Chronic low back pain associated with intervertebral disc degeneration (IVDD) is significantly aggravated in patients with diabetes mellitus (DM); however, the underlying molecular mechanisms remain unclear. This study explored the role of the long non-coding RNA AGEAT (AGE-associated transcript) in the pathogenesis of DM-associated IVDD. Whole-transcriptome sequencing of rat nucleus pulposus cells (NPCs) treated with advanced glycation end products (AGEs) revealed a time-dependent upregulation of AGEAT. AGEAT overexpression induced NPC apoptosis, mitochondrial dysfunction, and extracellular matrix (ECM) degradation. Mechanistically, RNA fluorescence in situ hybridization localized AGEAT to the cytoplasm, where it acted as a competing endogenous RNA (ceRNA) by directly binding miR-204-5p, thereby relieving repression of its target Mapk4. Silencing AGEAT via siRNA significantly reduced apoptosis, restored mitochondrial function, and preserved ECM integrity. In vivo, intra-discal injection of AAV-sh-AGEAT in diabetic IVDD rats significantly improved disc integrity, as evidenced by a reduction in MRI Pfirrmann grade and histological preservation of NPC density and collagen II content. Collectively, these findings establish AGEAT as a key ceRNA that exacerbates diabetic IVDD via the miR-204-5p/Mapk4 axis, promoting NPC apoptosis, mitochondrial dysfunction, and ECM degradation. Targeting this pathway-through AGEAT silencing or miR-204-5p activation-represents a promising therapeutic strategy for mitigating diabetes-associated disc degeneration. This study reveals the critical role of the AGEAT/miR-204-5p/Mapk4 axis in the progression of DM-associated IVDD, suggesting a potential therapeutic strategy for its treatment.

Intervertebral disc degeneration (IDD) is the leading cause of low back pain, which places heavy burdens on society and individuals. Surgical intervention is the conventional therapy for IDD, but patients who undergo surgery face relatively high risks of recurrence and complications. Therefore, a relatively less invasive and efficient treatment for IDD is urgently needed. In this study, we constructed a novel nanobiomaterial, named Hi-Exos, to slow IDD. Hi-Exos are exosomes derived from mesenchymal stem cells exposed to hypoxic and inflammatory environments. Hi-Exos could relieve the senescence of nucleus pulposus cells and slow IDD through an epigenetic modification mechanism by introducing the epigenetic factor miR-221-3p into senescent nucleus pulposus cells to reduce DDIT4 expression and inhibit the activation of NF-κB signalling pathway. This study provided a novel strategy for IDD treatment involving the use of Hi-Exos to deliver miR-221-3p to reduce the senescence of nucleus pulposus cells and repair IDD via epigenetic modifications.

Intervertebral disc degeneration (IDD) is the main pathological factor resulting in low back pain (LBP), the leading cause of disability globally. Inflammatory response and extracellular matrix (ECM) degradation are critical pathological features in the development of IDD. Gastrodin (GAS), a phenol compound isolated from Gastrodia elata Blume, plays an anti-inflammatory role in experimental models of multiple human diseases. Our study aimed to elucidate whether GAS alleviates TNF-α-induced inflammation in nucleus pulposus (NP) cells and IDD in vivo. The cytotoxicity of GAS was assessed by CCK-8 assay. Rat primary NP cells were stimulated with TNF-α to induce inflammatory response. The expression of proinflammatory cytokines, catabolic genes, and anabolic genes was detected by RT-qPCR, western blotting, and immunofluorescence staining. NF-κB and MAPK pathway activation was determined through western blotting and immunofluorescence staining. The IDD rat model was established by using percutaneous needle puncture. The therapeutic effects of GAS were confirmed by histology analysis. We found that TNF-α stimulation enhanced proinflammatory cytokine (COX2, iNOS, IL-6, and IL-1β) expression in NP cells, which was reversed by GAS treatment. GAS offset TNF-α-induced upregulation in catabolic gene (MMP3, MMP9, and MMP13) expression and downregulation in anabolic gene (Collagen II, SOX9, and Aggrecan) expression. The loss of ECM in TNF-α-treated NP cells was mitigated by GAS treatment. Mechanically, GAS abolished TNF-α-induced increase in p-IKKα, p-IKKβ, p-IκBα, p-p65, p-ERK, p-p38, and p-JNK protein levels in NP cells. In puncture-induced IDD rat models, GAS administration improved intervertebral disc (IVD) structure, increased Collagen II expression, and reduced the levels of proinflammatory factors in IVDs. Overall, GAS alleviates the inflammation and ECM degradation in NP cells via inhibiting NF-κB and MAPK pathway activation and alleviates IDD in vivo, which may be a novel treatment strategy for IDD.

Intervertebral disc degeneration (IDD) is a primary cause of degenerative disc disease; however, the mechanisms underlying it remain unknown. Although great efforts have been made to develop new regenerative therapies, their clinical success is limited. Recent research has indicated that microRNAs (miRNAs) are significantly involved in the progression of IDD. Investigating the role of miRNA intervention in IDD could facilitate the development of therapeutic strategies based on miRNAs. However, circulating miRNAs have not yet been recognized as standard biomarkers for IDD. In this study, we observed that the expression of miR-27b-3p was elevated in the blood and nucleus pulposus (NP) tissue of patients with IDD. Furthermore, reducing the expression of miR-27b-3p was shown to impede the progression of IDD. MiR-27b-3p could reduce the expression of collagen II and ACAN and promote the expression of MMP13 and ADAMT-5 in vitro and in vivo. miR-27b-3p aggravated IDD progression by directly targeting peroxisome proliferator-activated receptor gamma (PPARG), a negative regulator of the NF-κB signal pathway. This study also established that PPARG serves a protective role in IDD. The overexpression of PPARG was able to mitigate the detrimental effects caused by miR-27b-3p in NP cells and animal models of IDD, indicating that miR-27b-3p facilitates the progression of IDD through its interaction with PPARG. Additionally, the transcription factor ATF1 was found to enhance the expression of miR-27b-3p by targeting its promoter region, thereby promoting the degenerative impact of miR-27b-3p on NP cells. Given that miR-27b-3p can promote IDD both in vitro and in vivo, it holds potential as a biomarker, and the inhibition of miR-27b-3p expression may represent a novel therapeutic target for IDD.

The purpose of this study was to explore the genetic characteristics and immune cell infiltration related to intervertebral disc degeneration through multidataset analysis, predict potential therapeutic drugs, and provide a theoretical basis for clinical treatment. The gene expression profile data of the GSE70362, GSE186542, and GSE245147 datasets were downloaded from the Gene Expression Omnibus (GEO) database, and the hub genes were identified through differentially expressed gene analysis, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) functional annotation and Mendelian randomization analysis were performed. Hub genes and immune cells were identified. Infiltration status was determined through GSEA and GSVA to clarify the specific signalling pathways associated with key genes and explore the potential molecular mechanisms by which key genes affect disease progression. The key genes were reversely predicted using miRNA grid construction and transcription factor regulation, and genes related to disease regulation were obtained from the GeneCards database. Finally, the differentially expressed genes were used for drug prediction through the Connectivity Map database to identify potential drugs for the treatment of intervertebral disc degeneration. The feasibility of the predicted drugs was tested by molecular docking technology. Real-time quantitative PCR was used to confirm the expression of key genes in the tissue samples.A total of 126 differentially expressed genes were identified in the GEO database, and 4 differentially expressed hub genes (COL6A2, DCXR, GLRX, and PDGFRB) were identified through bioinformatics methods. Immune infiltration analysis revealed that NK cells, macrophages, and eosinophils were activated during IVDD, whereas mast cells and T cells were suppressed. GO and KEGG analyses revealed that key genes are involved in the development of this disease through signalling pathways such as the glycolysis pathway, the oxidative phosphorylation pathway, the cholesterol regulatory pathway, and the haem metabolism pathway. Analysis of the constructed miRNA grid revealed that key genes are jointly regulated by multiple transcription factors, among which the most important motif is cisbp_M5578. Disease regulation-related genes were obtained through the GeneCards database, analysis of the correlation with key genes was performed, and the expression levels of the two mRNA and miRNA were significantly correlated. Finally, drug prediction performed through the Connectivity Map database revealed that drugs such as Abt-751, LY-2183240, podophyllotoxin, and vindesine can alleviate or even reverse the disease state. Finally, we collected 10 IVDD and 10 healthy disc tissue samples, and the RT‒qPCR results were consistent with the bioinformatics results. We identified COL6A2, DCXR, GLRX, and PDGFRB as key genes involved in IVDD. In addition, drugs such as Abt-751 are expected to control and reverse the progression of the disease. In the future, these key genes and predicted drugs may provide new directions for further mechanistic studies as well as new therapies for IVDD patients.

Intervertebral disc degeneration (IVDD) is a primary contributor to low back pain, posing significant social and economic burdens. Increasing evidence shows that obesity contributes to IVDD, yet the underlying mechanisms remain elusive. Here, we firstly revealed a causal correlation between obesity and IVDD via a two-sample mendelian randomization analysis and identified fatty acid-binding protein 4 (FABP4) as the potential regulator to associate IVDD and obesity. Elevated FABP4 expression promoted extracellular matrix (ECM) disequilibrium and angiogenesis to exacerbate IVDD progression. Genetically knocking out or pharmacologically inhibiting FABP4 in high-fat diet-induced mice alleviated IVDD. Mechanistically, obesity activated the mammalian target of rapamycin complex 1 (mTORC1), which upregulated FABP4 expression, leading to the accumulation of advanced glycation end-products (AGEs) in intervertebral disc tissue. AGEs further activated the NF-κB signalling pathway, exacerbating ECM degradation and neovascularization. Conversely, rapamycin-mediated inhibition of mTORC1 suppressed FABP4 expression in nucleus pulposus cells (NPCs), alleviating IVDD in vivo. Collectively, our findings reveal a critical role of the obesity-induced mTORC1-FABP4 axis in ECM degradation and angiogenesis during IVDD progression. Targeting FABP4 may represent a promising therapeutic strategy for IVDD in obese individuals.

Intervertebral disc degeneration (IDD) is a degenerative spinal condition characterized by disc structural damage, narrowing of joint spaces, and nerve root compression, significantly reducing patients' quality of life. To address this challenge, a novel therapeutic strategy was developed using cellulose supramolecular hydrogel as a carrier to deliver IL4I1-modified MΦ membrane biomimetic nanoparticles (CHG@IL4I1-MNPs) to target tissues. This hydrogel exhibits excellent biocompatibility and mechanical properties while enabling sustained drug release in the degenerative disc microenvironment, enhancing therapeutic outcomes. CHG@IL4I1-MNPs effectively regulate MΦ polarization by promoting M2 MΦ activation, thereby improving immune microenvironment balance. Animal studies demonstrated that CHG@IL4I1-MNPs alleviated symptoms of IDD, reduced inflammation, and supported tissue repair, highlighting its potential to reduce reliance on long-term medication and improve quality of life. The strategy uniquely combines nanoparticle technology with immunomodulation, achieving precise targeting of MΦs. Beyond IDD, this approach offers potential applications in other immune-related diseases, providing a versatile platform for nanomedicine. This study introduces an innovative method to treat IDD and advances the integration of immunotherapy and nanotechnology, offering both clinical benefits and new directions for future research. These findings hold strong potential for improving patient outcomes and expanding treatment options for related diseases.

Intervertebral disc degeneration (IDD) is one of the most common diseases in the elderly population. Recently, immune disorders have been considered to play an important role in IDD. This study aimed to conduct a bioinformatic analysis to identify biomarkers associated with IDD immune cells.

We obtained the gene expression profiles of IDD by downloading the Gene Expression Omnibus Series (GSE)150408 and GSE124272 from the Gene Expression Omnibus (GEO) database. IDD and immune cell-related hub genes were identified via multiple bioinformatics analyses, and their diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. In addition, a long non-coding RNA (lncRNA)-signature gene co-expression network was constructed. Finally, the diagnostic accuracy of the biomarkers was verified using Real-time quantitative PCR (RT-qPCR).

ASAP1-IT1, IKZF2, KLHL14, lnc-C10orf131-1, and LOC101927805 were identified as signature genes of IDD. Further, ROC analysis revealed that the five signature gene models had a strong ability to discriminate between the IDD and healthy control samples. We also found that the five signature genes were significantly associated with immune-inflammatory feedback, cell cycle, and skeletal system. Furthermore, an lncRNA signature gene network was constructed to reveal the regulatory mechanisms of the biomarkers. Finally, RT-qPCR results verified that IKZF2 and KLHL14 were significantly downregulated in patients with IDD, and ASAP1-IT1 was significantly upregulated.

This study identified ASAP1-IT1, IKZF2, and KLHL14 as the key signature genes of IDD. These key hub genes may serve as potential therapeutic targets for IDD.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, and repair using nucleus pulposus-derived mesenchymal stem cells (NP-MSCs) represents a promising therapeutic approach. However, both endogenous and transplanted NP-MSCs demonstrate limited proliferative capacity, increased apoptosis, and reduced resilience to the harsh microenvironment within the degenerative intervertebral disc (IVD).

RNA sequencing (RNA-seq) was utilized to identify genes and associated mechanisms that mediate the responses of NP-MSCs to acidic conditions. Western blotting, qPCR, and immunofluorescence were used to evaluate follistatin-like 1 (FSTL1) expression in NP-MSCs. Apoptosis and extracellular matrix (ECM) anabolism were assessed via flow cytometry, TUNEL staining and Western blotting, while the TGF-β/Smad2/3 pathway was analyzed using Western blotting and immunofluorescence. FSTL1 knockdown with small interfering RNA (siRNA) was performed to determine its role in apoptosis and ECM regulation. The FSTL1 siRNA pretreatment was assessed in a puncture-induced rat IVDD model using MRI and histological staining.

Using RNA-seq, we identified FSTL1 as the primary acid-responsive gene in NP-MSCs. We further observed elevated FSTL1 expression in NP-MSCs isolated from degenerative IVDs in both humans and rats compared to normal IVDs. Acidic conditions upregulated FSTL1 expression in NP-MSCs in a pH-dependent manner. Notably, recombinant FSTL1 was shown to enhance cellular apoptosis and disrupt ECM metabolism. Conversely, silencing FSTL1 with siRNA reduced NP-MSC apoptosis and improved ECM anabolism. Importantly, TGF-β pathway inhibition partially reversed the pro-apoptotic and ECM catabolism effects of FSTL1. In the rat model of IVDD, pretreatment of NP-MSCs with FSTL1 siRNA significantly suppressed IVDD progression.

This study provides novel insights into the mechanistic role of FSTL1 in acid-induced apoptosis of NP-MSCs and its contribution to the progression of IVDD. These findings offer valuable perspectives for developing targeted therapeutic strategies to mitigate IVDD progression.

Intervertebral disc degeneration (IDD) is a significant contributor to low back pain, imposing a considerable socioeconomic burden. Ferroptosis, a novel form of cell death driven by iron and characterized by the accumulation of reactive oxygen species (ROS), has been associated with the progression of IDD. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) has been widely recognized as a pivotal factor promoting ferroptosis across various diseases; however, its precise role in the pathogenesis of IDD remains incompletely understood. Our experimental findings demonstrated a marked upregulation of NOX4 in degenerated cells, accompanied by elevated ROS levels and a diminished mitochondrial membrane potential, indicating the participation of ferroptosis. Furthermore, the expression of the critical regulatory factor GPX4 was reduced, while ACSL4 levels were significantly increased, further corroborating the involvement of ferroptosis. Functional loss and gain experiments revealed that NOX4 overexpression augmented ferroptosis and ROS production while promoting the secretion of inflammatory cytokines. Subsequent studies indicated that the knockdown of NOX4 could reverse tert-butyl hydroperoxide (TBHP)-induced ferroptosis. Mass spectrometry analysis identified leucine-rich repeat-containing 8A (LRRC8A) as an interacting protein of NOX4, and further validation confirmed that they co-regulate Nod-like receptor pyrin domain-3 (NLRP3) activation through their interaction. Utilizing a rat model of intervertebral disc degeneration, we further corroborated the role of NOX4 in IDD. This study provides theoretical support for the potential application of NOX4-targeting drugs in the treatment of IDD.

Defects in chaperone-mediated autophagy (CMA) are associated with cellular senescence, but the mechanism remains poorly understood. Here, we found that CMA inhibition induced cellular senescence in a calcium-dependent manner and identified its role in TNF-induced senescence of nucleus pulposus cells (NPC) and intervertebral disc degeneration. Based on structural and functional proteomic screens, PLCG1 (phospholipase C gamma 1) was predicted as a potential substrate for CMA deficiency to affect calcium homeostasis. We further confirmed that PLCG1 was a key mediator of CMA in the regulation of intracellular calcium flux. Aberrant accumulation of PLCG1 caused by CMA blockage resulted in calcium overload, thereby inducing NPC senescence. Immunoassays on human specimens showed that reduced LAMP2A, the rate-limiting protein of CMA, or increased PLCG1 was associated with disc senescence, and the TNF-induced disc degeneration in rats was inhibited by overexpression of Lamp2a or knockdown of Plcg1. Because CMA dysregulation, calcium overload, and cellular senescence are common features of disc degeneration and other age-related degenerative diseases, the discovery of actionable molecular targets that can link these perturbations may have therapeutic value.Abbreviation: ATRA: all-trans-retinoic acid; BrdU: bromodeoxyuridine; CDKN1A/p21: cyclin dependent kinase inhibitor 1A; CDKN2A/p16-INK4A: cyclin dependent kinase inhibitor 2A; CMA: chaperone-mediated autophagy; DHI: disc height index; ER: endoplasmic reticulum; IP: immunoprecipitation; IP3: inositol 1,4,5-trisphosphate; ITPR/IP3R: inositol 1,4,5-trisphosphate receptor; IVD: intervertebral disc; IVDD: intervertebral disc degeneration; KD: knockdown; KO: knockout; Leu: leupeptin; MRI: magnetic resonance imaging; MS: mass spectrometry; N/L: NH4Cl and leupeptin; NP: nucleus pulposus; NPC: nucleus pulposus cells; PI: protease inhibitors; PLC: phospholipase C; PLCG1: phospholipase C gamma 1; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription PCR; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SASP: senescence-associated secretory phenotype; STV: starvation; TMT: tandem mass tag; TNF: tumor necrosis factor; TP53: tumor protein p53; UPS: ubiquitin-proteasome system.

Intervertebral disc degeneration (IVDD) stands as a primary pathophysiological driver of low back pain, yet no therapeutic intervention effectively arrests its progression. Evidence shows that certain Sirt1 agonists may confer protective effects on intervertebral discs, but the underlying mechanisms remain unclear. This study aims to delineate the interaction between Sirt1 and the inflammatory microenvironment, offering potential novel avenues for IVDD prevention and treatment.

In vitro IL-1β-induced nucleus pulposus cells (NPCs) degenerative model and in vivo a mouse annulus fibrosus needle puncture model in Sirt1 transgenic (Sirt1TG) and the same litter WT mice were used to investigate the role of Sirt1 in homeostasis and inflammation. Mechanistic insights were obtained through RNA sequencing, co-immunoprecipitation (Co-IP), luciferase assays, and chromatin immunoprecipitation-(ChIP)-PCR. A co-culture system of Raw264.7 and NPCs was employed to assess the involvement of Lipocalin 2.

Our study demonstrated reduced Sirt1 expression in degenerating human nucleus pulposus (NP) tissue. Both in vitro and in vivo data revealed that NP-specific overexpression of Sirt1 inhibited extracellular matrix degradation and inflammation. Mechanistically, Sirt1 suppressed the acetylation of RelA/p65 at lysine 310 and phosphorylation at serine 536, with the C-terminus of Sirt1 and the RHD-NLS domain of RelA mediating to their interaction. Furthermore, NPCs-derived Lipocalin 2 was identified as a cytokine involved in macrophage chemotaxis and M1 polarization to exacerbate inflammation.

Our work revealed that Sirt1 negatively regulates Lipocalin 2, thereby ameliorating the inflammatory milieu and blocking NPCs and macrophages crosstalk.

This study illuminates the crucial role and molecular mechanisms of Sirt1 in regulating the NP microenvironment. These insights shed light on strategies for the prevention and treatment of IVDD-related herniation and low back pain. By pinpointing specific biological targets, the screening of smallmolecule compounds with significant clinical implications can be facilitated. This translational innovation promises to optimize cells communication within intervertebral disc microenvironment via localized drug delivery, potentially improving patient outcomes and satisfaction following spinal fusion or discectomy surgeries.

Intervertebral discs (IVDs) are rhythmic tissues that experience daily low-load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia-induced disordered metabolism. Meanwhile, Rev-erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev-erbα expression levels and IVD degeneration. Rev-erbα deficiency accelerated needle puncture or aging-induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev-erbα knockdown in NP cells aggravated rhIL1β-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev-erbα deficiency and needle puncture-induced IVD degeneration. Particularly, Rev-erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme-binding of nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev-erbα in NP cells following short-term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev-erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev-erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases.

Low back pain (LBP) is predominantly caused by degeneration of the intervertebral disc (IVD) and central nucleus pulposus (NP) region. Conservative treatments fail to restore disc function, motivating the exploration of nucleic acid therapies, such as the use of microRNAs (miRNAs). miRNAs have the potential to modulate expression of discogenic factors, while silencing the catabolic cascade associated with degeneration. To deliver these miRNAs, nonviral cell penetrating peptides (CPPs) are gaining favor given their low immunogenicity and strong targeting ability. Single miRNA therapies have been investigated for IVD repair, however dual miRNA delivery strategies have not been commonly examined and may augment regeneration.

Transfection of four pro-discogenic miRNAs (miRNA mimics:140-5p; 149-5p and inhibitors: 141-3p; 221-3p) and dual delivery of six miRNA pairings was performed using two CPPs, RALA and GET peptide (FLR), in primary rat NP monolayer culture, and in an ex vivo organ culture model of rat caudal discs. Protein expression of discogenic (aggrecan, collagen type II, and SOX9) and catabolic markers (ADAMTS5 and MMP13) were assessed.

Monolayer investigations signified enhanced discogenic marker expression following dual miRNA delivery, signifying a synergistic effect when compared to single miRNA transfection. Utilization of an appropriate model was emphasized in our ex vivo organ culture experiment, revealing the establishment of a regenerative microenvironment characterized by reduced catabolic enzyme activity and enhanced matrix deposition, particularly following concurrent delivery of FLR-miRNA-149-5p mimic and miRNA-221-3p inhibitor. Bioinformatics analysis of miRNA-149-5p mimic and miRNA-221-3p inhibitor identified distinct targets, pathways, and interactions, suggesting a mode of action for this amplified response.

Our findings suggest the potential of FLR-miRNA-149-5p + miRNA-221-3p inhibitor to create an anti-catabolic niche within the disc to foster regeneration in moderate cases of disc degeneration, which could be utilized in further studies with the overarching aim of developing treatments for LBP.

Intervertebral disc degeneration (IVDD) is a significant cause of chronic pain and disability, necessitating innovative therapeutic strategies. This study investigates the combined effect of a novel siCOL1A2-encapsulated hydrogel and acupuncture on IVDD in a rat model. We developed a hydrogel system, siCOL1A2-encapsulated G5-PBA hydrogel (siCOL1A2@G5-PBA@Gel), designed for sustained siRNA delivery to the degenerated discs and assessed its therapeutic efficacy alongside acupuncture treatment. Key inflammatory genes were identified through RNA-seq analysis, with COL1A2 highlighted as a crucial regulator of inflammatory responses in IVDD. Our in vivo experiments involved treating rats with hydrogel alone, acupuncture alone, and combining both. The treatments were evaluated through behavioral pain assessments, imaging techniques (X-ray and MRI), and histological analyses. Results indicated that the combination therapy significantly alleviated pain, reduced inflammation, and promoted disc regeneration more effectively than individual treatments. The hydrogel proved biocompatible and facilitated targeted gene silencing, while acupuncture enhanced therapeutic outcomes by improving local blood circulation and modulating inflammatory responses. These findings suggest that integrating siCOL1A2 hydrogel with acupuncture offers a promising approach to treating IVDD.

Intervertebral disc degeneration (IDD) is a chronic disabling disease caused by degeneration of nucleus pulposus cells, decreased activity and the number of nucleus pulposus cells, decreased extracellular matrix, and infiltration of inflammatory factors, resulting in low back and leg pain. Recent studies have shown that non-surgical treatment is of great significance in reversing the progression of degenerative disc disease, and there are more relevant literature reports. However, there is no bibliometric analysis in this area. This study aimed to describe the knowledge structure and thematic trends of non-surgical treatment methods for IDD through bibliometrics.

Articles and reviews on non-surgical treatment of disc degeneration from 1998 to 2022 were collected on the Web of Science. VOSviewer 1.6.18, CiteSpace 6.1.R3, R package "bibliometrix" and two online analysis platforms were used for bibliometric and visual literature analysis.

961 articles were screened for inclusion, including 821 articles and 140 reviews. The analysis of our study shows that publications in the non-surgical treatment of disc degeneration are increasing annually, with publications coming mainly from North America and Asia, with China and the United States dominating. Huazhong Univ Sci & Technol and Wang K are the most prolific institutions and authors, respectively, and Le Maitre CL is the most co-cited author. However, there is less collaboration between institutions in different countries. Spine is both the most published and the most cited journal. According to the co-citation and co-occurrence analysis results, "mesenchymal stem cells," "exosomes," "medication," and "tissue engineering" are the current research hotspots in this field.

This study employs bibliometric analysis to explore the knowledge structure and trends of non-surgical treatments for IDD from 2013 to 2022. Key research hotspots include mesenchymal stem cells, exosomes, medication, and tissue engineering. The number of publications, especially from China and the USA, has increased significantly, though international collaboration needs improvement. Influential contributors include Wang K and the journal Spine. These findings provide a comprehensive overview and highlight important future directions for the field.

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder that is associated with considerable morbidity. However, there is currently no drug available that has a definitive therapeutic effect on IDD. In this study, we aimed to identify the molecular features and potential therapeutic targets of IDD through a comprehensive multiomics profiling approach. By integrating transcriptomics, proteomics, and ultrastructural analyses, we discovered dysfunctions in various organelles, including mitochondria, the endoplasmic reticulum, the Golgi apparatus, and lysosomes. Metabolomics analysis revealed a reduction in total phosphatidylcholine (PC) content in IDD. Through integration of multiple omics techniques with disease phenotypes, a pivotal pathway regulated by the lysophosphatidylcholine acyltransferase 1 (LPCAT1)-PC axis was identified. LPCAT1 exhibited low expression levels and exhibited a positive correlation with PC content in IDD. Suppression of LPCAT1 resulted in inhibition of PC synthesis in nucleus pulposus cells, leading to a notable increase in nucleus pulposus cell senescence and damage to cellular organelles. Consequently, PC exhibits potential as a therapeutic agent, as it facilitates the repair of the biomembrane system and alleviates senescence in nucleus pulposus cells via reversal of downregulation of the LPCAT1-PC axis.

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which affects the patients' quality of life and health and imposes a significant socioeconomic burden. Despite great efforts made by researchers to understand the pathogenesis of IDD, effective strategies for preventing and treating this disease remain very limited. Sirtuins are a highly conserved family of (NAD+)-dependent deacetylases in mammals that are involved in a variety of metabolic processes in vivo. In recent years, sirtuins have attracted much attention owing to their regulatory roles in IDD on physiological activities such as inflammation, apoptosis, autophagy, aging, oxidative stress, and mitochondrial function. At the same time, many studies have explored the therapeutic effects of sirtuins-targeting activators or micro-RNA in IDD. This review summarizes the molecular pathways of sirtuins involved in IDD, and summarizes the therapeutic role of activators or micro-RNA targeting Sirtuins in IDD, as well as the current limitations and challenges, with a view to provide possible solutions for the treatment of IDD.

Intervertebral disc degeneration (IVDD) is a prevalent chronic condition causing spinal pain and functional impairment. This study investigates the role of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in regulating IVDD. Using RNA-seq, we analyzed differential expressions of lncRNA and miRNA in nucleus pulposus tissues from various mouse groups. We identified key regulatory molecules, MALAT1 and miRNA-138-5p, which contribute to IVDD. Further experiments demonstrated that MALAT1 can up-regulate SLC7A11 expression by competitively binding to miR-138-5p, forming a MALAT1/miR-138-5p/SLC7A11 coexpression regulatory network. This study elucidates the molecular mechanism by which hUCMSC-derived EVs regulate IVDD and could help develop novel therapeutic strategies for treating this condition. Our findings demonstrate that hUCMSCs-EVs inhibit ferroptosis in nucleus pulposus cells, thereby improving IVDD. These results highlight the therapeutic potential of hUCMSCs-EVs in ameliorating the development of IVDD, offering significant scientific and clinical implications for new treatments.

As one of the most widespread musculoskeletal diseases worldwide, intervertebral disc degeneration (IVDD) remains an intractable clinical problem. Currently, oxidative stress has been widely considered as a significant risk factor in the IVDD pathological changes, and targeting oxidative stress injury to improve the harsh microenvironment may provide a novel and promising strategy for disc repair. It is evident that spermidine (SPD) has the ability to attenuate oxidative stress across several disease models. However, limited research exists regarding its impact on oxidative stress within the intervertebral disc. Moreover, enhancing the local utilization rate of SPD holds great significance in IVDD management. This study aimed to develop an intelligent biodegradable mesoporous polydopamine (PDA) nanoplatform for sustained release of SPD. The obtained PDA nanoparticles with spherical morphology and mesoporous structure released loaded-therapeutic molecules under low pH and H2O2. Combined treatment with SPD loaded into PDA nanoparticles (SPD/PDA) resulted in better therapeutic potential than those with SPD alone on oxidative stress injury. Furthermore, both SPD and SPD/PDA could induce anti-inflammatory M2 macrophage polarization. Upon injection into degenerative IVDs, the SPD/PDA group achieved a good repair efficacy with a long-term therapeutic effect. These findings indicated that the synergized use of SPD with responsive drug delivery nanocarriers may steadily scavenge reactive oxygen species and provide an effective approach toward the treatment of IVDD.

Intervertebral disc degeneration (IVDD) is a common degenerative disease which is closely related to low back pain (LBP) and brings huge economic and social burdens. In this study, we explored the therapeutic effects of Homoplantaginin (Hom) for IVDD due to its convincing anti-inflammatory and antioxidant functions. TNF-α was used to simulate the inflammatory environment for nucleus pulposus (NP) cells in vitro. We verified that Hom could alleviate the TNF-α-induced inflammation and disturbance of ECM homeostasis through blocking the NF-κB/MAPK signaling pathways. Subsequently, we screened the binding targets of Hom and confirmed that Hom could directly bind to TAK1 and inhibit its phosphorylation to down-regulate the inflammation-related pathways. The therapeutic effects of Hom on IVDD were further validated through a needle puncture rat model in vivo. Overall, Hom was a promising small molecule for IVDD early intervention, possessing huge clinical translational value.

Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP), and inflammatory factors play crucial roles in its pathogenesis. Follistatin-like 1 (FSTL1) has been reported to induce an inflammatory response in chondrocytes, microglia and preadipocytes, but its role in the pathogenesis of nucleus pulposus cell (NPC) degeneration remains unclear. In this study, we mainly utilized an acidosis-induced NPC degeneration model and a rabbit puncture IVDD model to investigate the role of FSTL1 in IVDD both in vitro and in vivo. We confirmed that FSTL1 expression significantly increased in nucleus pulposus (NP) tissues from IVDD patients and rabbit puncture IVDD models. The expression levels of FSTL1 were significantly increased in all three models of NPC degeneration under harsh microenvironments. In addition, recombinant human FSTL1 (rh-FSTL1) was found to upregulate the expression of p16 and p21, increase the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells, induce senescence-related secretory phenotypes (SASP), and downregulate extracellular matrix (ECM) protein expressions, leading to an imbalance in ECM metabolism destructions. Conversely, silencing of FSTL1 by small interfering RNA (siRNA) ameliorated senescence of NPCs associated with inflammation in IVDD. Furthermore, Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway plays a crucial role in regulating NPC senescence through FSTL1 regulation. Inhibition of TLR4 expression partly reversed the effects of rh-FSTL1 on NPC senescence-associated inflammation. Finally, rabbit IVDD model experiments demonstrated that the specific FSTL1 siRNA markedly repressed the development of IVDD. These findings may offer a therapeutic approach for mitigating inflammation-induced senescence associated with IVDD.

Intervertebral discs (IVDs) have a limited self-regenerative capacity and current strategies for IVD regeneration are unsatisfactory. Recent studies showed that small extracellular vesicles derived from M2 macrophage cells (M2-sEVs) inhibited inflammation by delivery of various bioactive molecules to recipient cells, which indicated that M2-sEVs may offer a therapeutic strategy for the repair of IVDs. Herein, we investigated the roles and mechanisms of M2-sEVs on IVD regeneration. The in vitro results demonstrated that M2-sEVs inhibited pyroptosis, preserved cellular viability, and promoted migration of nucleus pulposus cells (NPCs). Bioinformatics analysis and verification experiments of microRNA (miR) expression showed that miR-221-3p was highly expressed in M2-sEVs. The mechanism of action was explored and indicated that M2-sEVs inhibited pyroptosis of NPCs through transfer of miR-221-3p, which suppressed the expression levels of phosphatase and tensin homolog and NOD-, LRR-, and pyrin domain-containing protein 3. Moreover, we fabricated decellularized ECM-hydrogel (dECM) for sustained release of M2-sEVs, which exhibited biocompatibility and controlled release properties. The in vivo results revealed that dECM-hydrogel containing M2-sEVs (dECM/M2-sEVs) delayed the degeneration of intervertebral disc degeneration (IDD) models. In addition to demonstrating a promising therapeutic for IDD, this study provided valuable data for furthering the understanding of the roles and mechanisms of M2-sEVs in IVD regeneration.

The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment.

The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations.

We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3 months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity.

NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD.

Intervertebral disc degeneration (IDD) is a highly prevalent musculoskeletal disorder affecting millions of adults worldwide, but a poor understanding of its pathogenesis has limited the effectiveness of therapy. In the current study, we integrated untargeted LC/MS metabolomics and magnetic resonance spectroscopy data to investigate metabolic profile alterations during IDD. Combined with validation via a large-cohort analysis, we found excessive lipid droplet accumulation in the nucleus pulposus cells of advanced-stage IDD samples. We also found abnormal palmitic acid (PA) accumulation in IDD nucleus pulposus cells, and PA exposure resulted in lipid droplet accumulation and cell senescence in an endoplasmic reticulum stress-dependent manner. Complementary transcriptome and proteome profiles enabled us to identify solute carrier transporter (SLC) 43A3 involvement in the regulation of the intracellular PA level. SLC43A3 was expressed at low levels and negatively correlated with intracellular lipid content in IDD nucleus pulposus cells. Overexpression of SLC43A3 significantly alleviated PA-induced endoplasmic reticulum stress, lipid droplet accumulation and cell senescence by inhibiting PA uptake. This work provides novel integration analysis-based insight into the metabolic profile alterations in IDD and further reveals new therapeutic targets for IDD treatment.

Intervertebral disc degeneration (IDD) is a main contributor to lower back pain, and compression stress-induced apoptosis of nucleus pulposus (NP) cells and extracellular matrix (ECM) degradation has been implicated in the IDD progression. The functions of platelet-rich plasma (PRP)-derived extracellular vesicles (PRP-EVs) in regulating these biological processes remain unclear in IDD. Here, we aimed to investigate the key role of long noncoding RNA (lncRNA) MALAT1 incorporated in PRP-EVs in IDD.

Tert-butyl hydroperoxide (TBHP)-induced damage in NP cells was treated with PRP-EVs extracted from healthy volunteers, followed by MTT, EdU, TUNEL, and Western blot assays. IDD mice were also treated with PRP-EVs. Histomorphological and pathological changes were evaluated. The pyroptosis of cells and the degradation of ECM were detected by ELISA and immunohistochemistry. We screened the differentially expressed lncRNAs in NP cells after PRP-EVs treatment by microarray analysis. The downstream targets of MALAT1 in NP cells were predicted and validated by rescue experiments.

TBHP induction reduced cell proliferation and exacerbated pyroptosis and ECM degradation, and PRP-EVs inhibited TBHP-induced cell damage. PRP-EVs-treated mice with IDD had reduced Thompson scores, increased NP tissue content, and restored ECM. PRP-EVs upregulated MALAT1 expression in vivo and in vitro, whereas MALAT1 downregulation exacerbated NP cell pyroptosis and ECM degradation. MALAT1 upregulated SIRT1 expression by downregulating microRNA (miR)-217 in NP cells. SIRT1 blocked the NF-κB/NLRP3 pathway-mediated pyroptosis, thereby alleviating IDD.

PRP-EVs deliver MALAT1 to regulate miR-217/SIRT1, thereby controlling NP cell pyroptosis in IDD.

Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.

The pathogenesis of Intervertebral Disc Degeneration (IDD) is complex and multifactorial, with cellular senescence of nucleus pulposus (NP) cells and inflammation playing major roles in the progression of IDD. The stimulator of interferon genes (STING) axis is a key mediator of inflammation during infection, cellular stress, and tissue damage. Here, we present a progressive increase in STING in senescent NP cells with the degradation disorder. The STING degradation function in normal NP cells can prevent IDD. However, the dysfunction of STING degradation through autophagy causes the accumulation and high expression of STING in senescent NP cells as well as inflammation continuous activation together significantly promotes IDD. In senescent NP cells and intervertebral discs (IVDs), we found that STING autophagy degradation was significantly lower than that of normal NP cells and IVDs when STING was activated by 2'3'-cGAMP. Also, the above phenomenon was found in STINGgt/gt, cGAS-/- mice with models of age-induced, lumbar instability-induced IDD as well as found in the rat caudal IVD puncture models. Taken together, we suggested that the promotion of STING autophagy degradation in senescent NP Cells demonstrated a potential therapeutic modality for the treatment of IDD.

Low back pain stands as a pervasive global health concern, afflicting almost 80% of adults at some point in their lives with nearly 40% attributable to intervertebral disc degeneration (IVDD). As only symptomatic relief can be offered to patients there is a dire need for innovative treatments.Given the accumulating evidence that multiple microRNAs (miRs) are dysregulated during IVDD, they could have a huge potential against this debilitating condition. The way miRs can profoundly modulate signaling pathways and influence several cellular processes at once is particularly exciting to tackle this multifaceted disorder. However, miR delivery encounters extracellular and intracellular biological barriers. A promising technology to address this challenge is the vectorization of miRs within nanoparticles, providing both protection and enhancing their uptake within the scarce target cells of the degenerated IVD. This comprehensive review presents the diverse spectrum of miRs' connection with IVDD and demonstrates their therapeutic potential when vectorized in nanomedicines.

Intervertebral disc degeneration (IVDD) is one of the etiologic factors of degenerative spinal diseases, which can lead to a variety of pathological spinal conditions such as disc herniation, spinal stenosis, and scoliosis. IVDD is a leading cause of lower back pain, the prevalence of which increases with age. Recently, Sirtuins/SIRTs and their related activators have received attention for their activity in the treatment of IVDD. In this paper, a comprehensive systematic review of the literature on the role of SIRTs and their activators on IVDD in recent years is presented. The molecular pathways involved in the regulation of IVDD by SIRTs are summarized, and the effects of SIRTs on senescence, inflammatory responses, oxidative stress, and mitochondrial dysfunction in myeloid cells are discussed with a view to suggesting possible solutions for the current treatment of IVDD.

This paper focuses on the molecular mechanisms by which SIRTs and their activators act on IVDD.

A literature search was conducted in Pubmed and Web of Science databases over a 13-year period from 2011 to 2024 for the terms "SIRT", "Sirtuin", "IVDD", "IDD", "IVD", "NP", "Intervertebral disc degeneration", "Intervertebral disc" and "Nucleus pulposus".

According to the results, SIRTs and a large number of activators showed positive effects against IVDD.SIRTs modulate autophagy, myeloid apoptosis, oxidative stress and extracellular matrix degradation. In addition, they attenuate inflammatory factor-induced disc damage and maintain homeostasis during disc degeneration. Several clinical studies have reported the protective effects of some SIRTs activators (e.g., resveratrol, melatonin, honokiol, and 1,4-dihydropyridine) against IVDD.

The fact that SIRTs and their activators play a hundred different roles in IVDD helps to better understand their potential to develop further treatments for IVDD.

This review summarizes current information on the mechanisms of action of SIRTs in IVDD and the challenges and limitations of translating their basic research into therapy.

Intervertebral disc degeneration (IVDD) is a major cause of morbidity and disability. Our study aimed to investigate the potential of cartilage oligomeric matrix protein (COMP) and ADAMTS7 (A disintegrin and metalloproteinases with thrombospondin motifs 7) as biomarkers for IVDD together with their functional relationship.

IVD tissues and peripheral blood samples were collected from IVDD rabbit models over 1-4 weeks. Tissues and blood samples were also collected from clinical patients those were stratified into four equal groups according to Pfirrmann IVDD grading (I-V) with baseline data collected for each participant. COMP and ADAMTS7 expression were analyzed and biomarker characteristics were assessed using linear regression and receiver operating curve (ROC) analyses.

COMP and ADAMTS7 expression increased in tissues and serum during IVDD progression. Serum COMP (sCOMP) and serum ADAMTS7 (sADAMTS7) levels increased in a time-dependent manner following IVD damage in the rabbit model while significant positive correlations were detected between sCOMP and sADAMTS7 and Pfirrmann grade in human subjects. ROC analysis showed that combining sCOMP and sADAMTS7 assay results produced an improved diagnostic measure for IVDD compared to individual sCOMP or sADAMTS7 tests. In vitro assays conducted on human cell isolates revealed that COMP prevented extracellular matrix degradation and antagonized ADAMTS7 expression although this protective role was uncoupled under microenvironmental conditions mimicking IVDD.

Increases in circulating COMP and ADAMTS7 correlate with IVDD progression and may play regulatory roles. Assays for sCOMP and/or sADAMTS7 levels can discriminate between healthy subjects and IVDD patients, warranting further clinical assessment.

Low back pain (LBP) is the main factor of global disease burden. Intervertebral disc degeneration (IVDD) has long been known as the leading reason of LBP. Increasing studies have verified that circular RNAs (circRNAs)-microRNAs (miRNAs)-mRNAs network is widely involved in the pathological processes of IVDD. However, no study was made to demonstrate the circRNAs-mediated ferroptosis, oxidative stress, extracellular matrix metabolism, and immune response in IVDD.

We collected 3 normal and 3 degenerative nucleus pulposus tissues to conduct RNA-sequencing to identify the key circRNAs and miRNAs in IVDD. Bioinformatics analysis was then conducted to construct circRNAs-miRNAs-mRNAs interaction network associated with ferroptosis, oxidative stress, extracellular matrix metabolism, and immune response. We also performed animal experiments to validate the therapeutic effects of key circRNAs in IVDD.

We found that circ_0015435 was most obviously upregulated and circ_0071922 was most obviously downregulated in IVDD using RNA-sequencing. Then we observed that hsa-miR-15a-5p was the key downstream of circ_0071922, and hsa-miR-15a-5p was the top upregulated miRNA in IVDD. Bioinformatics analysis was conducted to predict that 56 immunity-related genes, 29 ferroptosis-related genes, 23 oxidative stress-related genes and 8 ECM-related genes are the targets mRNAs of hsa-miR-15a-5p. Then we constructed a ceRNA network encompassing 24 circRNAs, 6 miRNAs, and 101 mRNAs. Additionally, we demonstrated that overexpression of circ_0071922 can alleviate IVDD progression in a rat model.

The findings of this study suggested that circ_0071922-miR-15a-5p-mRNA signaling network might affect IVDD by modulating the nucleus pulposus cells ferroptosis, oxidative stress, ECM metabolism, and immune response, which is an effective therapeutic targets of IVDD.

Intervertebral disc degeneration (IDD) is the main cause of low back pain (LBP), which significantly impacts global wellbeing and contributes to global productivity declines. Conventional treatment approaches, encompassing conservative and surgical interventions, merely serve to postpone the advancement of IDD without offering a fundamental reversal. Consequently, there is an urgent demand for an effective approach to prevent the progression of IDD. Recent investigations focusing on the treatment of IDD utilizing diverse bioactive substances integrated within various biomaterials have exhibited promising outcomes. Various bioactive substances, encompassing conventional small molecule drugs, small molecule nucleic acids, and cell therapies, exhibit distinct capacities for repairing IDD. Additionally, various biological material delivery systems, such as nano micelles, microspheres, and hydrogels, possess diverse biological and release characteristics. Consequently, these diverse materials and drugs hold promise for advancing the treatment of IDD. This article aims to provide a concise overview of the IDD process and investigate the research advancements in biomaterials and bioactive substances for IDD treatment, delving into their mechanisms.

Chronic low back pain (LBP) is an increasingly prevalent issue, especially among aging populations. A major underlying cause of LBP is intervertebral disc degeneration (IDD), often triggered by intervertebral disc (IVD) inflammation. Inflammation of the IVD is divided into Septic and Aseptic inflammation. Conservative therapy and surgical treatment often fail to address the root cause of IDD. Recent advances in the treatment of IVD infection and inflammation range from antibiotics and small-molecule drugs to cellular therapies, biological agents, and innovative biomaterials. This review sheds light on the complex mechanisms of IVD inflammation and physiological and biochemical processes of IDD. Furthermore, it provides an overview of recent research developments in this area, intending to identify novel therapeutic targets and guide future clinical strategies for effectively treating IVD-related conditions.

Intervertebral disc degeneration is a natural process during aging and a leading cause of lower back pain. Here, we generate a comprehensive atlas of nucleus pulposus cells using single-cell RNA-seq analysis of human nucleus pulposus tissues (three males and four females, age 41.14 ± 18.01 years). We identify fibrotic late-stage nucleus pulposus cells characterized by upregulation of serglycin expression which facilitate the local inflammatory response by promoting the infiltration of inflammatory cytokines and macrophages. Finally, we discover that daphnetin, a potential serglycin ligand, substantially mitigates the local inflammatory response by downregulating serglycin expression in an in vivo mouse model, thus alleviating intervertebral disc degeneration. Taken together, we identify late-stage nucleus pulposus cells and confirm the potential mechanism by which serglycin regulates intervertebral disc degeneration. Our findings indicate that serglycin is a latent biomarker of intervertebral disc degeneration and may contribute to development of diagnostic and therapeutic strategies.