JOR Spine最新文献

This review documents the impact of the Osti ovine annular lesion model of intervertebral disc (IVD) degeneration on the elucidation of degenerative changes in the ovine IVD also seen in human IVD degeneration (IVDD). The degenerative pathology knowledge base generated by the ovine model over the last 35 years has provided invaluable insights into degenerative events occurring in the human IVD. Changes in para-discal structures as a consequence of IVDD, in vertebral bone adjacent to the lesion site, cartilaginous endplates and spinal motion segment facet joints, and in the longitudinal ligaments and paraspinal muscles also affect spinal stability and flexibility. All of these spinal structures are richly innervated, and disturbance of their normal architecture due to IVDD also contributes to the generation of low back pain. Like human IVDD, when the ovine IVD is mechanically destabilized by the introduction of a controlled annular lesion, release of proteases is elevated, degradation of structural ECM components occurs, leading to IVDD and biomechanical impairment. When space-filling aggrecan is degraded in the IVD, a drop in internal hydrostatic pressure occurs, and the IVD becomes susceptible to an ingrowth of blood vessels and mechanosensitive nociceptors resulting in enhanced generation of low back pain by the biomechanically incompetent IVD. The ovine model is thus very useful to evaluate compounds or procedures that slow IVDD and, in some cases, promote regenerative processes. The large size of the ovine IVD allows the use of inter-disciplinary longitudinal approaches in the analysis of progressive changes in the degenerate IVD of relevance to the human IVD.

Clinical Significance

The ovine annular lesion model of IVDD displays similar pathological features to those displayed by the degenerate human IVD, making it an appropriate model for the evaluation of IVD reparative procedures. Furthermore, the resident ovine IVD cell populations are similar to those seen in the human IVD, with a disappearance of notochordal cells occurring in adolescence. This is not the case in many other popular animal (murine, rat, porcine, lapine, and non-chondrodystrophic canine) models of IVDD. The persistence of notochordal cells into adulthood in these breeds questions how translatable findings generated in these models are to the human IVD. The ovine model is thus relevant to the development of strategies exploring novel strategies in IVD repair and the recovery of normal IVD structure and function. Mesenchymal stem cells have impressive IVD repair and recovery of structure and function properties, showing promise in the treatment of the degenerate human IVD.

Background

Intervertebral disc degeneration (IDD) is a widespread issue associated with chronic lumbar pain and disability. This study aimed to identify lactate metabolism-related genes in IDD and elucidate their mechanistic roles in disease progression.

Methods

IDD datasets were analyzed using R packages GEOquery, sva, and limma for data retrieval, batch correction, and normalization. Differential gene expression analysis identified significant genes between IDD and control groups, from which lactate metabolism-related differentially expressed genes (LMRDEGs) were derived. Relationships among the LMRDEGs were assessed using Spearman's correlation analysis, and functional enrichment was conducted using ClusterProfiler. Gene set enrichment analysis identified biological processes associated with IDD. Diagnostic models were assessed using receiver operating characteristic (ROC) curve. Immune cell infiltration and correlations with core genes were analyzed via the CIBERSORT algorithm. Regulatory networks were constructed, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to validate the expression of hub LMRDEGs in IDD.

Results

A total of 1325 differentially expressed genes were identified, yielding seven LMRDEGs: TGFβ2, GSR, MB, MMP2, SLC16A7, PER2, and STAT3, which are enriched in blood circulation regulation and hypoxic response, as well as pathways like AGE–RAGE signaling in diabetic complications. ROC analysis indicated potential hub genes (MMP2, MB, TGFβ2, and PER2), while immune infiltration analysis uncovered significant variations in immune cell distribution. RT-qPCR confirmed MMP2, MB, and SLC16A7 as molecular indicators reflecting lactate metabolism abnormalities in IDD.

Conclusion

This study clarifies how lactate metabolism contributes to IDD through molecular mechanisms and its interplay with immunological features, providing a theoretical basis for understanding the early pathogenesis of IDD.

Background

Intervertebral disc degeneration (IVDD) is a major cause of global disability that increases with age. IVD age may affect its injury susceptibility, yet few studies examine spine biomechanical changes with age, fewer address multiple injury types, and none investigate the interplay between age and injury.

Methods

An ex vivo mouse lumbar spine biomechanical study to determine the effects of age, injury, and their interaction. IVDs of 4, 12, and 24 months' mice were subjected to two injury types: Full disc puncture (DP) mimicking advanced IVDD and annulus fibrosus and endplate (AF + EP) injury simulating herniation with endplate junction failure. Spines were tested biomechanically, analyzed radiologically for IVD dimensions, and with FTIR and histology for biochemical content.

Results

Both age and injury significantly altered biomechanical properties of IVDs. Injury had a greater effect than age, and DP caused larger changes than AF + EP injury. Injury and age exhibited an interactive effect, resulting in more pronounced biomechanical dysfunction in middle-aged (12 months) and geriatric IVDs (24 months), likely due to age-related loss of proteoglycans and collagen denaturation shown with FTIR and histology.

Conclusions

We conclude that both age and injury independently and synergistically affect ex vivo biomechanical properties of mouse lumbar spine. The more severe biomechanical change in middle-aged and geriatric mouse lumbar spines suggests similar injuries may cause greater spinal dysfunction in individuals of comparable ages. These findings provide context for future in vivo studies investigating long-term effects of acute spine injuries.

Background

Condoliase is a treatment for lumbar disc herniation. This enzyme exerts its medicinal effects by digesting chondroitin sulfate (CS), which is abundant in the nucleus pulposus. However, the behavior of administered condoliase in the nucleus pulposus is not clear. Because the purpose of this study is to understand the mechanism of enzyme action, we evaluated the properties of condoliase in the nucleus pulposus.

Methods

The following were evaluated: (1) The diffusibility of fluorescein labeled condoliase injected into isolated porcine nucleus pulposus. (2) The time dependence of condoliase activity in porcine nucleus pulposus or CS solution. (3) The morphology of the enzyme-treated nucleus pulposus tissue was characterized using scanning electron microscopy.

Results

After injection into the nucleus pulposus, condoliase was difficult to diffuse spontaneously, and the rate of CS-disaccharides production was significantly increased up to a peak at 24 h and decreased thereafter. Not all of the CS in the nucleus pulposus was digested by condoliase. These results suggested that condoliase digested CS locally without causing its spontaneous diffusion within the nucleus pulposus. Moreover, condoliase did not digest the collagen fibers that form the supportive architecture of the nucleus pulposus.

Conclusions

We demonstrated that condoliase is retained in the nucleus pulposus and exerts its pharmacological effects by locally degrading CS without degrading collagen fibers. The results obtained in this study can be useful in predicting the mechanism of the pharmacological action of condoliase in clinical practice.

Background

Accurate computation of radiological parameters related to spinal alignment is clinically crucial for diagnosing and managing conditions, such as adolescent idiopathic scoliosis and adult spinal deformities. Key parameters, including sacral slope, pelvic tilt, pelvic incidence, and lumbar lordosis, are required to assess lumbosacral alignment. Artificial Intelligence (AI) has demonstrated strong potential in automating these assessments, reducing clinician workload and improving consistency. However, AI models require large, diverse, high-quality datasets to perform reliably across different clinical settings. Privacy concerns and data ownership issues often hinder data sharing, limiting the creation of centralized datasets.

Methods

In this study, we demonstrate that federated learning (FL) enables the training of deep learning models across four hospitals without compromising patient privacy. In particular, we compared FL against a centralized approach, where data from all the hospitals are pooled together and a model is trained on them, and a local approach consisting of training individual models exclusively on data from each respective hospital, resulting in distinct hospital-specific models.

Results

FL achieved performance comparable to centralized training (errors ~5°), where data is pooled, and consistently outperformed models trained on data from individual hospitals, both in internal (~8°) and external (~10°) testing.

Conclusion

This work highlights FL as a viable solution for collaborative AI development in spinal imaging, facilitating the use of diverse, multi-institutional data while circumventing privacy barriers and complex data-sharing agreements. Additionally, FL demonstrates particular benefits for smaller hospitals, enabling them to achieve superior model performance by effectively leveraging data from hospitals with larger datasets.

Background

Intervertebral disc (IVD) degeneration (IDD) contributes to global disability and involves incompletely understood molecular processes. Recent advances in omics technologies help to unravel the complex biology of IDD and develop novel therapies.

Methods

This narrative review explores how omics approaches—particularly RNA sequencing—have advanced our understanding of IVD biology and how these findings contribute to leveraging the intrinsic regenerative potential of the IVD, with a specific focus on nucleus pulposus progenitor cells (NPPCs). Relevant literature addressing transcriptomic, genomic, proteomic, metabolomic, and epigenetic data, as well as emerging mult-iomics approaches, was summarized.

Results

Single-omics studies have provided insight into cellular heterogeneity, gene expression changes, genetic susceptibility loci, proteomic changes, metabolic alterations, and epigenetic regulation. Further, they have highlighted key pathways associated with extracellular matrix remodeling, inflammation, and progenitor cell depletion in IDD. Inconsistencies between TEK (the gene encoding TIE2) mRNA levels and TIE2 (Angiopoietin-1 receptor) protein expression, discussed in this review, emphasize the limitations of single-omics analyses and underscore the need for multi-omics studies, which are currently underrepresented in the field. By enabling a system-level understanding, multi-omics offers a comprehensive framework to decode the networks driving IDD and identify biomarkers and therapeutic targets to restore disc function and reduce pain.

Conclusions

Although NPPCs hold promise for IVD regeneration, translational challenges such as cell survival and efficacy persist. Omics-informed insights into the IVD microenvironment may support the development of combinatorial strategies, including co-delivery of modulators to enhance NPPC survival and the effectiveness of therapies.

Background

Stability 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.

Methods

Whole 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.

Results

Static 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: r_s = −0.63, G2: r_s = −0.71).

Conclusions

There 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.

Background

The nucleus pulposus (NP) in the intervertebral disc (IVD) is the first structure to exhibit degenerative changes during IVD degeneration (IDD). Currently, micro-computed tomography (micro-CT) imaging of the NP is a limiting factor in detecting IDD at an early stage. While contrast-enhanced micro-CT has been investigated, an effective contrast agent for IVD has not been identified. This study investigates potassium iodide (KI) as an effective contrast agent for micro-CT-based IVD visualization across multiple animal models to study IDD.

Methods

We collected tails and spines from mice, rats, rabbits, sheep, and stained them with KI followed by micro-CT imaging. For IDD, we performed caudal annular needle puncture surgery (NPS) in age and sex-matched mice (n = 10) and stained with KI for imaging with micro-CT. For the aging model, we compared IVDs from old to young mice.

Results

Compared to unstained IVDs, KI effectively stained and visualized the 3D structure of the NP, exhibiting X-ray attenuation properties comparable to bone. KI contrast staining enabled accurate and reproducible quantification of IVD height and NP volume. The cross-sectional micro-CT images of NPS IVDs were indistinguishable from the histological findings of the same sample and showed similar degenerative changes in the NP. We also found that KI staining is reversible, and the tissue remains compatible with downstream histological processing and immunostaining. Notably, KI successfully stained the NP in decalcified tissue, offering an advantage for NP analysis by removing bone background in micro-CT scans. Additionally, we estimated that up to 15 sagittal sections, each 5 μm thick with 75 μm spacing, would be needed to fully assess IVD degeneration in mice.

Conclusions

This study demonstrated that KI can be used to positively stain NP in the intact tail or spine and provide qualitative and quantitative data without any adverse effects on the immune/histological processing of the samples.