Association between vertebral endplate defects and patient-reported symptoms: an immunohistochemical study investigating the COX-2/PGE-2/EP-4 axis.

BACKGROUND CONTEXT: Vertebral endplate defects are often implicated in degenerative disc disorders, yet their connection to patient-reported symptoms remains unclear. COX-2 and PGE-2 are known for their roles in inflammation and pain, with EP-4 receptor involvement in pain signaling. Examining their expression in vertebral endplate tissues may provide insights into pathomechanism of low back pain. PURPOSE: To investigate the association between endplate defects and patient-reported symptoms and to further clarify the role of the COX-2/PGE-2/EP-4 axis in the pathogenesis of chronic low back pain. STUDY DESIGN/SETTING: Retrospective study. PATIENT SAMPLE: A total of 71 patients who had undergone single-level L4/5 or L5/S1 modified laminectomy decompression preserving proximal upper laminae and transforaminal lumbar interbody fusion surgery were included in this study, including 18 patients diagnosed with lumbar disc herniation, 19 with lumbar disc herniation accompanied by degenerative lumbar spinal stenosis, and 34 with degenerative spondylolisthesis. OUTCOME MEASURES: Demographic data, Pfirrmann grade, Modic changes, endplate defect score, visual analog scale (VAS) for back and leg pain, and Oswestry Disability Index (ODI) before surgery, 3-month and 6-month follow-up, and the percentage of immune-positive cells (COX-2, PGE-2, and EP-4) in endplate tissue sections. METHODS: Patients were divided into defect and non-defect groups according to endplate morphology on lumbar MR. All intraoperative endplate specimens were immediately fixed in 10% formaldehyde, and then embedded in paraffin 3 days later for tissue sections. The outcome measures were compared between the defect group and non-defect group. Data were analyzed using independent t-tests and χ² tests. Pearson's rank correlation test was used to assess correlations between patient-reported symptoms and the percentage of immune-positive cells in the groups. Multivariable logistic regression models using the forward stepwise likelihood ratio method were used to identify the factors that were independently associated with endplate defects. RESULTS: The age of Defect group was significantly higher than that of non-defect group (52.5±7.7 vs. 57.2±9.1. p=.024). There were no significant differences in gender, diagnosis, BMI, comorbidities, or surgical level between the two groups. Modic changes (Type Ⅱ/Type Ⅲ) were more common in patients of Defect group than non-defect group (38.5% vs. 11.1%, p<.001), and so was disc degeneration (Pfirrmann grade Ⅳ/Ⅴ) (69.2% vs. 33.3%, p<.001). Defect group had significantly higher VAS-Back (6.5±2.0 vs. 4.9±1.6, p<.001) and ODI scores (62.9±10.7 vs. 45.2±14.8, p<.001) than non-defect group, while there was no significant differences between the two groups during the 3 and 6-month follow-up after surgery. Histologically, Defect group was characterized by upregulation of COX-2, PGE-2, and EP-4 in endplate tissue sections. Both in defect and non-defect groups, VAS-Back showed moderate positive correlations with the expressions of COX-2 (r=0.643; r=0.558, p both<0.001), PGE-2 (r=0.611; r=0.640, p both<.001), and EP-4 (r=0.643; r=0.563, p both<.001). Multivariate regression analyses reveled that percentage of COX-2-positive cells was associated with endplate defects (OR=1.509, 95%CI [1.048-2.171], p=0.027), as well as percentage of PGE-2-positive (OR=1.291, 95%CI [1.106-1.508], p=.001) and EP-4-positive cells (OR=1.284, 95%CI [1.048∼2.171], p=.003). CONCLUSIONS: Patients with endplate defects had worse quality of life, more severe disc degeneration and Modic changes, and up-regulated COX-2/PGE-2/EP-4 axis expression in cartilage endplates in patients with defected endplates. Inflammatory factors may significantly contribute to the onset and progression of chronic low back pain in patients with endplate defects, consequently impacting patient-reported symptoms.

Optimal timing of starting growing rod treatment for early-onset scoliosis.

BACKGROUND CONTEXT: Growing rod (GR) systems require periodical surgical intervention and may cause associated complications, as well as worsened sagittal plane deformity. Generally, the risk of complications decreases with an increment in age at the time of the index surgery with GR construct placement. However, the optimal timing to begin GR treatment has not reached a consensus yet. PURPOSE: This study was performed to investigate the effect of age at the index GR surgery on the complication rates and formulate clinical guidelines for the optimal timing to begin GR treatment for EOS patients. STUDY DESIGN: Kaplan-Meier analysis was used to determine complication occurrence as a function of the age at the index surgery and to determine the survival rates for the procedures. The receiver operator characteristic (ROC) curve was used to determine optimal cut-off values for the optimal timing of index surgery based on whether complications occurred or not. PATIENT SAMPLE: 54 patients who met the criteria were enrolled in this study. OUTCOME MEASURES: The following spinal parameters were measured: major coronal Cobb angle, global kyphosis (GK), and coronal balance (CB). CB was defined as the horizontal distance from the C7 plumb line to the center sacral vertical line. METHODS: All patients had completed GR treatment and had a minimum 1-year follow-up duration after the final surgical intervention. Patient data were collected as follows: age at the index surgery, gender, diagnosis, type of GR construct, and the number of lengthening procedures. The standing full-spine radiographs were obtained before and after the index surgery, before and after each lengthening procedure, before and after the final surgical intervention, and at the latest follow-up. Complications were categorized as implant, alignment, and general. RESULTS: Kaplan-Meier analysis of complications demonstrated a declining trend in complication rates with increasing age at the index surgery. The absence of perioperative complications was targeted, we constructed the ROC curve and the cut-off value was 71.0 months. Age at the index surgery was therefore categorized into two groups: younger-age group (≤ 71.0 months) and advanced-age group (> 71.0 months). There was a higher complication rate for the younger-age group than versus the advanced-age group (61.5% vs 22.0%, p=.011). PJK as a major alignment-related complication, was more frequent in the younger-age group than in the advanced-age group (30.8% vs 4.9%, p=.025). But the advanced-age group exhibited significantly more severe deformities before GR surgery compared to the younger-age group. CONCLUSIONS: This study shows that the elevated risk of complications observed in the younger-age group, which can be attributed to the younger age at the index surgery and the increased number of lengthening procedures during treatment. We suggest deferring the initiation of GR treatment until after the age of six years for EOS patients. We hope it will serve as a basis for GR technique in the treatment of EOS, with the ultimate goal of enhancing treatment outcomes for this challenging disorder.

Utility of MRI-based vertebral bone quality scores and CT-based Hounsfield unit values in vertebral bone mineral density assessment for patients with diffuse idiopathic skeletal hyperostosis.

This study investigated bone mineral density assessment for patients with DISH. DXA-based T-scores overestimated bone quality, while MRI-based VBQ scores and CT-based HU values provided accurate assessments, particularly for advanced degenerative cases. This enhances accurate evaluation of BMD, crucial for clinical decision-making. PURPOSE: To investigate the diagnostic effectiveness of DXA, MRI, and CT in assessing bone mineral density (BMD) for diffuse idiopathic skeletal hyperostosis (DISH) patients. METHODS: Retrospective analysis of 105 DISH patients and 116 age-matched controls with lumbar spinal stenosis was conducted. BMD was evaluated using DXA-based T-scores, MRI-based vertebral bone quality (VBQ) scores, and CT-based Hounsfield unit (HU) values. Patients were categorized into three BMD subgroups. Lumbar osteophyte categories were determined by Mata score. Demographics, clinical data, T-scores, VBQ scores, and HU values were collected. Receiver operating characteristic (ROC) analysis identified VBQ and HU thresholds for diagnosing normal BMD using DXA in controls. Correlations between VBQ, HU, and lumbar T-score were analyzed. RESULTS: Age, gender, and BMI showed no significant differences between DISH and control groups. DISH patients had higher T-score (L1-4), the lowest T-score, and Mata scores. VBQ and HU did not significantly differ between groups. In controls, VBQ and HU effectively diagnosed normal BMD (AUC = 0.857 and 0.910, respectively) with cutoffs of 3.0 for VBQ and 104.3 for HU. DISH had higher normal BMD prevalence using T-scores (69.5% vs. 58.6%, P < 0.05), but no significant differences using VBQ (57.1% vs. 56.2%, P > 0.05) and HU (58.1% vs. 57.8%, P > 0.05). Correlations revealed moderate correlations between HU and T-scores (L1-4) in DISH (r = 0.642, P < 0.001) and strong in controls (r = 0.846, P < 0.001). Moderate negative correlations were observed between VBQ and T-scores (L1-4) in DISH (r = - 0.450, P < 0.001) and strong in controls (r = - 0.813, P < 0.001). CONCLUSION: DXA-based T-scores may overestimate BMD in DISH. VBQ scores and HU values could effectively complement BMD assessment, particularly in DISH patients or those with advanced lumbar degeneration.

Not All Osteophytes Are Located on the Right Side of the Vertebrae in Diffuse Idiopathic Skeletal Hyperostosis: A Quantitative Analysis in Relation to the Position of Aorta.

OBJECTIVE: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by osteophytes in the anterior vertebrae, and the presence of aorta may have an impact on their formation. However, the anatomical positional relationship between the aorta and osteophytes in patients with DISH remains controversial. This study aimed to evaluate the position of osteophytes in relation to aorta in DISH, and the influence of aortic pulsation on the formation of osteophytes from the perspective of morphology. METHODS: We conducted a retrospective review of 101 patients diagnosed with DISH and symptomatic lumbar spinal stenosis between June 2018 and December 2021. A total of 637 segments with heterotopic ossification in DISH were used for quantitative measurements on CT scans. The Cartesian coordinate system was built up on the axial CT scans to reflect the relative position between aorta and osteophytes. Osteophytes were divided into adjacent aorta group (AD group) and non-adjacent aorta group (N-AD group). In terms of the morphology, osteophytes in the AD group were further divided into convex, flat, and concave types. The relative position between aorta and osteophytes, and the aorta-osteophyte distance and morphology of osteophytes were compared. Univariate analysis of variance was performed for multiple groups, and two independent-samples t-tests were used for two groups. RESULTS: From T5 to L4, aorta gradually descended from left side to middle of vertebrae, and osteophytes gradually shifted from right side of vertebrae (T5-T10) to bilateral sides (T11-L4). Of 637 osteophytes in DISH, 60.1% (383/637) were in AD group, including convex type 0.6% (4/637), flat type 34.7% (221/637), and concave type 24.8% (158/637). The N-AD group accounted for 39.9% (254/637). Flat osteophytes were concentrated in T5-T12, while concave osteophytes in T11-L4. Overall, the aorta-osteophyte distance of concave type was significantly smaller than that of flat type. CONCLUSION: Osteophytes are not always located on the right side of vertebrae, but move with the position of the descending aorta. Furthermore, the morphology of osteophytes varies by vertebral segment in DISH, which is related to aorta descending anteriorly in the spine.

Halo-gravity traction combined with growing rod treatment: an effective preoperative management for severe early-onset scoliosis.

OBJECTIVE: The aim of this study was to investigate the effectiveness of preoperative halo-gravity traction (HGT) with subsequent growing rod (GR) treatment in patients with severe early-onset scoliosis (EOS). METHODS: The authors retrospectively reviewed a cohort of patients with severe EOS who had received preoperative HGT with subsequent GR treatment at their center between January 2008 and January 2020. Patients with a Cobb angle in the coronal or sagittal plane that was > 90° were included. All patients received at least 6 weeks of HGT before GR placement. Results of pulmonary function tests (PFTs) and blood gas tests were compared before and after HGT. Radiological parameters were compared pre-HGT, post-HGT, postindex surgery, and at the latest follow-up. RESULTS: A total of 28 patients (17 boys and 11 girls, mean age 6.1 ± 2.3 years) were included in this study. After a mean of 65.2 ± 22.9 days of traction, the Cobb angle decreased from 101.4° ± 12.5° to 74.5° ± 19.3° (change rate 26.5%), and the kyphosis angle decreased from 71.1° ± 21.2° to 42.7° ± 9.5° (change rate 39.9%). There was a significant improvement in BMI but a decrease in hemoglobin levels following HGT. No HGT-related complications were recorded except pin site infections in 2 patients. Statistically significant improvements in PFTs after HGT were observed in forced vital capacity (FVC) (p = 0.011), the percentage predicted FVC (p = 0.007), FEV1 (p = 0.015), and the percentage predicted forced expiratory volume in 1 second (FEV1) (p = 0.005). Fourteen patients received assisted ventilation due to preoperative hypoxia, alveolar hypoventilation, or hypercapnia. Significant improvement was seen in PaCO2 (p = 0.008), PaO2 (p = 0.005), actual bicarbonate (p = 0.005), and oxygen saturation (p = 0.012) in these patients. After the index surgery, the Cobb angle decreased to 49.5° ± 18.9° and the kyphosis angle decreased to 36.2° ± 25.8°. After a mean of 4.3 ± 1.4 lengthening procedures, the Cobb angle was 56.5° ± 15.8°, and the kyphosis angle was 38.8° ± 19.7°. Surgical complications occurred in 14 (50%) patients, but none of these patients required revision surgery at the latest follow-up. CONCLUSIONS: Preoperative HGT notably improved both spinal deformity and pulmonary function in patients with severe EOS. GR treatment after HGT is a safe and effective strategy for these patients.

Junctional Kyphosis after Correction with Long Instrumentation for Late Posttraumatic Thoracolumbar Kyphosis: Characteristics and Risk Factors.

OBJECTIVE: Junctional kyphosis is a common complication after corrective long spinal fusion for adult spinal deformity. Whereas there is still a paucity of data on junctional kyphosis, specifically among late posttraumatic thoracolumbar kyphosis (LPTK) patients. Thus, the aim of this study was to investigate the characteristics and risk factors of junctional kyphosis in LPTK patients receiving long segmental instrumented fusion. METHODS: We retrospectively reviewed a cohort of LPTK patients who had received long segmental instrumented fusion (>4 segments) in our center between January 2012 and January 2019. Radiographic assessments included the sagittal alignment, pelvic parameters, bone quality on CT images, and measurements of the cross-sectional area (CSA, cross-sectional area of muscle-vertebral body ratio × 100) and fat saturation fraction (FSF, cross-sectional area of fat-muscle body ratio × 100) of paraspinal muscles. Patients in this study were divided into those with junctional kyphosis or failure (Group J) and those without (Group NJ) during follow-up. Group J included patients with junctional kyphosis (Group JK) and patients with junctional failure (Group JF). RESULTS: A total of 65 patients (16 males and 49 females, average age 56.5 ± 23.4 years) were enrolled in this study. After (32.7 ± 8.5) months follow-up, 15 patients (23.1%) experienced junctional kyphosis, and four of them deteriorated into junctional failure. Eighty percent (12/15) of junctional kyphosis was identified within 6 months after surgery. In comparison with Group NJ, Group J were older (P = 0.026), longer fusion levels (P < 0.001), greater thoracic kyphosis (P = 0.01), greater global kyphosis (P = 0.023), lower bone quality (P < 0.001), less CSA (P = 0.005) and higher FSF (P <0.001) of paraspinal muscles. Preoperative global kyphosis more than 48.5° (P = 0.001, odds ratio 1.793) and FSF more than 48.4 (P = 0.010, odds ratio 2.916) were identified as independent risk factors of junctional kyphosis. Based on the statistical differences among Group NJ, Group JK and Group JF (P < 0.001), Group JF had lower bone quality than Group NJ (P < 0.001) and Group JK (P = 0.015). In terms of patient-reported outcomes, patients in Group JF had worse outcomes in ODI and VAS scores, and PCS and MCS of SF-36 than Group NJ and group JK CONCLUSION: The prevalence of junctional kyphosis was 23.1% in LPTK patients after long segmental instrumented fusion. Preoperative hyperkyphosis and advanced fatty degeneration of paraspinal muscles were independent risk factors of junctional kyphosis. Patients with lower bone quality were more likely to develop junctional failure.

Utility of the decubitus or the supine rather than the extension lateral radiograph in evaluating lumbar segmental instability.

OBJECTIVE: To determine the superiority of decubitus and supine radiographs for the reduction of olisthesis instead of the extension radiograph, and the inconsistency of the CT scout view, 3D-reconstruction and MR image in evaluating segmental instability. METHODS: A cohort of 154 low-grade lumbar degenerative spondylolisthesis patients with the average age of (60.9 ± 8.6) years were enrolled. Slip percentage was measured on the flexion, upright and extension radiographs, the decubitus lateral radiograph, CT scout view, the supine median sagittal 3D-reconstruction and MR image. The translational range of motion was calculated, and segmental instability was defined as translational motion ≥ 8%. RESULTS: The flexion radiograph showed higher slip percentage than upright radiograph (p < 0.001). The slip percentage of the MR image was lower than CT scout view (p = 0.003) and CT sagittal radiograph (p = 0.001) on the basis of statistical differences among three groups (p = 0.002). The slip percentage of the CT scout view, decubitus radiograph, and extension radiograph was statistically different (p = 0.01). The CT scout view and sagittal reconstruction had lower slip percentage than the extension radiograph (p = 0.042; p = 0.003, respectively). Both the flexion-supine and flexion-decubitus modality had larger translational motion than the flexion-extension modality (p = 0.007; p < 0.001, respectively). CONCLUSION: Many modalities and techniques are used to show the vertebral displacement and its possible change and any cane used in the daily practice. In this study, supine and decubitus lateral radiography have larger reduction of olisthesis than the extension radiograph. The flexion radiograph coupled with a supine or decubitus radiograph reveals greater mobility than the flexion-extension modality.

Galectin-3 Enhances Osteogenic Differentiation of Precursor Cells From Patients With Diffuse Idiopathic Skeletal Hyperostosis via Wnt/ß-Catenin Signaling.

Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflammatory skeletal disease characterized by the progressive ectopic ossification and calcification of ligaments and enthuses. However, specific pathogenesis remains unknown. Bone marrow mesenchymal stem cells (BMSCs) are a major source of osteoblasts and play vital roles in bone metabolism and ectopic osteogenesis. However, it is unclear whether BMSCs are involved in ectopic calcification and ossification in DISH. The current study aimed to explore the osteogenic differentiation abilities of BMSCs from DISH patients (DISH-BMSCs). Our results showed that DISH-BMSCs exhibited stronger osteogenic differentiation abilities than normal control (NC)-BMSCs. Human cytokine array kit analysis showed significantly increased secretion of Galectin-3 in DISH-BMSCs. Furthermore, Galectin-3 downregulation inhibited the increased osteogenic differentiation ability of DISH-BMSCs, whereas exogenous Galectin-3 significantly enhanced the osteogenic differentiation ability of NC-BMSCs. Notably, the increased Galectin-3 in DISH-BMSCs enhanced the expression of ß-catenin as well as TCF-4, whereas attenuation of Wnt/ß-catenin signaling partially alleviated Galectin-3-induced osteogenic differentiation and activity in DISH-BMSCs. In addition, our results noted that Galectin-3 interacted with ß-catenin and enhanced its nuclear accumulation. Further in vivo studies showed that exogenous Galectin-3 enhanced ectopic bone formation in the Achilles tendon in trauma-induced rats by activating Wnt/ß-catenin signaling. The current study indicated that enhanced osteogenic differentiation of DISH-BMSCs was mainly attributed to the increased secretion of Galectin-3 by DISH-BMSCs, which enhanced ß-catenin expression and its nuclear accumulation. Our study helps illuminate the mechanisms of pathological osteogenesis and sheds light on the possible development of potential therapeutic strategies for DISH treatment. © 2022 American Society for Bone and Mineral Research (ASBMR).

Iron regulatory protein 2 modulates the switch from aerobic glycolysis to oxidative phosphorylation in mouse embryonic fibroblasts.

The importance of the role of iron regulatory proteins (IRPs) in mitochondrial iron homeostasis and function has been raised. To understand how an IRP affects mitochondrial function, we used globally Irp2-depleted mouse embryonic fibroblasts (MEFs) and found that Irp2 ablation significantly induced the expression of both hypoxia-inducible factor subunits, Hif1α and Hif2α. The increase of Hif1α up-regulated its targeted genes, enhancing glycolysis, and the increase of Hif2α down-regulated the expression of iron-sulfur cluster (Fe-S) biogenesis-related and electron transport chain (ETC)-related genes, weakening mitochondrial respiration. Inhibition of Hif1α by genetic knockdown or a specific inhibitor prevented Hif1α-targeted gene expression, leading to decreased aerobic glycolysis. Inhibition of Hif2α by genetic knockdown or selective disruption of the heterodimerization of Hif2α and Hif1ß restored the mitochondrial ETC and coupled oxidative phosphorylation (OXPHOS) by enhancing Fe-S biogenesis and increasing ETC-related gene expression. Our results indicate that Irp2 modulates the metabolic switch from aerobic glycolysis to OXPHOS that is mediated by Hif1α and Hif2α in MEFs.