NF‐κB signalling pathways in nucleus pulposus cell function and intervertebral disc degeneration

Abstract Intervertebral disc degeneration (IDD) is a common clinical degenerative disease of the spine. A series of factors, such as inflammation, oxidative stress and mechanical stress, promote degradation of the extracellular matrix (ECM) of the intervertebral discs (IVD), leading to dysfunction and structural destruction of the IVD. Nuclear factor‐κB (NF‐κB) transcription factor has long been regarded as a pathogenic factor of IDD. Therefore, NF‐κB may be an ideal therapeutic target for IDD. As NF‐κB is a multifunctional functional transcription factor with roles in a variety of biological processes, a comprehensive understanding of the function and regulatory mechanism of NF‐κB in IDD pathology will be useful for the development of targeted therapeutic strategies for IDD, which can prevent the progression of IDD and reduce potential risks. This review discusses the role of the NF‐κB signalling pathway in the nucleus pulposus (NP) in the process of IDD to understand pathological NP degeneration further and provide potential therapeutic targets that may interfere with NF‐κB signalling for IDD therapy.


| INTRODUC TI ON
Intervertebral disc degeneration (IDD) is a common degenerative disease of the musculoskeletal system and is also the main cause of chronic low back pain (LBP), which seriously affects the quality of life of patients and places a huge economic burden on families and society. 1-3 It is estimated that about 20% of adolescents have mild IDD and 80% of the general population will experience back pain symptoms during their lifetime. 4 However, the specific pathogenesis of IDD is still not fully understood. At present, IDD is believed to be a complex cell-mediated process that ultimately leads to changes in intervertebral disc (IVD) structure and function. 5

| ECMdegradation
The physiological function of IVD depends on the molecular composition of the NP ECM. The NP is composed of ECM rich in type II collagen, elastin and proteoglycan, and it acts to offset and transmit the axial pressure load of the spine during a stress process. 20,25 The primary function of AF, which is composed of alternating type I collagen fibres, is to prevent the NP from protruding under pressure during the bending or twisting of the spine. CEP is a uniformly thick hyaline cartilage tissue, and its ECM is primarily composed of proteoglycans and collagen fibres. Because IVD is an avascular and nerveless tissue, CEP plays an important role in supplying nutrients to the intervertebral disc. The IVD exchanges nutrients and metabolic waste by diffusion through the CEP, thereby maintaining its normal structure and function. 26 Due to NP tissue not only lacks blood vessels and nerves, but also has limited repair ability after injury, so the protection of NP cells is very important for maintaining IVD health. 27 NP cells maintain homeostasis by synthesizing ECM, thereby retaining its structural and functional integrity. However, during the progression of IDD, NP cells lose the ability to maintain their integrity and survivability. This leads to the gradual loss of type II collagen and proteoglycan, resulting in a reduction in the IVD height, loss of the boundary between AF and NP and a decreased ability to withstand mechanical loads. 20,25 Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are the main catabolic enzymes in the NP and include MMP-3, MMP-9, MMP-13, ADAMTS-4 and ADAMTS-5. The expression of metabolic enzymes is increased in degenerated NP tissue; therefore, the catabolism of NP cells is greater than the protective function of NP cell anabolism, which eventually leads to IDD. 28,29

| Inflammation
As IDD progresses, the levels of proinflammatory factors, such as IL-1α, IL-1β, IL-6, IL-8, IL-17 and TNFα, increase significantly. These factors produce inflammatory stimuli on the sinus vertebral nerve endings resulting in nerve root pain, which is the main cause of chronic LBP in patients. 4 IL-1β is the most intensively studied proinflammatory factor. It has been shown to trigger higher levels of proinflammatory mediators (including TNFα, IL-6 and several matrixdegrading enzymes), disrupt the balance of ECM metabolism and impair its metabolism. 30 TNFα and IL-6 are essential proinflammatory factors that have been shown to be closely related to the progression of IDD. 31,32 TNFα can trigger inflammation, cause nerve swelling and neuropathic pain and aggravate cell apoptosis due to its cytotoxic effect, in individuals with LBP. 33 Krupkova et al 34 showed that IL-1β aggravated the local inflammatory response of IVD cells by activating the NF-κB pathway and aggravating nerve radiation pain in rats.

| Oxidativestress
With the progression of IDD, the levels of reactive oxygen species (ROS) in IVD increase significantly, including those of superoxide anions (O 2-), hydroxyl radicals (OH), hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO), which are the by-products of cellular oxidative metabolism. 35 NP cells are the most important functional cells in the IVD. They have been shown to be non-anaerobic and carry out aerobic metabolism in the body, with ROS being the main metabolic by-product. 36 Excessive ROS-mediated oxidative stress accelerates the IDD process through NF-κB signalling pathway. 37

| Mitochondrialdysfunction
Mitochondria contain important components that complete the tricarboxylic acid cycle and redox reactions, which lead to the production of adenosine triphosphate (ATP) through oxidative phosphorylation, thereby ensuring normal cell function. 39 Mitochondrial DNA damage intensifies with age, leading to mitochondrial dysfunction and abnormal electron leakage, thereby increasing ROS production. At the same time, the reduction of cellular redox balance leads to increased oxidative damage to cells by ROS, which in turn mediates cell damage. The impaired mitochondrial function in IVD cells is involved in the occurrence and development of IDD. 40 Studies have shown that the accumulation of the progerin protein in rat NP cells can increase the levels of ROS, destroy the mitochondrial membrane potential, reduce ATP production and change the activity of mitochondrial enzyme complexes, thereby destroying the structure and function of mitochondria and accelerating the IDD process. 41 Chen et al 42 studied the effect of bone marrow mesenchymal stem cells (BMSCs) on the regeneration of NP cells and found that co-culture with BMSCs can reduce the levels of ROS in NP cells and maintain the cell mitochondrial membrane potential and mitochondrial integrity, thereby reducing stress-induced mitochondrial damage in NP cells. Interestingly, excessive ROS-mediated oxidative stress further accelerates the IDD process through the NF-κB signalling pathway. 37 Accordingly, mitochondrial dysfunction leads to the accumulation of intracellular ROS which plays an important role in the IDD process.

| TelomereshorteningandDNAdamage
Mammalian telomeres are composed of repetitive DNA fragments (TTAGGG) that are 50-400 nucleotides in length. 43  In severe cases, it can lead to the loss of genetic information, cell cycle arrest and apoptosis. 46 Studies have shown that telomere shortening often causes DNA damage in cells and is an internal trigger for cell senescence. 21 Experimental results have shown that ionizing radiation can cause intracellular DNA damage and increase the number of p16-positive cells in NP tissues of wild-type mice. 47 Nasto et al 48 exposed adult wild-type and DNA repair gene Ercc1-deficient mice to ionizing radiation to induce DNA damage and studied its effect on the IVD structure. They found that in the IVD of the Ercc1-deficient mice, NP cell senescence and apoptosis increased significantly. Importantly, telomere shortening and DNA damage aggravate cell damage by activating the NF-κB signalling pathway to further increase the release of proinflammatory cytokines, thereby accelerating cellular senescence. 49

| Nutrientdeprivation
A reduction in cell nutrition is another important cause of IDD.
Previous studies have shown that serum starvation can inhibit the proliferation of artificially cultured IVD cells and increase their senescence rate, while administration of high concentrations of serum can increase the proliferation rate of NP cells. 50 A variety of growth factors derived from serum can promote cell proliferation, including insulin-like growth factor (IGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and transforming growth factorβ (TGFβ). 50,51 It is worth noting that in the pathological process of CEP degradation, the apoptosis and calcification of CEP cells block the nutrient supply of NP cells, thereby accelerating the senescence and apoptosis, ultimately leading to IDD. 21 In addition, aggravated NP degeneration is associated with a decreased supply of nutrients. Under the condition of serum deprivation, the NF-κB signalling pathway is activated, which further aggravates the apoptosis of NP cells. 52

| Abnormalmechanicalload
The human spine is subjected to multi-directional mechanical loads, including axial, radial, and circumferential compression, tension and shear. Abnormal mechanical load is a risk factor for IDD. 21 Studies have shown that an increase in the mechanical load on the spine caused by obesity is a risk factor for the development of IDD. The increase in body mass index changes the biomechanics of IVD and ultimately leads to the narrowing of the intervertebral disc space and the enhancement of the catabolism of the IVD cells. 53

| Epigeneticchanges
Epigenetics refers to reversible and heritable changes in gene function that do not involve alterations to the DNA sequences. It mainly includes DNA methylation, histone modification and non-coding RNA (ncRNA). These changes regulate the specific expression of genes through the interaction between the environment and the genome to make permanent changes and play an important role in the occurrence and development of diseases. 55 Ikuno et al 23 showed that in the late stage of IDD, the degree of DNA methylation increased significantly. Yang et al 24 reported that miR-143-5p was highly expressed in degenerated NP cells, and after adding miR-143-5p-specific inhibitors to NP cells, cell proliferation increased and apoptosis decreased. Epigenetic changes can further affect the IDD process by regulating the NF-κB signalling pathway. 8 Unfortunately, the research on epigenetic changes in IDD is still in its infancy, and the specific mechanisms still need to be clarified.

| G ENER ALFUN C TI ONAND REG UL ATI ONOFTHENFκ BS IG NALLING PATHWAY
NF-κB, first discovered in 1986 by Sen et al, 56 is a transcription factor that binds specifically to the enhancer region of the immunoglobulin κ light chain gene. 57 It was originally thought to be a regulator of B cell differentiation and function, but was later shown to be a ubiquitous transcription factor expressed in various cells. It plays a key regulatory role in immune response, inflammatory response and tumourigenesis. NF-κB exists as a dimer, which is a member of the Rel protein family that share a conserved sequence of about 300 amino acids at the N-terminus known as the Rel homology domain (RHD), which is derived from the retroviral oncoprotein, v-Rel, and is involved in DNA binding and dimerization, and is related to inhibitor of κB (IκB) proteins. 58 Common Rel proteins are Rel A (p65), Rel B, c-Rel, p50 and p52. The five Rel family proteins can be divided into two categories. The first category includes p50 and p52, which are produced from the precursor proteins p105 (NF-κB1) and p100 (NF-κB2), respectively. 59 Although there are many different ways of activating NF-κB, two major signalling pathways have been reported to lead to the activation of NF-κB target genes. These are referred to as the canonical and non-canonical pathways, in which the canonical approach dominates. 63 Generally, the activation of NF-κB can be summarized as the transfer of stimulating signals from ligands, receptors, adaptor proteins and deoxycytidine kinase (dCK) complexes to NF-κB. 62,64 Among them, the tumour necrosis factor receptor 1 (TNFR1)-, interleukin 1 receptor (IL-1R)-, Toll-like receptor (TLR)-, T cell receptor (TCR)-and B cell receptor (BCR)mediated NF -κB activation pathways have been studied most extensively. 44 In the resting state, NF-κB binds to IκB, a specific inhibitor of NF-κB, and exists in the cytoplasm as an inactive complex. It binds to the RHD region of NF-κB to prevent it from entering the nucleus to perform its function. The IκB proteins mainly include IKKα (IKK1), IKKβ (IKK2) and regulatory subunit IKKγ. IKKγ forms an IKK complex with IKKα/IKKβ dimers. 56  In turn, the released cytokines can reactivate NF-κB, which can mediate tissue inflammatory damage through a cascade reaction 65 ( Figure 1).
The non-canonical NF-κB activation pathway is mediated by the transcription factor p100/Rel B, which is mainly related to immune cells. The non-canonical NF-κB pathway is activated by a select group of TNFR superfamily members, including CD40, the lymphotoxinβ receptor (LTβR) and the receptor activator of NF-κB (RANK).
NF-κB-inducing kinase (NIK, also known as MAP3K14) and IKKα are necessary for the processing of p52 from p100 and result in dimerization and activation of the p52/Rel B heterodimer. 66 The activation of the non-canonical pathway of the NF-κB signalling pathway mainly depends on IκBα, rather than IκBβ and IκBγ. In the resting state, the N-terminus of p100 exhibits self-inhibition, blocking the transcriptional activity of p100/Rel B. Ligand stimulation, such as the binding of CD40L and CD40, can eliminate K48 ubiquitination of the key protein NIK (NF-κB). κB induces kinase and stops the degradation of NIK by the proteasome. Stable NIK activates p100, which leads to phosphorylation and ubiquitination of p100, which is recognized by the proteasome and partially degraded into p52. Finally, the nu-

| S I G NIFI C AN CEOFNFκ BINTHE PATHOG ENE S ISOFIDD
The destruction of the NP ECM is due to a decrease in NP cell anabolism and increase in catabolism/apoptosis. Genes that either increase or decrease the susceptibility to IDD have been identified using several models of IDD. The NF-κB pathway is one of the better characterized signalling pathways activated by IDD stimuli, such as inflammation and mechanical loading. Studies  75 NF-κB can also upregulate other transcription factors, such as hypoxia-inducible factor 2α (HIF-2α), which is regulated in development, and DNA damage response 1 (REDD1) and prolyl hydroxylase 3 (PHD3). Activated HIF-2α binds to the HIF-2α binding motif of the promoter of target genes and promotes the expression of matrixdegrading enzymes, such as MMP-13 and ADAMTS-4. HIF-2α controls the catabolic factors, MMP-13 and ADAMTS-4, which regulate metabolism of type II collagen and aggrecan. 76 REDD1, also known as RTP801, DDIT4, or DIG2, was initially identified as a hypoxiainducible factor 1 (HIF1) response protein, and the level of REDD1 expression was shown to be markedly increased under hypoxic conditions. 77 As a transcription factor, NF-κB binds to the REDD1 promoter region, and hypoxia can protect against ECM degradation caused by serum deprivation through the NF-κB/REDD1 pathway. 52 PHD3 is another important molecule involved in HIF-1α signalling, which forms a regulatory circuit with NF-κB and acts as a transcription coactivator. NF-κB-dependent induction of ADAMTS-5, MMP-13 and COX-2 is significantly reduced by PHD3 loss of function. 78 Taken together, these findings clearly indicate that the above factors are key components of the NF-κB signal transduction pathway in NP cells, which are likely to play key roles in the pathogenesis of IDD and represent new pharmacological targets.

| FactorsthatregulateNF-κBactivityviadirect interaction
The catabolism of NF-κB in NP cells is enhanced by several NF-κB binding proteins. Figure 2 shows the genes that have a stimulatory F I G U R E 2 Genes or factors that positively or negatively regulate NF-κB activation in NP or inhibitory effect during the activation of NF-κB in NP cells.
Stimulators that bind to the NF-κB subunit include tonicity- activity. 83 Therefore, targeting these factors that affect NF-κB signalling may represent a new therapeutic strategy for IDD.

| FactorsthatactivateNF-κBunder IDDconditions
Previous studies have shown that mechanical load is one of the risk factors for IDD. IVD cells are known to convert mechanical stress into biological signals, which can be integrated into cell responses and affect cell survival or death by regulating gene transcription. It is well known that inflammatory cytokines cause the induction of catabolic genes in NP cells through a mechanism involving activation of the NF-κB signalling pathway. Therefore, treatment of NP cells with traditional inflammatory cytokines, such as IL-1β and TNFα, has been widely used to prepare in vitro IDD models. IL-6 is a well-known NF-κB target gene, and it also has a pathogenic effect in the progression of IDD. 4

TNFα induces an increase in the expression of CHOP in NP cells and promotes NP cell apoptosis through
NF-κB signalling. 87 N-Acetylated proline-glycine-proline (N-Ac-PGP) is a chemokine involved in inflammatory diseases, and its expression is increased in degenerated IVDs. N-Ac-PGP has been shown to activate the NF-κB signalling pathway in NP cells, thereby promoting the expression of proinflammatory factors and matrix catabolic enzymes. 88 Another inflammatory mediator, high mobility group box 1 (HMGB1), is a chromatin protein with dual functions as a nuclear factor and an extracellular factor. It can also activate the NF-κB signalling pathway in NP cells. Recently, HMGB1 has been recognized as an effective proinflammatory mediator in the degenerative IVDs. 89 In the rat lipopolysaccharide (LPS)-induced IDD model, HMGB1 is significantly upregulated in the IVDs. HMGB1 promotes the release of inflammatory cytokines in human IVD cells through the NF-κB signalling pathway. 90 Accumulating evidence shows that endogenous molecules produced by cellular metabolism or ECM degradation can trigger inflammatory responses, acting as 'danger signals' called damage-associated molecular patterns (DAMPs). 91 As a class of DAMPs, the accumulation of advanced glycation end products (AGEs) in NP tissues may activate the NF-κB pathway, enhance the activity of NLRP3 inflammasomes and accelerate NP degeneration 92 ( Figure 2).
Due to the avascular nature of NP tissue, nutrient and metabolite transport are dependent on the osmotic effects of the CEP. Studies have shown that the oxygen content in NP is 1%, but NP cells are in a low-oxygen but not completely anaerobic microenvironment. 93,94 NP cells are well adapted to the hypoxic microenvironment and have a certain level of oxidative metabolism. 95,96 With the progress of IDD, the oxygen concentration of NP tissue decreases further, and anaerobic glycolysis provides the main energy source accompanied by the accumulation of a large number of acidic metabolites, which then activate the NF-κB signalling pathway. 38 The acid-sensing ion channels (ASICc) represent a subfamily of protonation channels, consisting of six isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4), which was activated by extracellular acidosis, lactic acid and arachidonic acid. The extracellular lactic acid regulates intercellular ROS levels through ASIC1 and ASIC3, and the ROS further activate the NF-κB signalling pathway, thereby promoting the activation of NLRP3 inflammasomes and the release of IL-1β, both of which promote NP degeneration. 97 In addition, under hypoxic conditions, IL-1β promotes the catabolism of human NP cells through the NF-κB signalling pathway. 98 Other studies have shown that as IDD progresses, IVD tissue neovascularization increases, thereby exposing NP cells to higher oxygen tension. 36,38,99 (Figure 2).
In addition, the abnormal expression of some genes in NP cells can further induce the development of IDD through the NF-κB signalling pathway. High temperature requirement serine protease A1 (HTRA1) is a conserved PDZ serine protease, which belongs to the HTRA family of serine proteases. It is a secreted enzyme and is widely expressed in human cells and tissues. 100 The degenerative changes of NP are known to be related to ECM degradation caused by locally produced MMPs and aggrecanase belonging to the ADAMTS family, resulting in tissue stiffness, loss of structural integrity and functional impairment. HTRA1 can induce the expression of ADAMTS-5 in human NP cells through the ERK/NF-κB/JNK signalling pathway. 13 BRD4 expression is increased in degenerated NP tissues. BRD4 enhances NF-κB signalling and activates autophagy to promote MMP-13 expression in IDD. 70 One of the members of the angiopoietin-like (ANGPTL) protein family, angiopoietin-like protein 8 (ANGPTL8), which is also known as betatrophin or lipasin, is a regulator of plasma lipid metabolism. 101 The level of ANGPTL8 expression is increased in degenerated NP tissues. TNFα treatment has been shown to promote the expression of ANGPTL8 in NP cells in vitro. ANGPTL8 regulates ECM metabolism and inflammatory response by activating the NF-κB signalling pathway. 71 Galectin-1 (Gal-1), a member of the galectin family, may further accelerate IDD through NF-κB signalling via enzymes that induce inflammatory mediators and ECM catabolism, such as IL-6, CXCL8 and MMP-1/3/13 102 (Figure 2).
Specifically, Wnt5a is a representative ligand that activates the βcatenin independent pathway in Wnt signalling, and inhibits TNFα-induced NF-κB signalling, thereby reducing the expression levels of downstream catabolic genes. In the rat IDD model, the synthesis of type II collagen and aggrecan was reported to be increased after intradiscal injection of Wnt5a. 103 TSG-6 is a 30-kD glycoprotein that can exert anti-inflammatory effects. By inhibiting activation of the NF-κB pathway, TSG-6 can reduce the expression of MMP-3 and MMP-13 in IL-1β-treated NP cells and increase the expression of type II collagen and proteoglycan. 104 The anti-ageing protein, Klotho, has impressive anti-inflammatory properties, and its expression is decreased in the degenerated NP. Overexpression of Klotho reduces the expression of inflammatory factors by inhibiting NF-κB signalling. 105 This makes increasing Klotho expression an attractive strategy for the treatment of IVD inflammatory diseases. NAMPT, also known as visfatin, is synthesized and secreted by fat, liver, skeletal muscle and other tissues. 106 The NAMPT inhibitor, APO866, can reverse the matrix degradation induced by IL-1β in NP cells through autophagy. 107

| Histonedeacetylases(HDACs)
Epigenetic changes of histones and non-histones play crucial roles in the process of IDD. In fact, HDACs seem to affect NF-κB activity and catabolic gene expression in NP cells. Interestingly, inhibition of NAD-dependent deacetylases (Class III) was reported to show a beneficial effect on IDD. 4 Sirtuins are a class of evolutionarily conserved nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases and are the main molecules that mediate life extension or delay ageing-related diseases. 113 To date, seven members of the sirtuin family have been identified, SIRT1-SIRT7, which belong to the class III HDACs and share a common catalytic core domain. SIRT1 can directly deacetylate p65 at residue 310 of lysine, thereby inhibiting the transactivation ability of p65 and inhibiting NF-κB-dependent gene transcription. 114 Previous studies have shown that downregulating the level of SIRT1 in NP cells increased NF-κBp65 and p-NF-κBp65 levels. This transcription factor leads to increased levels of various inflammatory factors (TNFα, IL-1β and IL-6), decreases in type II collagen and aggrecan levels and increases MMP-13 and ADAMTS-5 levels, thereby inducing NP cell anabolic metabolism. Significantly, the imbalance between catabolic activities initiates or exacerbates IDD. 115 SIRT6 at the chromatin level attenuates NF-κB signalling by deacetylating histone H3K9. The physical interaction between SIRT6 and NF-κB catalytic subunit p65 affects its transcriptional activity and thus affects the metabolism of NP ECM. 116,117 The above results indicate that SIRT1 and SIRT6 have protective roles in maintaining the structure and function of the NP. Supporting this concept, SIRT2, the closest homolog of SIRT1, can enable deacetylation of p65 Lys310 to regulate the expression of NF-κB-dependent genes, 118 and SIRT5 and SIRT7 regulate NF-κB activity by promoting the acetylation of p65. 119,120 SIRT3 and SIRT4 are also involved in the regulation of NF-κB. 121,122 Therefore, we speculate that SIRT2, 3, 4, 5 and 7 may also participate in the development of IDD by regulating the NF-κB pathway. However, their role in the pathogenesis of IDD is still unclear (Figure 2).
In contrast to the above effects, the classical zinc-dependent histone deacetylases (class I and II) accelerate destruction of articular cartilage in patients with osteoarthritis (OA) by regulating the activity of NF-κB. 123 Treatment with the HDAC6-specific inhibitor, ACY-1215, or pan-HDAC inhibitor, SAHA, inhibited NF-κB activation and catabolic gene expression in IL-1β-stimulated chondrocytes. 124,125 As NP cells are composed of small chondrocyte-like cells with typical morphology, they share a common developmental lineage with chondrocytes at the molecular level. 33 However, the effects of histone deacetylases (class I and II) on NP by regulating the activity of NF-κB are still unclear. Although further studies are needed to clarify the detailed molecular mechanisms underlying the roles of HDACs in IDD, these studies have shown that the activation of sirtuins has a beneficial effect in IDD. Although further studies are required, we speculate that the inhibition of classical HDACs will also have a beneficial role in IDD treatment.

| Non-codingRNAs
It has recently been reported that IDD is a complex cellular process mediated by multiple molecules, and it is becoming clear that noncoding RNAs are key factors affecting the pathogenesis of IDD.
Several types of non-coding RNAs have been described, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs). Here, we summarize the non-coding RNAs related to NF-κB signalling in NP cells (Table 1 and Figure 2). miRNA is a type of small non-coding RNA that can bind to target genes through special sequences to inhibit gene expression. These molecules further aggravate or delay the process of IDD by regulating the NF-κB signalling pathway. NF-κB induced by several miR-NAs promotes NP degeneration. For example, the expression levels of miR-141, miR-27a and miR-494 are increased in degenerated NP, resulting in acceleration of NP degeneration by activating the NF-κB signalling pathway. Specifically, miR-141 knockout was shown to significantly inhibit the expression of MMP-13, while the expression level of type II collagen was increased in mouse IDD models induced spontaneously or after surgery. 115 miR-27a activates NF-κB signalling and leads to significant increases in the production of proinflammatory factors IL-1β, IL-6 and TNFα. 126  and ultimately contributes to cell apoptosis. 135 The lncRNAs are endogenous non-coding transcripts longer than 200 nucleotides, and there is accumulating evidence that lncRNAs play key regulatory roles in biological processes. Abnormal lncRNA expression has been shown to be related to a variety of human diseases, including IDD and osteoarthritis. 136

| CON CLUS I ONANDFUTURE PER S PEC TIVE S
In this review, we summarized the results of published studies on the regulation of the NF-κB signalling pathway in NP cells during IDD.
In the IDD process, many factors (such as inflammation, oxidative stress, mitochondrial dysfunction, mechanical load and nutrient defi- in the IDD process. More and more researches in this area are still needed in the future to further clarify the underlying mechanisms, which will lay a theoretical foundation for the transformation and application of the corresponding molecular targets, and we hope that further research regarding NF-κB in IDD will yield important discoveries and lead to translational research in the future. English language editing.

CO N FLI C TO FI NTE R E S T
The authors declare no competing interests.

DATAAVA I L A B I L I T YS TAT E M E N T
Data sharing not applicable to this article as no data sets were generated or analysed during the current study.