Pathogenesis Of Intervertebral Disc Degeneration Research Articles

Role of non‑coding RNAs in cartilage endplate (Review).

Cartilage endplate (CEP) degeneration is considered one of the major causes of intervertebral disc degeneration (IDD), which causes non-specific neck and lower back pain. In addition, several non-coding RNAs (ncRNAs), including long ncRNAs, microRNAs and circular RNAs have been shown to be involved in the regulation of various diseases. However, the particular role of ncRNAs in CEP remains unclear. Identifying these ncRNAs and their interactions may prove to be is useful for the understanding of CEP health and disease. These RNA molecules regulate signaling pathways and biological processes that are critical for a healthy CEP. When dysregulated, they can contribute to the development disease. Herein, studies related to ncRNAs interactions and regulatory functions in CEP are reviewed. In addition, a summary of the current knowledge regarding the deregulation of ncRNAs in IDD in relation to their actions on CEP cell functions, including cell proliferation, apoptosis and extracellular matrix synthesis/degradation is presented. The present review provides novel insight into the pathogenesis of IDD and may shed light on future therapeutic approaches.

N-Acetylserotonin Protects Rat Nucleus Pulposus Cells Against Oxidative Stress Injury by Activating the PI3K/AKT Signaling Pathway

Current studies suggest that the pathogenesis of intervertebral disc degeneration (IDD) is related to oxidative stress damage in nucleus pulposus cells (NPCs). N-acetylserotonin (NAS) is an effective scavenger of reactive oxygen species, but its role in IDD and its underlying mechanisms are not yet clear. Therefore, the aim of this study was to investigate the effect of NAS on oxidative stress injury in NPCs and its mechanism. NP tissue of rat intervertebral disc was collected and NPCs were isolated. NPCs were treated with H2O2 to simulate the state of oxidative stress. The effects of NAS on cell viability, apoptosis, senescence, extracellular matrix (ECM), redox status and PI3K/AKT signal pathway were evaluated by cell counting kit-8, western blot, immunofluorescence, flow cytometry and SA-β-gal staining. Finally, the changes of the above indexes were further observed after the inhibition of PI3K pathway by LY294002. Flow cytometry showed that NAS reduced H2O2-induced apoptosis of NPCs. SA-β-Gal staining showed that H2O2-induced senescence of NP cells was reversed by NAS. Immunofluorescence staining showed that NAS inhibited H2O2-induced ECM degradation. Western blotting analysis revealed that NAS significantly decreased apoptosis, senescence and ECM degradation. Further analysis showed that NAS treatment activated the PI3K/AKT pathway in H2O2-stimulated NPCs. However, these protected effects were inhibited after LY294002 treatment. The results of the present study suggest that NAS inhibits H2O2-induced NPCs degeneration by activating PI3K/AKT pathway, suggesting that NAS has the potential to treat IDD.

The involvement of DDX3X in compression-induced nucleus pulposus pyroptosis.

A study has been conducted to investigate the relationship between DDX3X and nucleus pulposus (NP) pyroptosis. DDX3X and pyroptosis-related proteins (Caspase-1, Full-length GSDMD, Cleaved GSDMD) were measured in compression-induced human NP cells and tissue. DDX3X was overexpressed or knocked down by gene transfection. The expressions of NLRP3, ASC, and pyroptosis-related proteins were detected by Western blot assay. IL-1β and IL-18 were detected by ELISA. HE staining and immunohistochemistry were used to observe the expression of DDX3X, NLRP3, and Caspase-1 in the rat model of compression-induced disc degeneration. DDX3X, NLRP3, and Caspase-1 were highly expressed in degenerated NP tissue. Overexpression of DDX3X induced pyroptosis in NP cells and increased levels of NLRP3, IL-1β, IL-18, and pyroptosis-related proteins. Knockdown of DDX3X showed an opposite trend to overexpression of DDX3X. The NLRP3 inhibitor CY-09 effectively prevented the up-regulation of the expression of IL-1β, IL-18, ASC, Pro-caspase-1, Full-length GSDMD, and Cleaved GSDMD. Increased expression of DDX3X, NLRP3, and Caspase-1 was observed in the rat model of compression-induced disc degeneration. Our study showed that DDX3X mediates pyroptosis of NP cells by upregulating NLRP3 expression, which ultimately leads to intervertebral disc degeneration (IDD). This discovery deepens the understanding of IDD pathogenesis and provides a promising and novel therapeutic target for IDD.

Sequencing and bioinformatics analysis of miRNA from rat endplate chondrogenic exosomes.

Exosomes have a key role in various diseases, such as arthritis, heart disease and respiratory disease. Exosomes from various sources have also been indicated to improve intervertebral disc degeneration. However, the role of endplate chondrogenic exosomes in intervertebral disc degeneration has remained largely elusive. The aim of the present study was to compare exosomal microRNA (miRNA) expression patterns in endplate chondrocytes before and after degeneration, and their potential roles in the pathogenesis of intervertebral disc degeneration (IVDD). Endplate chondrocytes were extracted from rats and cultured to obtain pre- and post-degeneration chondrocytes. Exosomes were obtained from the chondrocytes by centrifugation. The two groups of exosomes were subjected to small RNA sequencing, miRNA identification, novel miRNA prediction, quantitative analysis of miRNA expression and differentially expressed (DE) miRNA screening, in addition to miRNA target gene (TG) prediction and TG functional annotation and enrichment analysis. The percentage of miRNAs isolated from the exosomes before and after degeneration was found to differ. A total of 58 DE miRNAs were analyzed, the expression levels of which were significantly different post-degeneration compared with pre-degeneration. Cell experiments were also performed, in which the exosomes were co-cultured with nucleus pulposus (NP) cells. The results indicated that the chondrocyte-derived exosomes were taken up by the NP cells and influenced the expression of aggrecan and collagen 1A and 2A, suggesting that they may inhibit IVDD via their action on NP cells. The specific miRNAs present in exosomes during IVDD may be used to develop new targets for the treatment and diagnosis of this condition. DE exosomal miRNAs derived from endplate cartilage pre- and post-degeneration may be associated with the risk of IVDD and could help to distinguish patients with IVDD. Furthermore, the expression of certain miRNAs may be associated with disease progression, which may contribute to understanding the pathophysiology of IVDD from an epigenetic perspective.

PTEN inhibitor VO-OHpic protects endplate chondrocytes against apoptosis and calcification via activating Nrf-2 signaling pathway.

Cartilage endplate (CEP) degeneration and calcification is an important contributor to the onset and pathogenesis of intervertebral disc degeneration (IDD). However, the underlying mechanisms of CEP degeneration remain elusive, let alone according treatment strategies to prevent CEP degeneration. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and recent studies indicated that PTEN is overexpressed in degenerated intervertebral disc. However, whether direct inhibition of PTEN attenuates CEP degeneration and IDD development remains largely unknown. In the present study, our in vivo experiments demonstrated that VO-OHpic could attenuate IDD progression and CEP calcification. We also found that VO-OHpic inhibited oxidative stress induced chondrocytes apoptosis and degeneration by activating Nrf-2/HO-1 pathway, thus promoted parkin mediated mitophagy process and inhibited chondrocytes ferroptosis, alleviated redox imbalance and eventually improved cell survival. Nrf-2 siRNA transfection significantly reversed the protective effect of VO-OHpic on endplate chondrocytes. In conclusion, our study demonstrated that inhibition of PTEN with VO-OHpic attenuates CEP calcification and IDD progression. Moreover, VO-OHpic protects endplate chondrocytes against apoptosis and degeneration via activating Nrf-2/HO-1 mediated mitophagy process and ferroptosis inhibition. Our results suggest that VO-OHpic may be a potential effective medicine for IDD prevention and treatment.

Constructing intervertebral disc degeneration animal model: A review of current models.

Low back pain is one of the top disorders that leads to disability and affects disability-adjusted life years (DALY) globally. Intervertebral disc degeneration (IDD) and subsequent discogenic pain composed major causes of low back pain. Recent studies have identified several important risk factors contributing to IDD's development, such as inflammation, mechanical imbalance, and aging. Based on these etiology findings, three categories of animal models for inducing IDD are developed: the damage-induced model, the mechanical model, and the spontaneous model. These models are essential measures in studying the natural history of IDD and finding the possible therapeutic target against IDD. In this review, we will discuss the technical details of these models, the duration between model establishment, the occurrence of observable degeneration, and the potential in different study ranges. In promoting future research for IDD, each animal model should examine its concordance with natural IDD pathogenesis in humans. We hope this review can enhance the understanding and proper use of multiple animal models, which may attract more attention to this disease and contribute to translation research.

Identification of mitochondria-related key gene and association with immune cells infiltration in intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration and its inflammatory microenvironment can result in discogenic pain, which has been shown to stem from the nucleus pulposus (NP). Increasing evidence suggests that mitochondrial related genes are strictly connected to cell functionality and, importantly, it can regulate cell immune activity in response to damaged associated signals. Therefore, identification of mitochondria related genes might offer new diagnostic markers and therapeutic targets for IVD degeneration. In this study, we identified key genes involved in NP tissue immune cell infiltration during IVD degeneration by bioinformatic analysis. The key modules were screened by weighted gene co-expression network analysis (WCGNA). Characteristic genes were identified by random forest analysis. Then gene set enrichment analysis (GSEA) was used to explore the signaling pathways associated with the signature genes. Subsequently, CIBERSORT was used to classify the infiltration of immune cells. Function of the hub gene was confirmed by PCR, Western blotting and ELISA. Finally, we identified MFN2 as a crucial molecule in the process of NP cell pyroptosis and NLRP3 inflammasome activation. We speculate that the increased MFN2 expression in NP tissue along with the infiltration of CD8+ T cells, NK cell and neutrophils play important roles in the pathogenesis of IVD degeneration.

ROS-responsive magnesium-containing microspheres for antioxidative treatment of intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a degenerative disease characterized by lower-back pain, causing disability globally. Antioxidant therapy is currently considered one of the most promising strategies for IVDD treatment, given the crucial role of reactive oxygen species (ROS) in IVDD pathogenesis. Herein, a ROS-responsive magnesium-containing microsphere (Mg@PLPE MS) was constructed for the antioxidative treatment of IVDD. The Mg@PLPE MS has a core-shell structure comprising poly(lactic-co-glycolic acid) (PLGA) and ROS-responsive polymer poly(PBT-co-EGDM) as the shell and a magnesium microparticle as the core. The poly(PBT-co-EGDM) can be destroyed by H2O2 through the H2O2-triggered hydrophobic-to-hydrophilic transition, subsequently promoting an Mg-water reaction to produce H2. Thus, Mg@PLPE MS provides a valuable platform for H2O2 elimination and controlled H2 release. The generated H2 scavenge for ROS by reacting with noxious •OH. Notably, the Mg@PLPE MS exerted significant antioxidative and anti-inflammatory effects in a disc degeneration rat model and alleviated extracellular matrix degradation and disc cells apoptosis, thereby underlining its efficacy in IVDD treatment. The Mg@PLPE MS also exhibited robust biocompatibility and negligible toxicity, presenting the promise for the antioxidative treatment of IVDD in vivo. STATEMENT OF SIGNIFICANCE: Antioxidant therapy is currently considered one of the most promising strategies for intervertebral disc degeneration (IVDD) treatment, given the crucial role of reactive oxygen species (ROS) in IVDD pathogenesis. Here, ROS-responsive magnesium-containing microspheres (Mg@PLPE MSs) were constructed to alleviate IVDD through controlled release of hydrogen gas. The Mg@PLPE MSs can effectively scavenge overproduced ROS by simultaneously reacting with H2O2 and •OH, thus creating a suitable microenvironment for inhibition of ECM degradation. As a result, Mg@PLPE MSs treated IVDD rats exhibit minimal nucleus pulposus decrease, less extracellular matrix degradation, minimal radial fissure of fibrous rings, and higher disc height index. Therefore, the as-prepared Mg@PLPE MSs may shed a new light on clinical treatment of IVDD.

Modifications of miRNAs in intervertebral disc degeneration: a key to the future development of genetic-based therapies.

Intervertebral disc degeneration (IDD) is the main cause of low back pain, which is a healthcare concern associated with high social and economic burden. The current medical and surgical therapies are inadequate and ineffective. Several miRNAs have been identified that modulate (via up- or down-regulation) the pathogenesis of IDD through various signaling pathways. Understanding the nature of this regulation and their signaling pathways will enable researchers to manipulate miRNA regulation to develop miRNA-based therapies. The development of miRNA-based therapies opens a future window through which to decrease the IDD process or regenerate the intervertebral disc. In the near future, the obstacles associated with miRNA-based therapies will be overcome and these therapies will move from the bench to the bedside.

Docosahexaenoic acid alleviates the excessive degradation of extracellular matrix in the nucleus pulposus by reducing the content of lncRNA NEAT1 to prevent the progression of intervertebral disc degeneration.

The pathogenesis of intervertebral disc degeneration (IVDD), as a multifactorial disease, has not been fully elucidated. However, damage to the stress-bearing system in the intervertebral disc (IVD) mediated by the excessive decomposition of extracellular matrix (ECM) in nucleus pulposus (NP) cells caused by local stimulation is widely considered the core pathological process underlying IVDD. Docosahexaenoic acid (DHA) plays a protective role in various chronic diseases. However, whether it can have such effects in IVDD has not been clearly reported. In recent years, in-depth research on the role of long non-coding RNA (lncRNA) nuclear-enriched transcript 1 (NEAT1) in various diseases has continuously emerged, but such research in the field of IVD is not sufficient. In this study, tert-butyl hydroperoxide (TBHP) was used to induce oxidative stress in human NP cells and construct a cell model of excessive ECM decomposition in vitro. A plasmid over-expressing lncRNA NEAT1 was introduced into human NP cells to establish an NP cell model. For this specific experiment, Cell Counting Kit 8 was used to explore the timing and concentration of DHA and TBHP activity. A common gene chip platform was also used to select potential lncRNAs. Western blot and immunofluorescence assays were used to detect the expression of ECM-related proteins in NP cells in each group. Quantitative real-time polymerase chain reaction was used to detect the expression of lncRNA NEAT1 in NP cells in each group. On this basis, we proved that DHA alleviates excessive degradation of the ECM in NP cells in response to oxidative stress by reducing the content of lncRNA NEAT1. In conclusion, our study reveals the mechanism through which DHA relieves excessive ECM decomposition in NP cells and provides a potential new idea for the treatment of IVDD in clinical practice.

Identifification and validation of ferroptosis signatures and immune infifiltration characteristics associated with intervertebral disc degeneration.

Ferroptosis and immune infiltration play an important role in the pathogenesis of intervertebral disc degeneration (IDD). However, there is still a lack of comprehensive analysis on the interaction between ferroptosis-related genes (FRGs) and immune microenvironment in IDD patients. Therefore, this study aims to explore the correlation between FRGs characteristics and immune infiltration in the progression of IDD. The expression profiles (GSE56081 and GSE70362) and FRGs were downloaded from the comprehensive gene expression omnibus (GEO) and FerrDb database, respectively, and the differences were analyzed using R. The intersection of IDD related differential genes (DEGs) and FRGs was taken as differentially expressed FRGs (DE-FRGs) and GO and KEGG enrichment analysis was conducted. Then, we used least absolute shrinkage and selection operator (LASSO) regression algorithm and support vector machine (SVM) algorithm to screen feature genes and draw ROC curve judge the diagnostic value of key DE-FRGs. Then CIBERSORT algorithm is used to evaluate the infiltration of immune cells and analyze the correlation between key DE-FRGs and immune infiltration. Based on the analysis results, we conducted single gene GSEA analysis on key DE-FRGs. RT-PCR and immunohistochemistry further verified the clinical value of the results of biochemical analysis and screening. Seven key DE-FRGs were screened, including the upregulated genes NOX4 and PIR, and the downregulated genes TIMM9, ATF3, ENPP2, FADS2 and TFAP2A. Single gene GSEA analysis further elucidates the role of DE-FRGs in IDD associated with ferroptosis. Correlation analysis showed that seven key DE-FRGs were closely related to immune infiltration in the development of IDD. Finally, RT-PCR and immunohistochemical staining showed that NOX4, ENPP2, FADS2 and TFAP2A were statistically significant differences. In this study, we explored the connection between ferroptosis related characteristics and immune infiltration in IDD, and confirmed that NOX4, ENPP2, FADS2, and TFAP2A may become biomarkers and potential therapeutic targets for IDD.

Glucose-stimulated PGC-1α couples with CBP and Runx2 to mediate intervertebral disc degeneration through transactivation of ADAMTS4/5 in diet-induced obesity mice.

Emerging evidence suggests that type 2 diabetes mellitus (T2DM) is associated with the pathogenesis of intervertebral disc degeneration (IDD). However, it is still unclear how T2DM contributes to IDD. Herein, we observed the accumulation of blood glucose and degenerative lumbar discs in mice fed a high-fat diet. Detection of differentially expressed genes in degenerative lumbar discs revealed that ADAMTS4 (A Disintegrin and Metalloproteinase with Thrombospondin motifs) and ADAMTS5 genes were significantly increased. In vitro analyses demonstrated that Runt-Related Transcription Factor 2 (Runx2) recruited both PPARgamma Coactivator 1alpha (PGC-1α) and CREB-Binding Protein (CBP) to transactivate the expression of ADAMTS4/5. Glucose stimulation could dose-dependently induce the accumulation of PGC-1α and promoted the binding of the CBP-PGC-1α-Runx2 complex to the promoters of ADAMTS4/5. Depletion of CBP-PGC-1α-Runx2 complex members and treatment with either PGC-1α inhibitor SR-18292 or CBP inhibitor EML425 in vitro could dramatically inhibit the glucose-induced expression of ADAMTS4/5. Administration of SR-18292 and EML425 in diabetic mice could prevent the degeneration of lumbar discs. Collectively, our results revealed a molecular mechanism by which the hyperglycemia-dependent CBP-PGC-1α-Runx2 complex was required for the transactivation of ADAMTS4/5. The blockage of this complex in diabetic mice may help prevent IDD.

The CRL4DCAF6 E3 ligase ubiquitinates CtBP1/2 to induce apoptotic signalling and promote intervertebral disc degeneration.

Inflammation and apoptosis are two important pathological causes of intervertebral disc degeneration (IDD). The crosstalk between these two biological processes during IDD pathogenesis remains elusive. Herein, we discovered that chronic inflammation induced apoptosis through a cullin-RING E3 ligase (CRL)-dependent mechanism. Two cullin proteins, CUL4A and 4B, recruited DNA damage-binding protein 1 (DDB1), RING-box protein 1 (RBX1) and DDB1- and CUL4-associated factor 6 (DCAF6) to assemble a CRL4DCAF6 E3 ligase in intervertebral discs (IVDs) derived from IDD patients. The CRL4DCAF6 E3 ligase ubiquitinated and degraded C-terminal-binding protein 1 and 2 (CtBP1/2), two homologues of transcriptional corepressors. The degradation of CtBP1/2 disassociated from the p300-forkhead box O3a (FOXO3a) complex, inducing the expression of B-cell lymphoma 2 (Bcl2)-binding component 3 (BBC3) and causing BBC3-dependent apoptosis. TSC01131, a small molecule that specifically targets CUL4-DDB1 interaction, could inhibit the ubiquitination of CtBP1/2 in vitro and in vivo, thereby decreasing the BBC3 expression level and preventing apoptosis signalling. Using a mouse chronic inflammation model, we found that chronic inflammation could accelerate the IDD process through a conserved CRL4DCAF6-mediated mechanism. The administration of TSC01131 to mice could significantly improve the outcome of IDD. Collectively, our results revealed that inflammation-dependent CRL4DCAF6 E3 ligase triggered apoptosis through the removal of CtBP-mediated transrepression. The blockage of the CRL4DCAF6 E3 ligase by TSC01131 may represent a new therapeutic strategy for IDD treatment. KEY MESSAGES: CUL4A and CUL4B recruited DDB1, RBX1 and DCAF6 to assemble a CRL4DCAF6 E3 ligase in human IDD biopsies. The CRL4DCAF6 E3 ligase ubiquitinated and degraded CtBP1/2, causing BBC3-dependent apoptosis. A small molecule TSC01131 that specifically targets CUL4-DDB1 interaction could inhibit the ubiquitination of CtBP1/2, improving the outcome of IDD in a mouse model.

Constitutive and conditional gene knockout mice for the study of intervertebral disc degeneration: Current status, decision considerations, and future possibilities.

There have been an increasing number of patients with degenerative disc diseases due to the aging population. In light of this, studies on the pathogenesis of intervertebral disc degeneration have become a hot topic, and gene knockout mice have become a valuable tool in this field of research. With the development of science and technology, constitutive gene knockout mice can be constructed using homologous recombination, zinc finger nuclease, transcription activator-like effector nuclease technology and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) system, and conditional gene knockout mice can be constructed using the Cre/LoxP system. The gene-edited mice using these techniques have been widely used in the studies on disc degeneration. This paper reviews the development process and principles of these technologies, functions of the edited genes in disc degeneration, advantages, and disadvantages of different methods and possible targets of the specific Cre recombinase in intervertebral discs. Recommendations for the choice of suitable gene-edited model mice are presented. At the same time, possible technological improvements in the future are also discussed.

A microarray data analysis investigating the pathogenesis and potential biomarkers of autophagy and ferroptosis in intervertebral disc degeneration.

Background: Intervertebral disc degeneration (IDD) entails complex pathological changes and causes lower back pain (LBP). However, there is still a lack of understanding of the mechanisms involved in IDD, particularly regarding the roles of autophagy and ferroptosis. The current study used microarray data to investigate the pathogenesis of IDD and potential biomarkers related to autophagy and ferroptosis in IDD. Methods: Differentially expressed genes (DEGs) were identified by analyzing the mRNA and miRNA expression profiles of IDD patients from the Gene Expression Omnibus (GEO). The protein-protein interaction network, Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were utilized. The Human Autophagy Database (HADb) and Ferroptosis Database were used in conjunction with hub genes to identify autophagy- and ferroptosis-related genes. The Transcription Factor -hub gene-miRNA network was constructed. Lastly, the expression of DEGs in normal and degenerated nucleus pulposus cells (NPCs) was investigated via the quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: A total of 362 DEGs associated with IDD were identified. GO and KEGG analyses indicated that oxidative stress, extracellular matrix, PI3K-AKT signaling pathway, and ferroptosis were key factors in IDD occurrence. GSEA indicated that IDD was associated with changes in autophagy, iron ion homeostasis, extracellular matrix, and oxidative stress. Eighty-nine hub genes were obtained, including five that were autophagy-related and three that were ferroptosis-related. Of these, TP53 and SESN2 were the intersections of autophagy- and ferroptosis-related genes. In qRT-PCR analysis, CANX, SLC38A1, and TP53 were downregulated in degenerative NPCs, whereas GNAI3, SESN2, and VAMP3 were upregulated. Conclusion: The current study revealed aspects of autophagy- and ferroptosis-related genes involved in IDD pathogenesis, warranting further investigation.

Mechanobiology of MicroRNAs in Intervertebral Disk Degeneration.

Intervertebral disk degeneration (IDD) is an intricate pathological process contributing to one of the major causes of low back pain. The degradation of the extracellular matrix (ECM), inflammation, and apoptosis have all been investigated as critical factors involved in the pathology of degenerative disk disease. Additionally, the presence of aberrant microRNAs (miRNAs), conserved molecules that regulate the amount protein post-transcriptionally, may play a crucial role in the pathogenesis of IDD. Research regarding the dysfunction of miRNAs in IDD has been well researched over the past five years. Here, we provide a critical overview of the current knowledge of miRNAs, emphasizing the processes involved in the degenerative disk pathology.

Role of the mechanosensitive piezo1 channel in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a multifactorial skeletal disease involving mechanical, genetic, systemic, and biological factors, and it is characterized by apoptosis of the nucleus pulposus cells and breakdown of the extracellular matrix (ECM), which will impair the structure and function of the intervertebral disc (IVD), and cause low back pain. Recently, the piezo1 is recognized as a critical mechanically activated ion channel of IDD. Numerous studies have reported that the piezo1 ion channel was aberrantly activated in the degenerated disc tissues and deeply participated in the pathogenesis of IDD. Inactivating or interfering with the piezo1 channel could effectively prevent the progression of IDD under the experimental conditions. It may be a promising target for the prevention and treatment of the disabling disease. Therefore, we have to make a comprehensive investigation and understanding of the mechanisms and functions of the piezo1 in the biomechanics of the spine. This study mainly elucidates the role of the piezo1 channel in IDD, which may facilitate the development of therapeutic targets for this disease.

Correlation between Adrenoceptor Expression and Clinical Parameters in Degenerated Lumbar Intervertebral Discs

Despite advanced knowledge of the cellular and biomechanical processes of intervertebral disc degeneration (IVDD), the trigger and underlying mechanisms remain unclear. Since the sympathetic nervous system (SNS) has been shown to exhibit catabolic effects in osteoarthritis pathogenesis, it is attractive to speculate that it also influences IVDD. Therefore, we explored the adrenoceptor (AR) expression profile in human IVDs and correlated it with clinical parameters of patients. IVD samples were collected from n = 43 patients undergoing lumbar spinal fusion surgery. AR gene expression was analyzed by semi-quantitative polymerase chain reaction. Clinical parameters as well as radiological Pfirrmann and Modic classification were collected and correlated with AR expression levels. In total human IVD homogenates α1A-, α1B-, α2A-, α2B-, α2C-, β1- and β2-AR genes were expressed. Expression of α1A- (r = 0.439), α2A- (r = 0.346) and β2-AR (r = 0.409) showed a positive and significant correlation with Pfirrmann grade. α1A-AR expression was significantly decreased in IVD tissue of patients with adjacent segment disease (p = 0.041). The results of this study indicate that a relationship between IVDD and AR expression exists. Thus, the SNS and its neurotransmitters might play a role in IVDD pathogenesis. The knowledge of differential AR expression in different etiologies could contribute to the development of new therapeutic approaches for IVDD.

Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications.

Intervertebral disc degeneration (IDD), a progressive and multifactorial pathological process, is predominantly associated with low back pain and permanent disability. Pyroptosis is a type of lytic programmed cell death triggered by the activation of inflammasomes and caspases. Unlike apoptosis, pyroptosis is characterized by the rupture of the plasma membrane and the release of inflammatory mediators, accelerating the destruction of the extracellular matrix (ECM). Recent studies have shown that pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in nucleus pulposus (NP) cells is activated in the progression of IDD. Furthermore, targeting pyroptosis in IDD demonstrates the excellent capacity of ECM remodeling and its anti-inflammatory properties, suggesting that pyroptosis is involved in the IDD process. In this review, we briefly summarize the molecular mechanism of pyroptosis and the pathogenesis of IDD. We also focus on the role of pyroptosis in the pathological progress of IDD and its targeted therapeutic application.

The new ceRNA crosstalk between mRNAs and miRNAs in intervertebral disc degeneration.

Degeneration of the intervertebral disc has been linked to lower back pain. To date, pathophysiological mechanisms of intervertebral disc degeneration (IDD) remain unclear; it is meaningful to find effective diagnostic biomarkers and new therapeutic strategies for IDD. This study aimed to reveal the molecular mechanism of IDD pathogenesis from the multidimensional transcriptomics perspective. Here, we acquired IDD bulk omics datasets (GSE67567 and GSE167199) including mRNA, microRNA expression profiles, and single-cell RNA sequencing (GSE199866) from the public Gene Expression Omnibus (GEO) database. Through principal component analysis and Venn analysis, we found different expression patterns in the IDD transcription level and identified 156 common DEGs in both bulk datasets. GO and KEGG functional analyses showed these dysregulators were mostly enriched in the collagen-containing extracellular matrix, cartilage development, chondrocyte differentiation, and immune response pathways. We also constructed a potentially dysregulated competing endogenous RNA (ceRNA) network between mRNAs and miRNAs related to IDD based on microRNA target information and co-expression analysis of RNA profiles and identified 36 ceRNA axes including ZFP36/miR-155-5p/FOS, BTG2/hsa-miR-185-5p/SOCS3, and COL9A2/hsa-miR-664a-5p/IBA57. Finally, in integrating bulk and single-cell transcriptome data analyses, a total of three marker genes, COL2A1, PAX1, and ZFP36L2, were identified. In conclusion, the key genes and the new ceRNA crosstalk we identified in intervertebral disc degeneration may provide new targets for the treatment of IDD.