Low back pain (LBP), one of the most common health problems, is the leading cause of disability globally. Intervertebral disc degeneration (IDD) accounts for most LBP. However, the molecular mechanism underlying IDD remains unclear, and the existing treatment strategy for IDD is still limited. A growing body of evidences suggest that the Hedgehog (HH) pathway plays an essential role in the formation, maintenance, and degeneration of intervertebral discs (IVDs), with Sonic HH (SHH) being primarily involved in the development and maturation of the IVDs and a strong link between Indian HH(IHH) and disc calcification. This review provides an overview of the role of the HH signaling pathway in the developmental maturation and degeneration of IVDs and suggests potential therapeutic targets for IDD that may interfere with HH signaling.

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain and associated disability worldwide. The cartilage endplate (CEP) is a critical structure in maintaining the homeostasis of the intervertebral disc, by exosomes (Exos)-mediated intracellular communication between cartilage endplate stem cells (CESCs) and nucleus pulposus cells (NPCs). However, whether the senescence of CESCs influences the functionality of CESCs-derived Exos (CESCs-Exos) and participates in the progress of IVDD remains unclear. In this study, we explored the role and mechanism of the Exos-based intracellular communication between senescent CESCs and NPCs in IVDD. CESCs isolated from aged individuals (S-CESCs) exhibited high levels of senescence compared with CESCs isolated from young individuals (Y-CESCs). Exos from Y-CESCs (Y-Exos) and from S-CESCs (S-Exos) were extracted and identified. Surprisingly, we found that S-Exos lost the therapeutic effects as the Y-Exos exhibited in mitigating IVDD, and even aggravated IVDD by inducing oxidative stress injury in NPCs. MicroRNA-sequencing revealed significant upregulation of miR-29b-3p expression in S-Exos. Through microRNA target prediction, dual luciferase assays, RNA-sequencing, lentivirus-mediated overexpression and suppression, we demonstrated that miR-29b-3p regulates the expression of FOXO3 and downstream antioxidant enzymes to induce oxidative stress injury in NPCs. In vivo experiments further verified that countering miR-29b-3p by antagomir reversed the detrimental effects of S-Exos in exacerbating IVDD. This work elucidates the role and mechanism of senescent CESCs in disrupting redox homeostasis in the nucleus pulposus and exacerbating IVDD by Exos-mediated intracellular communication and offers an experimental foundation for the selection of proper CESCs-Exos to obtain better therapeutic effects in IVDD.

Degenerative disc disease (DDD) is commonly associated with chronic low back pain (cLBP) and disability, yet its impact on spinal mobility remains underexplored. This study investigates the association between lumbar disc degeneration and spinal mobility to assess its functional consequences.

In this cross-sectional study, participants were recruited from the general population. Individuals with specific LBP were excluded. Intervertebral disc degeneration was graded using the Pfirrmann classification, and an overall lumbar Pfirrmann grade (PG) was calculated. Uni- and multivariable linear regression models were performed to analyze the relationship between disc degeneration and spinal mobility, accounting for age, sex, BMI, physical activity, and pain intensity, with additional subgroup analysis by sex, cLBP status, and age.

909 participants (44.1% female) were included in the study; 421 (46.3%) were affected by cLBP. After accounting for confounders, a higher lumbar PG was significantly associated with reduced sagittal lumbar and rotational mobility (p < 0.001) and increased thoracic sagittal mobility (p = 0.005)in males. Subgroup analyses indicated that associations with mobility impairments were more pronounced in individuals with cLBP and older patients.

This study providesevidence linking lumbar disc degeneration to reductions in spinal mobility, particularly in individuals with chronic low back pain. The pronounced mobility loss in cLBP patients suggests that chronic pain may disrupt compensatory mechanisms. These findings validate the role of disc degeneration within the context of cLBP and highlight the need for targeted interventions.

To assess the agreement between lumbar disc degeneration (DD) grading by the convolutional neural network model SpineNet and radiologist's visual grading.

In a 14-year follow-up MRI study involving 19 male volunteers, lumbar DD was assessed by SpineNet and two radiologists using the Pfirrmann classification at baseline (age 37) and after 14 years (age 51). Pfirrmann summary scores (PSS) were calculated by summing individual disc grades. The agreement between the first radiologist and SpineNet was analyzed, with the second radiologist's grading used for inter-observer agreement.

Significant differences were observed in the Pfirrmann grades and PSS assigned by the radiologist and SpineNet at both time points. SpineNet assigned Pfirrmann grade 1 to several discs and grade 5 to more discs compared to the radiologists. The concordance correlation coefficients (CCC) of PSS between the radiologist and SpineNet were 0.54 (95% CI: 0.28 to 0.79) at baseline and 0.54 (0.27 to 0.80) at follow-up. The average kappa (κ) values of 0.74 (0.68 to 0.81) at baseline and 0.68 (0.58 to 0.77) at follow-up. CCC of PSS between the radiologists was 0.83 (0.69 to 0.97) at baseline and 0.78 (0.61 to 0.95) at follow-up, with κ values ranging from 0.73 to 0.96.

We found fair to substantial agreement in DD grading between SpineNet and the radiologist, albeit with notable discrepancies. These findings indicate that AI-based systems like SpineNet hold promise as complementary tools in radiological evaluation, including in longitudinal studies, but emphasize the need for ongoing refinement of AI algorithms.

The most common degenerative condition affecting the musculoskeletal system, and the leading cause of persistent low back pain, is intervertebral disc degeneration (IDD). IDD is increasingly common with age and has a variety of etiologic factors including inflammation, oxidative stress, extracellular matrix (ECM) degradation, and apoptosis that interact with each other to cause IDD. Because it is difficult to determine the exact pathogenesis of IDD, there is a lack of effective therapeutic agents. Melatonin has been intensively studied for its strong anti-inflammatory, antioxidant, and anti-apoptotic properties. Melatonin is a pleiotropic indole-stimulating hormone produced by the pineal gland, which can be used to treat a wide range of degenerative diseases. Therefore, melatonin supplementation may be a viable treatment for IDD. This article reviews the current mechanisms of IDD and the multiple roles regarding melatonin's anti-inflammatory, antioxidant, anti-apoptotic, and mitigating ECM degradation in IDD, incorporating new current research perspectives, as well as recent studies on drug delivery systems.

Genome editing technologies, particularly CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), have broadened the possibilities of genetic research and molecular biology by enabling precise modifications of the genome, offering novel therapeutic potential for various disorders. Herein, we present an overview of traditional genome editing techniques and delve deeper into the CRISPR toolbox, with particular attention given to epigenetic and transcriptional regulation. In the context of the intervertebral disc (IVD), CRISPR offers an unprecedented approach to address the mechanisms underlying tissue degeneration, advancing the development of revolutionary therapies for Low Back Pain (LBP). As so, we showcase how to leverage CRISPR systems for IVD. This cutting-edge technology has been successfully used to improve our understanding of IVD biology through functional studies and disease modeling. Most relevant research prioritizes new targets associated with the extracellular matrix (ECM), pain sensing or inflammatory pathways. Promising CRISPR applications encompass IVD regeneration by recapitulation of a regenerative environment or by targeting important degenerative catalysts. In the future, priority should be given to fetal gene reactivation, multiple healthy gene expression enhancement and disease-associated polymorphisms' correction. Despite several challenges such as effective delivery, off-target effects, as well as ethical and safety concerns, exciting clinical trials are anticipated in the years to come, providing more effective and long-lasting solutions for IVD degeneration.

Intervertebral disc (IVD) degeneration is a leading cause of back pain, and while studies have revealed the roles resident nucleus pulposus (NP) and annulus fibrosus (AF) cells play in degeneration, tissue-engineered IVD models are needed to better investigate the mechanisms underpinning these cell-driven changes. This study therefore integrated suspension baths with bioprinting to create four multi-material, whole IVD analogues and investigated the combined effect of reduced oxygen tension and increased regional matrix stiffness on disc cell phenotype since these factors correlate with IVD degeneration. Primary NP and AF cells were seeded into alginate-collagen hydrogels and bioprinted into biphasic IVD structures. The nascent area, intensity, and integrated density of pro-collagen type I, collagen type VI, aggrecan, and hyaluronic acid were quantified using immunofluorescence staining in each region. Stiffness-mediated collagen and glycosaminoglycan production was observed in the AF, and increased stiffness downregulated collagen type VI in the AF but upregulated it in NP. Oxygen tension impacted proteoglycan production, with hypoxia increasing aggrecan and hyaluronic acid in both regions. This work represents a step towards the automated biofabrication of whole IVD analogues and expands the state-of-the-art in suspension bioprinting using regionally specific matrix cues. The findings provide important insights into two key microenvironmental factors driving IVD degeneration. STATEMENT OF SIGNIFICANCE: This manuscript outlines an original application of suspended layer additive manufacturing to biofabricate novel, biphasic intervertebral disc analogues containing patient-derived primary human cells. Significantly, the bioprinted models demonstrated biological function and were used to assess the effect of stiffness and oxygen concentration on regional matrix production using a range of internationally-recognized phenotypic intervertebral disc cell markers. The study therefore furthers the state-of-the-art in suspended bioprinting using regionally specific matrix cues and paves the way for future bioprinted disc models that can serve as biosimulators capable of generating insights into key mechanisms governing tissue development, homeostasis, and degeneration.

Intervertebral disc degeneration progresses with normal aging; yet common disc grading schemes do not account for age. Degeneration progression also varies between spine levels and is similarly not accounted for by current grading schemes. These limitations inhibit differentiation between discs with normal and expected aging (non-pathological) and discs with accelerated degeneration (which may be pathological). We sought to develop a statistical model to quantify normal age and spine level dependent disc degeneration.

Eighty-four asymptomatic adult subjects ranging evenly from 18 to 83 years old underwent magnetic resonance imaging (MRI) of the lumbar spine. Subject traits, MRI-derived disc geometry, and MRI biomarkers of T2 relaxation time were evaluated and used to develop a statistical model to predict effective disc age, the age at which normal aging would produce a disc's observed phenotype.

After evaluating several models, a 4-predictor model utilizing 1) subject height, 2) nucleus pulposus T2 relaxation time, 3) disc mid-sagittal area and 4) disc 3D volume, optimally estimated effective disc age. The effective age closely tracked true age for spine levels L1-L5 (R2 ≈ 0.7, RMSE ≈ 10 years) and moderately tracked true age for L5-S1 (R2 = 0.4, RMSE = 14 years). The uncertainty in the effective disc age prediction was ± 3 years as assessed by fivefold cross validation.

We offer a data-driven, quantitative tool to quantify normal, expected intervertebral disc aging. This effective age model allows future research to target discs with accelerated degeneration.

Intervertebral disc degeneration (IDD) arises from a complex interplay of genetic, environmental, and age-related factors, culminating in a spectrum of low back pain (LBP) disorders that exert significant societal and economic impact. The present therapeutic landscape for IDD poses formidable clinical hurdles, necessitating the exploration of innovative treatment modalities. The hydrogel, as a biomaterial, exhibits superior biocompatibility compared to other biomaterials such as bioceramics and bio-metal materials. It also demonstrates mechanical properties closer to those of natural intervertebral discs (IVDs) and favorable biodegradability conducive to IVD regeneration. Therefore, it has emerged as a promising candidate material in the field of regenerative medicine and tissue engineering for treating IDD. Hydrogels have made significant strides in the field of IDD treatment. Particularly, injectable hydrogels not only provide mechanical support but also enable controlled release of bioactive molecules, playing a crucial role in mitigating inflammation and promoting extracellular matrix (ECM) regeneration. Furthermore, the ability of injectable hydrogels to achieve minimally invasive implantation helps minimize tissue damage. This article initially provides a concise exposition of the structure and function of IVD, the progression of IDD, and delineates extant clinical interventions for IDD. Subsequently, it categorizes hydrogels, encapsulates recent advancements in biomaterials and cellular therapies, and delves into the mechanisms through which hydrogels foster disc regeneration. Ultimately, the article deliberates on the prospects and challenges attendant to hydrogel therapy for IDD.

There are no appropriate mouse models to study the pathophysiology of spontaneous disc herniations in a wild-type setting. SM/J mice, a poor healer inbred strain, presented a high incidence of age-associated lumbar disc herniations with neurovascular innervations. Transcriptomic comparisons of the SM/J annulus fibrosus with human tissues showed shared pathways related to immune cell activation and inflammation. Notably, aged SM/J mice showed increased pain sensitization and neuroinflammation with altered extracellular matrix regulation in the dorsal root ganglia and spinal cord. There were increased T cells in the vertebral marrow, and cytometry by time-of-flight analysis showed increased splenic CD8+ T cells, nonspecific activation of CD8+ memory T cells, and enhanced interferon-γ production in the myeloid compartment. Single-cell RNA sequencing of peripheral blood mononuclear cells showed more B cells, with lower proportions of T cells, monocytes, and granulocytes. This study highlights the contribution of genetic background and aging to increased susceptibility of spontaneous intervertebral disc herniations in a clinically relevant murine model.

Degeneration of intervertebral discs and facet joints are common conditions that are thought to be interrelated. This study aimed to investigate the morphological interplay between disc and facet degeneration, as well as relationships between adjacent discs and facets. This prospective study involved 712 participants (307 males, 405 females) categorized into three groups: no back pain (no-BP), intermittent (iLBP), and chronic low back pain (cLBP). The Pfirrmann classification was used to assess intervertebral disc degeneration of index and adjacent segments, while the Fujiwara classification evaluated facet joint degeneration. Spearman's correlation coefficient analyzed relationships between degenerative changes in discs and facets. Overall, from the 712 participants 254 were with no-BP, 159 with intermittent LBP, and 299 with chronic LBP. The severity of both intervertebral disc and facet joint degeneration in the MRI sequences increased from upper to lower segments, with a significant clear directionality in differences between the uppermost and lowermost levels (p < 0.01). A strong positive correlation was observed between degenerative changes of adjacent intervertebral discs, especially in the upper and middle lumbar spine (ρ > 0.69). However, correlations between intervertebral disc and facet joint degeneration were weak in all populations studied (ρ < 0.31). The data indicate a directionality in the disease progression, with a strong correlation observed between adjacent intervertebral discs, suggesting a concurrent degenerative process. In contrast, the weak correlations between disc and facet joint degeneration imply that these structures undergo independent degenerative processes, particularly in the early stages of degeneration. Further research is essential to elucidate the underlying mechanisms and to develop precise therapeutic interventions for lumbar spine degeneration.

Early diagnosis of intervertebral disc (IVD) degeneration is of great significance for prevention of the disease from progressing to a serious stage. This study aimed to investigate the signature genes and their association with immune cells in IVD degeneration.

We analyzed differentially expressed genes (DEGs) in a dataset of IVD degeneration samples from the GEO database. Weighted gene coexpression network analysis (WGCNA) and DEGs were employed to pinpoint the key modules and IVD degeneration genes. Functional enrichment analysis was performed for these IVD degeneration genes. Signature genes were identified using least absolute shrinkage and selection operator (LASSO) analysis. Gene set enrichment analysis (GSEA) was used to explore signaling pathways related to signature genes, and CIBERSORT® was used to classify immune cell infiltration. Function of the hub gene was confirmed by PCR, Western blotting and ELISA.

2,254 DEGs were identified from GSE56081, and WGCNA grouped the data into 9 modules. MEbrown module had a significant correlation with IVD degeneration (cor = 0.99, P = 8.00 × 10-8). LASSO analysis selected HSPA1B, TOB1, ECM1, PTTG1IP as signature genes with excellent diagnostic efficiency. Furthermore, we assessed the diagnostic efficacy of every signature gene in predicting IVD degeneration using an external validation group (GSE70362). The results showed that two of the signature genes (TOB1, ECM1) had significant diagnostic effect in predicting the degeneration of IVD. GSEA analysis showed TOB1 and ECM1 involve in NOD like receptor signaling pathway, phenylalanine metabolism. Ether lipid metabolism, glycosaminoglycan biosynthesis keratin sulfate, RNA degradation pathway. CIBERSORT® suggested TOB1 and ECM1 may participate in immune cells infiltration. Finally, we identified TOB1 as a crucial molecule in the process of NP cell pyroptosis and NLRP3 inflammasome activation.

TOB1 may show remarkable diagnostic performance in IVD degeneration and may be implicated in the infiltration of immune cells.

The rising demand for organ transplants and the need for precise tissue models have positioned the in vitro biomanufacturing of tissues and organs as a pivotal area in regenerative treatment. Considerable development has been achieved in growing tissue-engineered intervertebral disc (IVD) scaffolds, designed to meet stringent mechanical and biological compatibility criteria. Among the cutting-edge approaches, 3D bioprinting stands out due to its unparalleled capacity to organize biomaterials, bioactive molecules, and living cells with high precision. Despite these advancements, polymer-based scaffolds still encounter limitations in replicating the extracellular matrix (ECM)-like environment, which is fundamental for optimal cellular activities. To overcome these challenges, integrating polymers with hydrogels has been recommended as a promising solution. This combination enables the advancement of porous scaffolds that nurture cell adhesion, proliferation, as well as differentiation. Additionally, bioinks derived from the decellularized extracellular matrix (dECM) have exhibited potential in replicating biologically relevant microenvironments, enhancing cell viability, differentiation, and motility. Hydrogels, whether derived from natural sources involving collagen and alginate or synthesized chemically, are highly valued for their ECM-like properties and superior biocompatibility. This review will explore recent advancements in techniques and technologies for IVD regeneration. Emphasis will be placed on identifying research gaps and proposing strategies to bridge them, with the goal of accelerating the translation of IVDs into clinical applications.

Degenerative disc disease (DDD) is a common spinal condition characterized by the deterioration of intervertebral discs, leading to chronic back pain and reduced mobility. While magnetic resonance imaging (MRI) has long been the standard for late-stage DDD diagnosis, its limitations in early-stage detection prompt the exploration of advanced imaging methods. Positron emission tomography/computed tomography (PET/CT) using 18F- fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) has shown promise in identifying metabolic imbalances and age-related spinal degeneration, thereby complementing CT grading of the disease. The novel hybrid imaging modality PET/MRI provides new opportunities and are briefly discussed. The complex pathophysiology of DDD is dissected to highlight the role of genetic predisposition and lifestyle factors such as smoking and obesity. These etiological factors significantly impact the lumbosacral region, manifesting in chronic low back pain (LBP) and potential nerve compression. Traditional grading systems, like the Pfirrmann classification for MRI, are evaluated for their limitations in capturing the full spectrum of DDD. The potential to identify early disease processes and predict patient outcomes by the use of artificial intelligence (AI) is also briefly mentioned. Overall, the manuscript aims to spotlight advancements in imaging technologies for DDD, emphasizing their implications in refining both diagnosis and treatment strategies. The role of ongoing and future research is emphasized to validate these emerging techniques and overcome current limitations for more effective early detection and treatment.

Degenerative disc disease (DDD) is associated with chronic lower back pain that may have impacts on individual's quality of life and functional ability. Lumbar interbody fusion can be carried out with a variety of bone grafting products, the choice depends on several factors including the patient, site, procedure, cost and indication. This systematic review (SR) intends to validate and consolidate the existing evidence base supporting bone graft materials related to lumbar interbody fusion procedures for DDD, specifically anterior lumbar interbody fusion (ALIF) and oblique lumbar interbody fusion (OLIF).

An SR was conducted in February 2023. Clinical and economic studies of adults with DDD in regions L2 to S1 undergoing lumbar interbody fusion with Infuse™, allograft, synthetic bone grafts, demineralized bone matrices or cell-based matrices were eligible for inclusion.

Twenty-one studies (reported in 25 publications) were included in the review. Eighteen studies (reported in 22 publications) reported clinical outcomes, while 4 studies reported economic outcomes. Nine studies (in 5 publications) investigated Infuse™, including 3 randomized controlled trials (RCTs), one cohort study and 4 case series. Ten studies investigated allograft bone, bone harvested from the vertebral spur combined with apacerum powder, or tricalcium phosphate soaked in autologous bone marrow aspirate, including one RCT, 2 cohort studies, and 7 case series.

The SR shows that Infuse™ offers comparable results to iliac crest bone graft with the benefit of not requiring harvested bone and offers significant benefits in surgical time and blood loss. There is a lack of comparative evidence for any other bone grafts identified in this SR, highlighting the need for further well-designed studies to be conducted in this area.

Disturbances in calcium and phosphorus homeostasis resulting from chronic kidney disease (CKD) may lead to atherosclerotic changes in blood vessels, potentially altering bone marrow perfusion. Our study aimed to investigate vertebral bone marrow perfusion using dynamic contrast-enhanced (DCE) MRI with a pharmacokinetic model. We also measured possible changes in water and fat content and bony trabeculae using T2* quantification, MR spectroscopy (MRS), and microcomputed tomography (μCT).

Twelve rats were randomly separated into a normal control group and a CKD (5/6 nephrectomy) group. Their lumbar spines were imaged, with monitoring of the L5 vertebral body conducted at 0, 8, 16, 30, and 43 weeks. After Week 43, all rats were sacrificed, and histologic changes were correlated with MRI and μCT results.

The CKD group demonstrated significantly lower A and k el values (p < 0.05), significantly increased T2* values (p < 0.05), significantly decreased fat content and trabeculation (p < 0.05), sinusoidal dilatation, and decreased adipocytes in the vertebral bone marrow.

Using quantitative MRI and μCT to assess CKD-related arthropathy of the vertebral body is feasible. Lumbar spine bone marrow perfusion deficiency in experimental CKD may be associated with decreased fat content, increased water content, and sparse trabeculation.

Chronic low back pain (LBP), often correlated with intervertebral disc degeneration, is a leading source of disability worldwide yet remains poorly understood. Current treatments often fail to provide sustained relief, highlighting the need to better understand the mechanisms driving discogenic LBP. During disc degeneration, the extracellular matrix degrades, allowing nociceptive nerve fibers to innervate previously aneural disc regions. Persistent mechanical and inflammatory stimulation of nociceptors can induce plastic changes within dorsal root ganglia (DRG) neurons, characterized by altered gene expression, enhanced excitability, and lowered activation thresholds. Although these transcriptional changes have been described in other pain states, including osteoarthritis, they remain underexplored in discogenic LBP. To address this gap, this study represents the first application of comprehensive single-nuclei RNA sequencing of DRG neurons in a rat model of chronic discogenic LBP. Eighteen distinct DRG subpopulations were identified and mapped to existing mouse and cross-species atlases revealing strong similarities in neuronal populations with the mouse. Differential expression analysis revealed increased expression of pain-associated genes, including Scn9a and Piezo2, and neuroinflammatory mediators such as Fstl1 and Ngfr, in LBP animals. Axial hypersensitivity, measured using grip strength, significantly correlated with increased expression of Scn9a, Fstl1, and Ngfr, which suggests their role in maintaining axial hypersensitivity in this model. These findings establish a relationship between DRG transcriptomic changes and axial hypersensitivity in a discogenic LBP model, identifying potential molecular targets for non-opioid treatments and advancing understanding of discogenic LBP mechanisms.

Despite being a leading cause of chronic pain and disability, the underlying mechanisms of intervertebral disc (IVD) degeneration (IVDD) remain unclear. Emerging evidence suggests that mechanosensation (the ability of the skeletal system to perceive mechanical and biochemical signals) mediated by abnormal mechanical loading plays a critical role in the regulation of IVD health. This review examines the complex interactions amongIVDs, intraosseous sensory mechanisms, and the central nervous system (CNS), with a particular focus on the roles of pathways such as PGE2/EP4, Wnt/β-catenin, and NF-κB. This review elucidates the manner in which mechanical stress and aberrant signaling disrupt the homeostasis of the nucleus pulposus (NP), cartilaginous endplate (CEP) and annulus fibrosus (AF), thereby driving degeneration and exacerbating pain. Furthermore, targeted therapeutic strategies, including the modulation of skeletal interoception and dynamic mechanical loading, present novel avenues for reversing IVDD progression. By integrating skeletal biology with spinal pathology, this work offers a novel perspective on the pathogenesis of IVDD and identifies promising strategies for clinical intervention. These findings highlight the potential of targeting skeletal interoception to mitigate IVDD and associated pain, paving the way for innovative, mechanism-driven therapies.

The limited understanding of the mechanisms underlying human discogenic low back pain (DLBP) has hampered the development of effective treatments. While there is much research on disc degeneration, the association between degeneration and pain is weak. Therefore, there is an urgent need to identify pain-inducing molecular mechanism to facilitate the development of mechanism-specific therapeutics. This scoping review aims to determine the current knowledge of molecular mechanisms associated with human DLBP. A systematic search on CENTRAL, CINAHL, Citation searching, ClinicalTrials.gov, Embase, Google Scholar, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science, and World Health Organization was performed. Studies with human DLBP as diagnosed by discography or imaging that analyzed human disc tissues and reported pain-related outcomes were included, and those on predominant radicular pain were excluded. The search returned 6012 studies. Most studies did not collect pain-related outcomes. Those that included pain assessment relied on self-report of pain intensity and disability. Six studies qualified for data extraction and synthesis. The main molecular mechanisms associated with DLBP were the expressions of nociceptive neuropeptides and cytokines, particularly TNF-αdue to its strong association with pain outcomes. Activation of NF-κB signaling pathway, alterations in adrenoceptor expressions, and increase in reactive oxygen species (ROS) were also associated with DLBP through regulation of pro-inflammatory factors and pain-related neuropeptides. Current evidence converges to TNF-α, NF-κB signaling, and ROS-induced pro-inflammation. Major weaknesses in the current literature are the focus on degeneration without pain phenotyping, and lack of association of molecular findings with pain outcomes. PERSPECTIVE: This scoping review identified TNF-α, NF-κB signaling, and ROS-induced pro-inflammation as relevant mechanisms of human discogenic low back pain. Major weaknesses in the current literature are the focus on degeneration without pain phenotyping, and lack of association of molecular findings with pain outcomes.

Intervertebral disc degeneration (IVDD) is intricately associated with various forms of programmed cell death (PCD). Identifying key PCD types and associated genes is essential for understanding the molecular mechanisms underlying IVDD and discovering potential therapeutic targets. This study aimed to elucidate core PCD types, related genes, and potential drug interactions in IVDD using comprehensive bioinformatic and experimental approaches. Using datasets GSE167199, GSE176205, GSE34095, GSE56081, and GSE70362, relevant gene expression and clinical data were analyzed. Differential expression gene (DEG) analysis identified upregulated genes linked to 15 PCD types. Gene Set Variation Analysis (GSVA) was employed to pinpoint key PCD types contributing to disc degeneration. Core genes were identified through machine learning techniques, while immune infiltration and single-cell analysis helped identify apoptosis-related cell types. Molecular docking, along with in vivo and in vitro experiments using a murine IVDD model, validated potential drug interactions. The results identified apoptosis, autophagy, ferroptosis, and necroptosis as key PCD types in IVDD. A gene module associated with apoptosis showed a strong correlation with the severity of disc degeneration, revealing 34 central genes in the gene network. Drug screening identified Glibenclamide as effectively interacting with PDCD6 and UBE2K. Subsequent in vitro and in vivo experiments demonstrated that Glibenclamide reduced apoptosis and delayed disc degeneration progression. This study provides a comprehensive bioinformatics analysis of PCD in IVDD, identifying four primary PCD types contributing to the disease's progression. The findings offer novel insights into the molecular pathology of disc degeneration and suggest promising therapeutic strategies for future treatment development.

Nucleus pulposus cells (NPC) are important for the development of intervertebral disc degeneration (IVDD). miR-4478 can aggravate IVDD, but whether it can aggravate IVDD by regulating ferroptosis in NPC remains unclear. The optimal level of ferroptosis activator RSL3 for eliciting ferroptosis in NPC was screened by Western blot and CCK-8 assay. The targeting relationship between miR-4478 and its potential target solute carrier family 7 member 11 (SLC7A11) was explored based on dual luciferase assay. On this basis, IVDD models were constructed. After over-expression or knockdown of miR-4478 or SLC7A11, CCK-8 and calcein-AM/PI assays were employed to evaluate cell damage. Flow cytometry, Western blot and Prussian blue staining were employed to evaluate oxidation and ferroptosis levels, and histopathological staining was applied to evaluate the intervertebral disc tissue injury degree. The optimal concentration of RSL3 was 1 μM. Under these conditions, miR-4478 or SLC7A11 can be effectively over-expressed or knocked down after transfection. Knockdown of miR-4478 can improve the survival rate of NPC, the level of Fe2+ ions, improve the pathological damage of intervertebral disc structure, reduce iron deposition in tissues, and significantly reduce expression of reactive oxygen species (ROS) and ferroptosis-related protein. The levels of antioxidant enzymes were significantly increased. When miR-4478 was over-expressed, the above phenomenon was reversed. On this basis, after SLC7A11 was over-expressed, the effect of miR-4478 up-regulation was weakened, and NPC ferroptosis was improved. miR-4478 can target SLC7A11 to promote NPC damage, peroxide accumulation and iron metabolism disorders, leading to ferroptosis, thereby inducing IVDD.

Pain and disability secondary to degenerative disc disease continue to burden the healthcare system, creating an urgent need for effective, disease-modifying therapies. Contemporary research has identified potential therapies that include protein-, cellular- and/or matrix-related approaches; however, none have yet achieved a meaningful clinical impact. The tissue-specific realities of the intervertebral disc create considerable therapeutic challenges due to the disc's location, compartmentalization, hypovascularization and delicate physiological environment. Furthermore, the imaging modalities currently used in practice are largely unable to accurately identify sources of pain ostensibly discogenic in origin. These obstacles are considerable; however, recent research has begun to shed light on possible breakthrough technologies. Such breakthroughs include revolutionary imaging to better identify tissue sources of pain. Furthermore, novel molecular therapies have been shown to be able to mediate the progression of degenerative disc disease in some large animal studies, and even provide some insight into suppressing the development of tissue sources of discogenic pain. These potential breakthrough technologies have yet to be translated for clinical use.

Notochordal cells (NCs) present in the nucleus pulposus (NP) of the developing human intervertebral disc (IVD) disappear during the first decade of life. This loss coincides with the onset of IVD degeneration, therefore these cells are hypothesized to be important in NP homeostasis. Putative NC-derived (CD24+) and progenitor (TIE2+/GD2+) cell sub-populations have previously been identified in the adult human NP, but their characteristics have yet to be compared. Here, we used CD24, TIE2 and GD2 to identify and then isolate discrete cell sub-populations to assess cell phenotype.

CD24, GD2 and TIE2 positivity was assessed in a cohort of human pediatric and adult NP samples across a range of ages and histological degeneration grades using immunohistochemistry and flow cytometry. FACS sorting was used to isolate different cell sub-populations (CD24+/GD2+; CD24+/GD2-; CD24-/GD2+; CD24-/GD2-). Cell phenotype was assessed using qPCR for known NC and NP markers as well as catabolic genes.

CD24+ and GD2+ cells were localized in all samples, irrespective of age or degeneration grade, while TIE2+ cell number was consistently very low. The same positivity trend was confirmed using flow cytometry. A small CD24+/GD2+ sub-population was present and maintained marker expression with time in culture. CD24+ subpopulations showed a significantly higher expression of NC markers than the CD24- subpopulations and unsorted samples, suggesting a healthier phenotype in the CD24+ cells. GD2 did not appear to influence gene expression.

This study provides a better understanding of different cell sub-populations present in the adult NP, with identification of CD24+/GD2+ cells that are maintained with aging and degeneration. Healthy, NC-like phenotypic profiles appeared reliant on CD24, rather than GD2. The study highlights the importance of studying discrete cell sub-populations, especially CD24+ NP cells to better understand their role in NP homeostasis.

The aim of this study was to investigate the relationship between serum adiponectin and leptin levels, which are cytokines released from fatty tissue, and pain, function and intervertebral disc degeneration (IVDD).

Between January 2018 and November 2019, a total of 85 patients (34 males, 51 females; mean age: 42.1±10.7 years; range, 18 to 62 years) who were diagnosed with IVDD and 84 healthy volunteers (34 males, 50 females; mean age: 41.9±10.7 years; range, 22 to 64 years) were included in this cross-sectional study. The Visual Analog Scale (VAS, 0-10 cm) and Oswestry Disability Index (ODI) scales were used in the patient group. Serum adiponectin and leptin levels were measured in all participants. The grading of IVDD was determined using the Pfirrmann Classification.

There was no significant difference in serum adiponectin (p=0.35) and leptin (p=0.19) levels between the patient group and the control group. No relationship was found between serum adiponectin and leptin levels and pain intensity (VAS), pain duration, and disability (ODI) in patients with low back pain. No relationship was found between the severity of IVDD as evidenced by magnetic resonance imaging (MRI) and adiponectin (p=0.18) and leptin (p=0.11) levels. There was a positive correlation between the severity of disc degeneration and body mass index (r=0.35, p=0.008) and waist circumference (r=0.34, p=0.01).

Serum adipokine levels were not associated with low back pain symptoms and IVDD severity as evidenced by MRI. These findings suggest that the effects of obesity on chronic low back pain and disc degeneration cannot be explained by systemic inflammatory effects alone.

Disc degeneration is a risk factor of pyogenic spondylitis. However, its degree in patients with pyogenic spondylitis is unknown. This study aimed to determine differences in disc degeneration between patients with pyogenic spondylitis and those with noninfectious lumbar spondylosis.

A total of 85 patients with lumbar pyogenic spondylitis (the infected group) and 156 with lumbar spondylosis who underwent posterior lumbar interbody fusion (the noninfected group) were retrospectively evaluated. Patients with a previous history of spinal fusion, tuberculous spondylitis, and multilevel infection and those receiving dialysis were excluded. Magnetic resonance imaging of the lumbar spine was conducted. Each disc at the L1/2-L5/S levels was graded. The total score of the four discs, excluding the affected disc, was used as the modified disc degenerative disease (DDD) score. Propensity score matching was performed using independent variables such as age, sex, diabetes mellitus, cancer, and steroid use. The modified DDD scores at all and each disc level were compared between the two matched groups.

After matching, 48 patients in the infected group and 88 in the noninfected group were finally included in the study. The mean modified DDD scores of the infected and noninfected groups were 7.63 and 5.40, respectively. The modified DDD scores at all and each disc level were higher in the infected group than in the noninfected group.

The incidence of disc degeneration at all and each disc level was higher in patients with pyogenic spondylitis than in those with noninfectious lumbar spondylosis.

Low back pain (LBP) is a highly prevalent condition that comprise a large portion of outpatient practice, challenging the diagnosis and treatment. However, the diagnostic tools are limited to clinical history, physical examination and imaging. Degenerative disc disease (DDD) is a significant cause of LBP, and emerging literature confirms the elevated levels of biomarkers in the discs. These biomarkers may serve as a tool for diagnosis, but may also be useful in predicting the treatment outcome. Here, we examine the expression of various cytokines on 1-year recovery from patients with LBP.

Patient-reported outcome (PRO) in terms of pain intensity (VAS), disability (ODI), and quality of life (Eq-5D) is collected from 44 patients at baseline and 12 months after surgery to study the influence of baseline TNF-α, IL-1β, and IL-6 mRNA expression in both annulus fibrosus (AF) and nucleus pulposus (NP).

Between baseline and follow-up, our cohort showed improvement in VAS back pain (p < 0.001), VAS leg pain (p < 0.001), ODI (p = 0.02), and Eq-5D (p = 0.01). Baseline levels of IL-1 β was positively correlated with VAS back pain scores in AF (p = 0.05) and NP (p = 0.01) at 1-year follow-up. TNF-α expression at baseline was also positively correlated to ODI scores (p = 0.01) at follow-up and inversely correlated to improvements in ODI score between baseline and follow-up, suggesting that high TNF-α expression at baseline is associated with poor outcomes from surgery.

The results from our study support that TNF-α expression at baseline can serve as a very important predictor of treatment response from lumbar fusion surgery.

Intervertebral disk degeneration (IVDD) may lead to an increase in extracellular matrix (ECM) stiffness, potentially contributing to the progression of the disease. Melatonin reportedly mitigates IVDD; however, its potential to attenuate elevated matrix stiffness-induced IVDD remains unexplored. Therefore, we aimed to investigate whether melatonin can alleviate the progression of IVDD triggered by increased matrix stiffness and elucidate its underlying mechanisms. Nucleus pulposus (NP) tissues were collected from patients, and ECM stiffness, reactive oxygen species (ROS) levels, apoptosis rates, and P65 expression in these tissues with varying Pfirrmann scores were determined. In vitro experiments were conducted to investigate the effects of melatonin on various pathophysiological mechanisms within the NP cells cultured on soft substrates with differing stiffness levels. Our findings revealed a positive correlation between ECM stiffness in human NP tissue and degree of IVDD. In addition, phosphorylation of P65 exhibited a strong association with matrix stiffness. Enhanced levels of ROS and cellular apoptosis were observed within degenerated intervertebral disks. In vitro experiments demonstrated that melatonin significantly inhibited catabolism and apoptosis induced by stiff matrices, along with elevated ROS levels. Furthermore, we observed that melatonin inhibited NP cell catabolism and apoptosis by reducing the melatonin receptors mediated activation of the PI3K/AKT and nuclear factor-kappa B (NF-κB) pathways. Also, we found that the reduction of ROS by melatonin can assist in inhibiting the activation of the NF-κB pathway. The outcomes of the in vivo experiments corroborated the results of the in vitro experiments, illustrating that melatonin treatment could alleviate the compression-induced upregulation of matrix stiffness in NP and IVDD. Collectively, melatonin can potentially alleviate high matrix stiffness-induced IVDD by reducing intracellular ROS levels and inhibiting the PI3K/AKT/NF-κB pathway.NEW & NOTEWORTHY Melatonin mitigates intervertebral disk degeneration (IVDD) induced by matrix stiffness through reactive oxygen species (ROS) reduction. Matrix stiffness is related to increased nucleus pulposus cell ROS, apoptosis, and degeneration. Melatonin inhibits PI3K/AKT/NF-κB pathways via melatonin receptors in a stiff matrix environment. In vivo, melatonin restores disk height and alleviates IVDD progression.

Intervertebral disc degeneration (IDD) is one of the most frequent causes of low back pain. No treatment is currently available to delay the progression of IDD. Conservative treatment or surgical interventions is only used to target the symptoms of IDD rather than treat the underlying cause. Currently, numerous potential therapeutic strategies are available, including molecular therapy, gene therapy, and cell therapy. However, the hostile environment of degenerated discs is a major problem that has hindered the clinical applicability of such approaches. In this regard, the design of drugs using alternative delivery systems (macro-, micro-, and nano-sized particles) may resolve this problem. These can protect and deliver biomolecules along with helping to improve the therapeutic effect of drugs via concentrating, protecting, and prolonging their presence in the degenerated disc. This review summarizes the research progress of diagnosis and the current options for treating IDD.

Intervertebral disc (IVD) function is achieved through integration of its two component regions: the nucleus pulposus (NP) and the annulus fibrosus (AF). The NP is soft (0.3-5 kPa), gelatinous and populated by spherical NP cells in a polysaccharide-rich extracellular matrix (ECM). The AF is much stiffer (∼100 kPa) and contains layers of elongated AF cells in an aligned, fibrous ECM. Degeneration of the disc is a common problem with age being a major risk factor. Progression of IVD degeneration leads to chronic pain and can result in permanent disability. The development of therapeutic solutions for IVD degeneration is impaired by a lack ofin vitromodels of the disc that are capable of replicating the fundamental structure and biology of the tissue. This study aims to investigate if a newly developed suspended hydrogel bioprinting system (termed SLAM) could be employed to fabricate IVD analogues with integrated structural and compositional features similar to native tissue. Bioprinted IVD analogues were fabricated to recapitulate structural, morphological and biological components present in the native tissue. The constructs replicated key structural components of native tissue with the presence of a central, polysaccharide-rich NP surrounded by organised, aligned collagen fibres in the AF. Cell tracking, actin and matrix staining demonstrated that embedded NP and AF cells exhibited morphologies and phenotypes analogous to what is observedin vivowith elongated, aligned AF cells and spherical NP cells that deposited HA into the surrounding environment. Critically, it was also observed that the NP and AF regions contained a defined cellular and material interface and segregated regions of the two cell types, thus mimicking the highly regulated structure of the IVD.

Chronic low back pain, affecting up to 58% of the population, often stems from intervertebral disc degeneration. Although magnetic resonance imaging (MRI) is commonly used for diagnostics, challenges arise in pinpointing pain sources due to frequent asymptomatic findings. Single-photon emission tomography (SPECT) integrated with computed tomography (CT) offers a promising approach, enhancing sensitivity and specificity.

In this retrospective study, spanning 2016 to 2022, SPECT/CT imaging was performed on 193 patients meeting specific criteria. We correlated SPECT/CT findings with lumbar MRI results, utilizing Pfirrmann and Rajasekaran classifications for disc degeneration and endplate damage assessment. Logistic regression analysis adjusted for age and sex evaluated associations.

Of 965 spinal levels assessed, SPECT/CT positivity strongly correlated with higher Pfirrmann grades and Rajasekaran endplate classifications. Notably, Modic changes (MCs) on MRI displayed a nonsignificant relationship with SPECT/CT positivity. Significant associations were observed in older patients with positive MCs, Pfirrmann grades, and Rajasekaran classifications.

This comprehensive study, the largest of its kind, establishes a significant link between SPECT/CT positivity and advanced lumbar degenerative changes. Higher Pfirrmann grades and increased Rajasekaran endplate damage demonstrated substantial correlations with SPECT/CT positivity. Notably, MCs did not exhibit such association. Our findings underscore the potential of SPECT/CT in identifying pain generators in degenerative spinal conditions, offering valuable insights for future interventions.

One of the frequent causes of low back pain is intervertebral disc degeneration (IDD), which is followed by discogenic pain. Some significant risk factors that have been linked to the onset and progression of IDD include age, mechanical imbalance, changes in nutrition and inflammation. According to recent studies, five types of animal models are established for producing IDD: the spontaneous models, the puncture models, the biomechanical models, the chemical models and the hybrid models. These models are crucial in studying and understanding IDD's natural history and identifying potential treatment targets for IDD. In our study, we'll talk about the technical aspects of these models, the time between model establishment and the apparition of observable degradation, and their potential in various research. Each animal model should be compared to the human natural IDD pathogenesis to guide future research efforts in this area. By improving knowledge and appropriate application of various animal models, we seek to raise awareness of this illness and further translational research.

Selecting the lowest instrumented vertebra (LIV) in fusion for adolescent idiopathic scoliosis is potentially the most nuanced decision a surgeon has to make. This article reviews the literature on the range-of-motion loss related to the LIV, ability to return to sports based on LIV, correlation between LIV and disk degeneration, and short-term and long-term clinical outcomes related to LIV.

Biomaterials, such as hydrogels, have an increasingly important role in the development of regenerative approaches for the intervertebral disc. Since animal models usually resist biomaterial injection due to high intradiscal pressure, preclinical testing of the biomechanical performance of biomaterials after implantation remains difficult. Papain reduces the intradiscal pressure, creates cavities within the disc, and allows for biomaterial injections. But papain digestion needs time, and cadaver experiments that are limited to 24 h for measuring range of motion (ROM) cannot not be combined with papain digestion just yet. In this study, we successfully demonstrate a new organ culture approach, facilitating papain digestion to create cavities in the disc and the testing of ROM, neutral zone (NZ), and disc height. Papain treatment increased the ROM by up to 109.5%, extended NZ by up to 210.9%, and decreased disc height by 1.96 ± 0.74 mm. A median volume of 0.73 mL hydrogel could be injected after papain treatment, and histology revealed a strong loss of proteoglycans in the remaining nucleus tissue. Papain has the same biomechanical effects as known from nucleotomies or herniations and thus creates a disc model to study such pathologies in vitro. This new model can now be used to test the performance of biomaterials.

Prospective cohort study.

Investigate load-induced effects in lumbar intervertebral discs (IVDs) and differences between low back pain (LBP) patients and controls.

T2-map values, obtained from quantitative MRI sequences, reflect IVD tissue composition and integrity. Feasibility studies with T2-mapping indicate different load-induced effects in entire IVDs and posterior IVD parts between LBP patients and controls. Larger studies are required to confirm these findings and increase the understanding of specific characteristics distinguishing IVD changes in LBP patients compared with controls.

Lumbar IVDs of 178 patients (mean age: 43.8 yr; range: 20-60 yr) with >3 months of LBP and 74 controls (mean age: 40.3 yr; range: 20-60 yr) were imaged with T2-map sequence in a 3T scanner in supine position without axial load, immediately followed by a repeated examination, using the same sequence, with axial load. On both examinations, mean T2-map values were obtained from entire IVDs and from central/posterior IVD parts on the three midsagittal slices in 855 patient IVDs and 366 control IVDs. Load-induced effect was compared with Fold-change ratio and adjusted for IVD-degeneration grade.

Loading induced an increase in T2-map values in both patients and controls. Excluding most extreme values, the ranges varied between -15% and +35% in patients and -11% and +36% in controls (first to 99th percentile). Compared with controls, the T2-map value increase in patients was 2% smaller in entire IVDs (Fold-change: 0.98, P =0.031), and for central and posterior IVD parts 3% (Fold-change: 0.98, P =0.005), respectively, 2% (Fold-change: 0.9, P =0.015) smaller.

This quantitative study confirmed diverse load-induced behaviors between LBP patients and controls, suggesting deviant biomechanical characteristics between IVDs in patients and controls not only attributed to the global grade of degeneration. These findings are an important step in the continuous work of identifying specific IVD phenotypes for LBP patients.

Level II.

Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of Sdc4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that Sdc4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in Sdc4 KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc.

Retrospective cohort study.

To identify whether thresholds exist beyond which operative duration or age increases risks for complications among patients ≥65 years undergoing elective spine surgery.

Elective inpatient spine procedures unrelated to infection/trauma/tumor diagnoses in patients <65 years recorded in the 2006-2019 American College of Surgeons National Surgical Quality Improvement database were identified. Univariate analyses was used to compare 30 day complication rates among 5 operative duration and age-stratified groups. To quantify the risk of prolonged operative duration on complications, multivariate analyses were performed controlling for confounders. A generalized linear model was used to assess the individual and combined effect strength of age and operative duration on complication rates.

Among 87,705 patients stratified by operative duration, 30 day complication rates rose nonlinearly as operative duration increased, with a sharp rise after 4.0-4.9 hours (28.3% at 4.0-4.9 hours, 51.7% at ≥5 hours, P < .001). Multivariate analysis found operative duration was independently associated with increased risk of overall complications (odds ratio 1.10→1.69, P < .001) and medical complications (odds ratio 1.19→1.98, P < .001). Although complication rates rose by age (all P < .001), age was not independently predictive of overall complications within any operative duration group on multivariate analysis. Operative duration had a greater effect (η2P = .067) than age (η2P = .003) on overall complication rates.

Increased operative duration was strongly associated with 30 day complication rates, particularly beyond a threshold of 5 hours. Furthermore, operative duration had a notably larger effect on overall complication rates than age.

Cadaveric intervertebral discs are often studied for a variety of research questions, and outcomes are interpreted in the in vivo context. Unfortunately, the cadaveric disc does not inherently represent the LIVE condition, such that the disc structure (geometry), composition (T2 relaxation time), and mechanical function (opening pressure, OP) measured in the cadaver do not necessarily represent the in vivo disc.

We conducted serial evaluations in the Yucatan minipig of disc geometry, T2 relaxation time, and OP to quantify the changes that occur with progressive dissection and used axial loading to restore the in vivo condition.

We found no difference in any parameter from LIVE to TORSO; thus, within 2 h of sacrifice, the TORSO disc can represent the LIVE condition. With serial dissection and sample preparation the disc height increased (SEGMENT height 18% higher than TORSO), OP decreased (POTTED was 67% lower than TORSO), and T2 time was unchanged. With axial loading, an imposed stress of 0.20-0.33 MPa returned the disc to in vivo, LIVE disc geometry and OP, although T2 time was decreased. There was a linear correlation between applied stress and OP, and this was conserved across multiple studies and species.

To restore the LIVE disc state in human studies or other animal models, we recommend measuring the OP/stress relationship and using this relationship to select the applied stress necessary to recover the in vivo condition.

The intervertebral disc is an important structure for load transfer through the spine. Its injury and degeneration have been linked to pain and spinal fractures. Disc injury and spine fractures are associated with high stresses; however, these stresses cannot be measured, necessitating the use of finite element (FE) models. These models should include the disc's complex structure, as changes in disc geometry have been linked to altered mechanical behavior. However, image-based models using disc-specific structures have yet to be established. This study describes a multiphasic FE modeling approach for noninvasive estimates of subject-specific intervertebral disc mechanical behavior based on medical imaging. The models (n = 22) were used to study the influence of disc geometry on the predicted global mechanical response (moments and forces), internal local disc stresses, and tractions at the interface between the disc and the bone. Disc geometry was found to have a strong influence on the predicted moments and forces on the disc (R2 = 0.69-0.93), while assumptions regarding the side curvature (bulge) of the disc had only a minor effect. Strong variability in the predicted internal disc stresses and tractions was observed between the models (mean absolute differences of 5.1%-27.7%). Disc height had a systematic influence on the internal disc stresses and tractions at the disc-to-bone interface. The influence of disc geometry on mechanics highlights the importance of disc-specific modeling to estimate disc injury risk, loading on the adjacent vertebral bodies, and the mechanical environment present in disc tissues.

Degenerated endplate appears with cheese-like morphology and sensory innervation, contributing to low back pain and subsequently inducing intervertebral disc degeneration in the aged population.1 However, the origin and development mechanism of the cheese-like morphology remain unclear. Here in this study, we report lumbar instability induced cartilage endplate remodeling is responsible for this pathological change. Transcriptome sequencing of the endplate chondrocytes under abnormal stress revealed that the Hippo signaling was key for this process. Activation of Hippo signaling or knockout of the key gene Yap1 in the cartilage endplate severed the cheese-like morphological change and disc degeneration after lumbar spine instability (LSI) surgery, while blocking the Hippo signaling reversed this process. Meanwhile, transcriptome sequencing data also showed osteoclast differentiation related gene set expression was up regulated in the endplate chondrocytes under abnormal mechanical stress, which was activated after the Hippo signaling. Among the discovered osteoclast differentiation gene set, CCL3 was found to be largely released from the chondrocytes under abnormal stress, which functioned to recruit and promote osteoclasts formation for cartilage endplate remodeling. Over-expression of Yap1 inhibited CCL3 transcription by blocking its promoter, which then reversed the endplate from remodeling to the cheese-like morphology. Finally, LSI-induced cartilage endplate remodeling was successfully rescued by local injection of an AAV5 wrapped Yap1 over-expression plasmid at the site. These findings suggest that the Hippo signaling induced osteoclast gene set activation in the cartilage endplate is a potential new target for the management of instability induced low back pain and lumbar degeneration.

The onset of locomotive syndrome (LS) precedes that of frailty. Therefore, the first step in extending healthy life expectancy is to implement measures against LS in young adults. The aim of this study was to investigate the prevalence of LS and its associated factors in young adults for early detection and prevention of LS.

The participants of this study comprised 413 university students specializing in health sciences (192 males and 221 females) with an average age of 19.1 ± 1.2 years. All participants voluntarily participated in the study and reported no serious health problems. The presence or absence of LS was evaluated using the stand-up test, two-step test, and the 25-question Geriatric Locomotive Function Scale. Additionally, musculoskeletal assessment (one-leg standing, squatting, shoulder elevation, and standing forward bend), body composition analysis (weight, body mass index, body fat mass, body fat percentage, skeletal muscle mass index (SMI), and phase angle), handgrip strength test, physical activity assessment, and nutritional assessment were conducted. Sex-stratified analyses were performed, comparing groups with and without LS. Factors associated with LS were explored using binomial logistic regression.

Of the 413 young adults studied, 86 individuals (20.8%) were found to have LS. When stratified by sex, LS was observed to have a considerably higher prevalence in females (55, 24.9%) than in males (31, 16.1%). In males, the notable differences between the groups with and without LS were observed in one-leg standing and phase angle, whereas in females, differences were identified in body fat mass, body fat percentage, SMI, musculoskeletal pain, and handgrip strength. Two types of binomial logistic regression analysis revealed that the inability to perform one-leg standing was associated with LS in males, while the presence of musculoskeletal pain and a high body fat percentage were identified as factors associated with LS in females.

One in five young adults were found to have LS in this study, underscoring the necessity for early intervention and LS health education. Furthermore, effective management of musculoskeletal pain is also crucial.