Intervertebral disc degeneration (IDD) imposes substantial economic and healthcare burdens, yet its mechanisms remain incompletely understood and effective pharmacological treatments are lacking. This study aimed to elucidate key factors driving IDD progression, specifically investigating lysosomal dysfunction and lysosomal membrane permeability (LMP) in human nucleus pulposus (NP) cells, and to identify potential therapeutic targets. We employed an integrative multiomics approach (transcriptomics, proteomics, metabonomics, and lipomics) combined with functional validation. Luciferase reporter assays investigated transcriptional regulation. The role of PLA2G15 in palmitic acid (PA)-induced lysosomal dysfunction was assessed invitro and invivo. Integrated analysis identified lysosomal dysfunction and increased LMP as the key molecular features in human NP cells during IDD. PLA2G15 expression was significantly upregulated under PA overload conditions. PLA2G15-mediated PA-induced alterations in lysosomal membrane lipid composition and subsequent LMP by hydrolyzing lysosomal membrane phospholipids. The transcription factor C/EBPα directly bound the PLA2G15 promoter, regulating its transcription under PA overload conditions. Crucially, invivo inhibition of PLA2G15 mitigated PA-induced LMP by restoring normal lysosomal membrane lipid composition, thereby attenuating IDD progression. This study demonstrates that PLA2G15 inhibition mitigates PA-induced IDD progression by preventing lysosomal dysfunction and LMP. Our findings reveal the significance of lysosomal membrane lipid composition alterations in human NP cells and identify PLA2G15 as a potential therapeutic target for IDD treatment.

ABSTRACT Background Intervertebral disc degeneration (IDD) involves complex inflammatory and oxidative stress pathways within nucleus pulposus (NP) cells, leading to catabolic remodeling and loss of disc function. Traditional single‐analyte assays capture only a small part of these coordinated networks. Leveraging the multiplex capability of Luminex, this study uses targeted immunoassays to simultaneously quantify 73 extracellular proteins and 21 intracellular signaling molecules in primary human NP cells stimulated with IL‐1β, Pam2CSK4, or hydrogen peroxide, enabling comparison of shared and stimulus‐specific responses. Methods Human NP cells isolated from patients undergoing spine surgery were plated in monolayer or encapsulated in alginate and stimulated for 1 week with either: 100 pg/mL or 1 ng/mL Interleukin (IL)‐1β, or the Toll‐Like Receptor (TLR) 2/6 agonist Pam2CSK4 at 100 ng/mL, or 50 μM Hydrogen Peroxide (H 2 O 2 ). The role of the stimuli was investigated using mRNA expression analysis and Luminex multiplex immunoassays. Results TLR2/6 agonist and IL‐1β stimulation significantly up‐regulated IL‐6, IL‐8, IL‐1β, and MMP‐3 mRNA expression, while H 2 O 2 failed to induce any changes. The secretome showed that IL‐8, IL‐6, MMP‐7, Intercellular Adhesion Molecule 1 (ICAM‐1), and Growth‐Regulated Oncogene‐α (GRO‐α) were the most responsive proteins across treatments and culture conditions. Intracellularly, phosphorylation of Jun Proto‐Oncogene AP‐1 Transcription Factor Subunit (cJUN), Nuclear Factor Kappa B (NF‐kB), and Inhibitor of Nuclear Factor Kappa B Alpha (IKBA) was observed following IL‐1β and Pam2CSK4 stimulation. Conclusions Across inflammatory and innate immune activation and under both monolayer and 3D culture, a concise five‐marker panel, namely IL‐6, IL‐8, GRO‐α (CXCL‐1), ICAM‐1, and MMP‐7 captured NP cell responses with high consistency, while phosphoproteomics demonstrated convergence on NF‐κB/AP‐1 signaling. These markers are well established within disc‐degeneration pathways (inflammation, innate immunity, and ECM remodeling); thus, they offer practical, reusable readouts for comparative pharmacology, assay qualification, and early biomarker development in translational spine research.

Traumatic cervical spinal cord injury (TCSCI) often leads to significant patient paralysis. Current clinical diagnosis relies heavily on empirical interpretation of magnetic resonance imaging (MRI) and the American Spinal Injury Association Impairment Scale (AIS) grade, lacking robust quantitative markers to precisely reflect injury severity. This study aimed to build an artificial intelligence (AI) pipeline for AIS grade prediction based on radiomic features extracted from manually defined regions. We included 189 patients with TCSCI who underwent MRI within 48 h post-injury. MRI images from 130 patients were used for developing an AI model encompassing image segmentation. Radiomic features were extracted from manually delineated volumes of interest (VOIs). T2-weighted imaging (T2WI) sagittal images were randomly divided into training (n = 104), validation (n = 13), and test (n = 13) sets for segmentation. A total of 183 patients (excluding AIS E) were included in the AIS grade prediction task. Model performance was evaluated using mean dice similarity coefficient (mDICE), mean intersection over union (mIOU), mean specificity, and mean sensitivity. An optimized UCTransnet network, leveraging a Transformer architecture for formal training, combined with a U-Net++ network for pretraining, achieved promising results in segmenting the spinal cord injury site on T2WI sagittal images (mDICE: 0.777 ± 0.021, mIOU: 0.646 ± 0.025, mean specificity: 0.998 ± 0.001, mean sensitivity: 0.895 ± 0.015). Subsequently, an ensemble model (we named Em-En) constructed using selected radiomic features from the manual VOIs demonstrated superior performance for predicting AIS grades in terms of sensitivity, specificity, accuracy, and clinical decision-making benefit compared to other tested models. This study presents an AI-assisted pipeline for predicting the severity of TCSCI. The developed resources provide a theoretical foundation for the clinical application of AI-assisted diagnostic methods, potentially lowering the interpretation barrier for MRI and offering clinicians preliminary quantitative indicators of injury severity. The source code is publicly available.

Biomaterials play an increasing role in intervertebral disc regeneration and require preclinical testing, typically performed using organ culture and invitro models. Native human discs are limited, and animal models often fail to mimic human disc degeneration. Thus, enzymes like chondroitinase ABC (chABC) and papain are used to simulate degenerative tissue changes and enable biomaterial injection. In previous work, we characterized the biomechanical and morphological effects of papain, which forms cavities in the disc. In contrast, chABC does not form cavities, but its biomechanical effects remain insufficiently characterized. This study aims to evaluate the macroscopic and biomechanical effects of chABC-specifically, range of motion (ROM), neutral zone (NZ), and disc height-in a bovine organ culture model, and assess the distribution of an injected hydrogel, comparing the results to published papain data. Four groups of fresh bovine tail segments were prepared (n ≥ 10) and three received injections of chABC, papain, or PBS, followed by 7 days of culture. For papain and PBS, published data were supplemented with new specimens. Complex simulated physiological loading was applied to diminish disc swelling. The maximum volume of a serum-albumin-hydrogel was injected into all four groups. ROM, NZ, and disc height were measured before and after enzyme treatment, loading, and injection. Post-injection, microCT scans visualized material distribution within the discs. ChABC increased ROM by up to 92.1%, NZ by up to 79.4%, and decreased disc height by 2.1 mm. Hydrogel injection decreased ROM and NZ but increased disc height in all groups while enzyme treatments allowed more hydrogel injection (0.6 mL for chABC). Exemplary scans showed cloud-like hydrogel spread for chABC and a round-shaped degradation defect for papain. The findings indicate that chABC better simulates disc degeneration, whereas papain better models nucleotomies, and both enzymes preserve annulus integrity-providing valuable models for biomechanical testing.

ABSTRACTBackgroundLow back pain (LBP) is a leading cause of disability, often progressing to chronic low back pain (CLBP), which often involves facet joint degeneration. The Weishaupt grading system is widely used to evaluate facet joint degeneration, but precise, quantitative methods for early diagnosis are lacking. This study aims to develop a predictive model for facet joint degeneration using magnetic resonance imaging (MRI)‐derived curve fitting and some radiographic parameters, enhancing early, quantitative assessment and providing more accurate analysis for effective treatment planning.MethodsThis study included 48 patients (161 joints), aged 20–80 years. Imaging parameters such as intervertebral space height (ISH), lumbar range of motion (ROM‐L), intervertebral disc degeneration, facet joint degeneration, facet joint cross‐sectional area (FJCSA), vertebral bone quality (VBQ) scores, subcutaneous fat tissue thickness (SFTT) and grayscale values of lumbar facet joint were analyzed. Statistical correlations were evaluated using spearman rank correlation and ordinal logistic regression. Curve fitting was performed to analyze and model the grayscale value changes in lumbar facet joints.ResultsCorrelation analysis revealed positive correlations between facet joint degeneration and intervertebral disc degeneration, FJCSA and SFTT, while negative correlations were observed with ISH and ROM‐L. Ordinal logistic regression identified ROM‐L and FJCSA as significant factors influencing degeneration. The locally estimated scatterplot smoothing (LOESS) curve fitting method of grayscale value for facet joint degeneration provided a more accurate predictive model, refining the joint degeneration grading system for improved quantitative assessment.ConclusionThe study identified some radiographic factors, including ISH, FJCSA, ROM‐L, SFTT and intervertebral disc degeneration, associated with facet joint degeneration. This study refined the joint degeneration grading system using LOESS curve fitting, providing a more quantitative approach for evaluating facet joint degeneration. This grading system offered greater precision and reliability in clinical assessments, supporting better diagnostic accuracy for patients with facet joint‐related CLBP.

ABSTRACTIntroductionPedicle screw fixation in osteoporotic spines remains challenging. Bazedoxifene (BZA) and denosumab (Dmab) are widely used agents for osteoporosis, but their comparative effects on spinal instrumentation are not well understood. This study aimed to evaluate the effects of BZA and Dmab on biomechanical parameters of spinal instrumentation using finite element analysis (FEA).MethodsIn this prospective, open‐label study, postmenopausal women with primary osteoporosis were assigned to receive either BZA (daily oral, 20 mg) or Dmab (subcutaneous, 60 mg every 6 months) for 12 months. FEA models of the L4 vertebra were generated from CT scans using a calibration phantom (Mindways, Austin, TX, USA). Vertebral compression force was evaluated to represent overall vertebral strength. Pedicle screw fixation strength was assessed under axial (pullout strength) and non‐axial directional forces (cranial, caudal, lateral, medial). Inverse probability of treatment weighting (IPTW) and multivariable regression were used to balance baseline differences and compare biomechanical outcomes between groups.ResultsThirty patients were enrolled (15 per group); the final analysis included 12 in the BZA group and 13 in the Dmab group. Compared to BZA, Dmab significantly improved compression strength (adjusted mean difference: 8.1% [95% CI, 0.9–15.3], p = 0.030) and pullout strength (15.8% [95% CI, 6.2–25.4], p = 0.003). Directional FEA revealed greater resistance to cranial (17.4% [95% CI, 4.9–30.0], p = 0.009) and lateral (10.8% [95% CI, 0.9–20.8], p = 0.035) loading with Dmab, while no significant difference was observed in caudal‐ and medial‐directed force.ConclusionFinite element modeling suggested that Dmab enhanced pedicle screw fixation more effectively than BZA, particularly against axial and cranial/lateral‐directed forces. These biomechanical differences underscore the potential advantage of Dmab in preoperative osteoporosis management to improve pedicle screw stability.

ABSTRACTBackgroundAdolescent idiopathic scoliosis (AIS) describes an asymmetrical formation of the spine that develops rapidly during adolescence. It is well known that the forces applied to bones, such as from paraspinal muscles, are substantial moderators of growth and adaptation. Despite the intimate relationship between the paraspinal muscles and the spine, very little is known about these muscles, particularly during adolescence when there is the greatest risk of the development and progression of AIS. Here, we aimed to quantify paraspinal muscle volume, intramuscular fat, and fat‐free muscle asymmetry in female adolescents with AIS and a healthy adolescent control cohort.MethodsTwenty‐nine female adolescents with primary‐right‐thoracic scoliosis (range: Cobb angle mean [SD]: 39 [15]°; age mean [SD]: 13.8 [1.5] years) and 19 age‐matched female control participants without scoliosis (age mean [SD]: 13.1 [1.8] years). Participants underwent T1‐weighted and coronal mDixon magnetic resonance image scans. An Asymmetryindex of muscle volume, intramuscular‐fat, and fat‐free muscle were determined for five paraspinal muscles across 11 vertebral levels (T4‐L4/5) (Asymmetryindex = Ln [right‐side/left‐side]).ResultsAIS participants have greater asymmetry in paraspinal muscle volume, intramuscular fat, and fat‐free muscle compared to controls (p < 0.05, linear mixed effects analysis). Across numerous vertebral levels adjacent to the primary thoracic curve apex in AIS, multifidus volume and multifidus, longissimus, and spinalis intramuscular fat asymmetries were greater in AIS (13%–57% larger on the left side) than in the control group (1%–20%), p < 0.05. In the lumbar spine, multifidus volume and multifidus, longissimus, and psoas intramuscular fat were greater on the right side of the lumbar curve in AIS (18%–54%) than in controls (1%–14%), p < 0.05. Scoliosis curve severity was moderately correlated with asymmetries in muscle volume, intramuscular fat, and fat‐free muscle (range: R = 0.40–0.64, p < 0.05).ConclusionsThese findings provide evidence that asymmetries in paraspinal muscle size and composition exist along the length of the scoliotic spine. The asymmetries are associated with curve severity; therefore, supporting the need to further consider muscle in the pathogenesis of AIS.

ABSTRACTBackgroundStability of the spine and intervertebral disc (IVD) integrity is enabled by the highly organized fibrocartilaginous annulus fibrosus (AF). The shear properties of the AF are important in maintaining IVD integrity. AF shear mechanics in degenerative disc (DD) remain underexplored, especially in comparing minimally degenerative (non‐DD) and symptomatic DD individuals. This study measured tissue mechanical properties (AF simple shear modulus and dynamic shear properties) and examined structure (with optical coherence tomography (OCT)) in surgical DD and non‐DD control individuals.MethodsWhole AF tissue samples were collected from non‐DD donors (N = 13) and DD surgical individuals (N = 30). Two anterior outer AF (OAF) 5 mm cubes were sectioned from each sample and subjected to shear in two orientations, radial (coronal plane, G1) and circumferential (sagittal plane, G2). Tissues underwent static shear and dynamic shear protocols to a maximum of 10% shear strain. Following mechanical tests, average lamellar thickness was assessed using OCT.ResultsStatic shear moduli were significantly reduced for DD tissue compared to non‐DD in both the radial (G1) (non‐DD: 83.0 ± 41.3 kPa, DD: 24.1 ± 23.7 kPa) and the circumferential (G2) (non‐DD: 226.2 ± 81.9 kPa, DD: 54.0 ± 40.2 kPa) orientations (p < 0.05). Further dynamic mechanical alterations were detected in hysteresis, phase shift, and dynamic modulus. Shear moduli correlated negatively with lamellar thickness (G1: rs = −0.63, G2: rs = −0.71).ConclusionsThere were significant alterations in AF shear moduli and dynamic properties in DD individuals when compared to non‐DD controls. Structural correlations highlight the role of the highly organized AF lamellar structure on shear modulus values. These findings suggest that altered AF mechanics may contribute to DD pathology and associated low back pain, warranting further investigation into structural and functional AF changes in symptomatic individuals.

ABSTRACTBackgroundScrew loosening is a frequently reported complication following pedicle screw fixation, resulting in various adverse outcomes. The primary trigger for screw loosening is biomechanical deterioration. Iatrogenic injury to the pedicle is a commonly observed scenario. This alteration can lead to an increased risk of pedicle screw loosening. Bilateral pedicle screws distribute load during the patient's daily activities and can be regarded as an integrated structure from a biomechanical perspective. Consequently, biomechanical interactions are prevalent between the two sides of the pedicle screws. This study aimed to determine whether unilateral pedicle injury influences contralateral screw loosening by deteriorating the local biomechanical environment.MethodsThe numerical model of the L5 vertebral body, developed in our previous studies, was employed in this investigation. Bilateral pedicle screws were inserted following the standard trajectory. Simulations of both half and complete ventral and dorsal side pedicle injuries were performed on the right‐side pedicle. Stress and strain values of the screw trajectory, along with screw displacement values on the contralateral side, were recorded to assess the potential risk of screw loosening.ResultsCompared to the model without pedicle injury, models with pedicle injuries exhibited higher interfacial stress and strain, as well as greater screw displacement. This effect was particularly pronounced when the pedicle on the side of torque restriction (e.g., caudal side pedicle injury under the flexion loading condition) was considered. Furthermore, unilateral iatrogenic injury to the pedicle can trigger multi‐degree‐of‐freedom coupled motion under a single‐direction torque.ConclusionsSingle‐side iatrogenic pedicle injury can lead to multi‐degree‐of‐freedom coupled motion of the screw‐fixed vertebral body, and biomechanical deterioration of the contralateral screw trajectory, thereby increasing the risk of contralateral pedicle screw loosening.