliferation. miR-495-3p stimulates ECM degradation and inhibits chondrocyte cell proliferation by inhibiting Cbp/P300-interacting transactivator with glu/asp rich carboxy-terminal domain 2, whereas circSNHG5 alleviates the negative effects by sponging miR-495-3p. However, in IDD tissues, the expression of circSNHG5 is repressed, resulting in an aberrantly higher level of miR-495-3p and IDD. The upregulation of circRNA_0058097 expression was observed in the loading group that was subjected to an ICMT of 0.5 Hz and 10% elongation degeneration. Furthermore, circRNA_0058097 can sponge miR-365a-5p and overexpression of miR-365a-5p alleviates tension-induced chondrocyte degeneration (130). These results suggest that the fate of CEP cells in IDD can be modulated by circRNAs, which have the potential to serve as therapeutic targets.