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The main pathological mechanism of intervertebral disc degeneration (IVDD) is the programmed apoptosis of nucleus pulposus (NP) cells. Oxidative stress is a significant cause of IVDD. Whether mitophagy is induced by strong oxidative stress in IVDD remains to be determined. This study aimed to investigate the relationship between oxidative stress and mitophagy and to better understand the mechanism of IVDD in vivo and in vitro. To this end, we obtained primary NP cells from the human NP and subsequently exposed them to TBHP. We observed that oxidative stress induced mitophagy to cause apoptosis in NP cells, and we suppressed mitophagy and found that NP cells were protected against apoptosis. Interestingly, TBHP resulted in mitophagy through the inhibition of the HIF-1α/NDUFA4L2 pathway. Therefore, the upregulation of mitochondrial NDUFA4L2 restricted mitophagy induced by oxidative stress. Furthermore, the expression levels of HIF-1α and NDUFA4L2 were decreased in human IVDD. In conclusion, these results demonstrated that the upregulation of NDUFA4L2 ameliorated the apoptosis of NP cells by repressing excessive mitophagy, which ultimately alleviated IVDD. These findings show for the first time that NDUFA4L2 and mitophagy may be potential therapeutic targets for IVDD. Disc degeneration: Mitochondria at the root of the problem A study in rats highlights the role of mitochondria in intervertebral disc degeneration (IVDD), one of the most important and prevalent predisposing factors for lower back pain. Previous studies have shown that in IVDD, oxidative stress results in the gradual loss of cells in the inner part of vertebral discs which cushion the space between vertebrae. Sheng-Dan Jiang and Lei-Sheng Jiang at Shanghai Jiaotong University School of Medicine found that oxidative stress in these cells causes the selective degradation of mitochondria by preventing the expression of a protein that is essential for mitochondrial function. Overexpressing this protein in the intervertebral discs of rats with IVDD alleviated degeneration, suggesting that restoring mitochondrial function could be an effective therapeutic strategy for easing the pain associated with the condition.

Intervertebral disc degeneration (IVDD) is the most common contributor to low back pain (LBP). Recent studies have found that oxidative stress and reactive oxygen species (ROS) play an important role in IVDD. As a by‐product of aerobic respiration, ROS is mainly produced in the mitochondria by the electron transport chain and other mitochondrial located proteins. With the excessive accumulation of ROS, mitochondria are also the primary target of ROS attack in disc cells. A disrupted balance between intracellular ROS production and antioxidant capacity will lead to oxidative stress, which is the key contributor to cell apoptosis, cell senescence, excessive autophagy, and mitochondrial dysfunction. As the pivotal ingredient of oxidative stress, mitochondrial dysfunction manifests as imbalanced mitochondrial dynamics and dysregulated mitophagy. Mitochondria can alter their own dynamics through the process of fusion and fission, so that disabled mitochondria can be separated from the mitochondrial pool. Moreover, mitophagy participates by clearing these dysfunctional mitochondria. Abnormality in any of these processes either increases the production or decreases the clearance of ROS, leading to a vicious cycle that results in the death of intervertebral disc cells in large quantities, combined with degradation of the extracellular matrix and overproduction of matrix metalloproteinase. In this review, we explain the changes in mitochondrial morphology and function during oxidative stress‐mediated IVDD and highlight the important role of mitochondria in this process. Eventually, we summarize the IVDD therapeutic strategies targeting mitochondrial dysfunction based on current understanding of the role of oxidative stress in IVDD. Graphic overview of the role of mitochondrial dysfunction in the pathogenesis of IVDD. An imbalance between ROS intercellular production and antioxidant defense capacity will directly give rise to the occurrence of oxidative stress, which is mainly represented by cell apoptosis, abnormal autophagy, cell senescence, and mitochondrial dysfunction. Among the oxidative stress‐related pathophysiological processes, mitochondrial dysfunction plays an essential role in the disc pathology of IVDD, which manifests as imbalanced dynamics and dysregulated mitophagy. ROS promotes the fusion of mitochondria, which decreases their fission process, so that disabled mitochondria can be separated from the mitochondrial pool. Further, mitophagy serves as the quality control mechanism, which can be dysregulated under the condition of oxidative stress by overwhelmingly clearing both dysfunctional and normal mitochondria. Overall, the effects of mitochondria dysfunction result in the massive disc cell death with overproduction of MMP and the degradation of ECM, eventually the pathogenesis of IVDD.

Mitochondrial unfold protein response (UPR ) can induce mitophagy to protect cell from unfold protein. However, how UPR induces mitophagy to protect cell is not yet clear. Herein, Sesn2 was considered to be a key molecule that communicated UPR and mitophagy in the intervertebral disc. Silencing of Sesn2 was able to reverse the protective effects of Nicotinamide riboside (NR) on nucleus pulposus (NP) cells and inhibit mitophagy induced by UPR . UPR upregulated Sesn2 through Eif2ak4/eIF2α/Atf4, and further induced mitophagy. Sesn2 promoted the translocation of cytosolic Parkin and Sqstm1 to the defective mitochondria respectively, thereby enhancing mitophagy. The translocation of cytosolic Sqstm1 to the defective mitochondria was dependent on Parkin. The two functional domains of Sesn2 were necessary for the interaction of Sesn2 with Parkin and Sqstm1. The cytosolic interaction of Sesn2 between Parkin and Sqstm1 was independent on Pink1 (named as PINK1 in human) but the mitochondrial translocation was dependent on Pink1. Sesn2-/- mice showed a more severe degeneration and NR did not completely alleviate the intervertebral disc degeneration (IVDD) of Sesn2-/- mice. In conclusion, UPR could attenuate IVDD by upregulation of Sesn2-induced mitophagy. This study will help to further reveal the mechanism of Sesn2 regulating mitophagy, and open up new ideas for the prevention and treatment of IVDD.

Bone health requires adequate bone mass, which is maintained by a critical balance between bone resorption and formation. In our study, we identified beraprost as a pivotal regulator of bone formation and resorption. The administration of beraprost promoted differentiation of mouse bone mesenchymal stem cells (M-BMSCs) through the PI3K–AKT pathway. In co-culture, osteoblasts stimulated with beraprost inhibited osteoclastogenesis in a rankl-dependent manner. Bone mass of p53 knockout mice remained stable, regardless of the administration of beraprost, indicating that p53 plays a vital role in the bone mass regulation by beraprost. Mechanistic in vitro studies showed that p53 binds to the promoter region of neuronal precursor cell-expressed developmentally downregulated 4 (Nedd4) to promote its transcription. As a ubiquitinating enzyme, Nedd4 binds to runt-related transcription factor 2 (Runx2), which results in its ubiquitination and subsequent degradation. These data indicate that the p53–Nedd4–Runx2 axis is an effective regulator of bone formation and highlight the potential of beraprost as a therapeutic drug for postmenopausal osteoporosis.

Purpose To assess the safety and efficacy of the extra-facet puncture technique applied in unilateral percutaneous vertebroplasty (PVP) for treating osteoporotic vertebral compression fractures. Methods Demographics (age, gender, body mass index and underlying diseases) were recorded for analyzing. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores as well as their corresponding minimal clinically important difference (MCID) were used to evaluate clinical outcomes. The segmental kyphotic angle, the vertebral compression ratio and bone cement distribution pattern were evaluated by the plain radiographs. The facet joint violation (FJV) was defined by the postoperative computed tomography scan. Binary logistic regression analysis was performed to investigate relationships between multiple risk factors and residual back pain. Results VAS and ODI scores in both traditional puncture group and extra-facet puncture group were significantly decreased after PVP surgery ( p  < 0.05). However, no significant difference was observed between the two groups according to VAS and ODI scores. The proportion of patients achieving MCID of VAS and ODI scores was higher in extra-facet puncture group as compared to traditional puncture group within a month ( p  < 0.05). Finally, multivariate logistic regression analysis showed that FJV (odds ratio 16.38, p  < 0.001) and unilateral bone cement distribution (OR 5.576, p  = 0.020) were significant predictors of residual back pain after PVP surgery. Conclusions Extra-facet puncture percutaneous vertebroplasty can decrease the risk of FJV and it also has the advantage of more satisfied bone cement distribution.

Purpose. There have been many studies in the operative management of pyogenic spondylodiscitis with foreign materials. However, it still remains an issue of debate on whether the allografts may be used in pyogenic spondylodiscitis. This study sought to evaluate the safety and effectiveness of PEEK cages and the cadaveric allograft in transforaminal lumbar interbody fusion (TLIF) for treating lumbar pyogenic spondylodiscitis. Methods. From January 2012 to December 2019, 56 patients underwent surgery for lumbar pyogenic spondylodiscitis. The posterior debridement of all patients and their fusion with allografts, local bone grafts, and bone chip cages were performed before posterior pedicle screw fusion. An assessment of the residual pain, the grade of neurological injury, and the resolution of infection was conducted on 39 patients. The clinical outcome was evaluated using a visual analog scale (VAS) and the Oswestry Disability Index (ODI), and neurological outcomes were appraised based on Frankel grades. The radiological outcomes were evaluated via focal lordosis, lumbar lordosis, and the state of the fusion. Results. Staphylococcus aureus and Staphylococcus epidermidis were the most common causative organisms. The mean preoperative focal lordosis was −1.2° (−11.4° to 5.7°), and the mean postoperative focal lordosis increased to 10.3° (4.3°–17.2°). At the final follow-up, there were five cases with subsidence of the cage, no case of recurrence, and no case with cage and screw loosening or migration. The mean preoperative VAS and ODI scores were 8.9 and 74.6%, respectively, and improvements in VAS and ODI were 6.6±2.2 and 50.4±21.3%, respectively. The Frankel grade D was found in 10 patients and grade C in 7. Following the final follow-up, only one patient improved from Frankel grade C to grade D while the others recovered completely. Conclusion. The PEEK cage and cadaveric allograft combined with local bone grafts is a safe and effective choice for intervertebral fusion and restoring sagittal alignment without increased incidence of relapse for treating lumbar pyogenic spondylodiscitis.

Purpose Evaluate the efficacy of a novel unilateral dual‐plane puncture technique in improving bone cement distribution and reducing vertebral re‐collapse following percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures (OVCFs). By introducing the novel unilateral dual‐plane puncture technique, this study aims to improve cement distribution, reduce the incidence of re‐collapse, and enhance long‐term clinical outcomes for patients suffering from OVCFs. Methods This is a randomized trial conducted from April 2021 to December 2022, enrolling 145 patients diagnosed with OVCFs. Patients were allocated into either traditional or unilateral dual‐plane puncture groups. Bone cement distribution, vertebral height, and segmental kyphotic angle were measured through postoperative x‐ray, while clinical outcomes were evaluated using the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). Statistical analysis was performed using the Mann–Whitney U test and independent samples t test for continuous variables, and chi‐square or Fisher's exact test for categorical variables. Results The unilateral dual‐plane puncture technique notably augmented bone cement contact with both superior and inferior endplates compared to conventional methods, achieving rates of 64.86% versus 40.85% (p < 0.001). This contributed to a significant reduction in the incidence of vertebral re‐collapse within the first year post‐operation: 18.92% in the unilateral dual‐plane group as opposed to 42.25% in the traditional group (p < 0.001). Furthermore, the unilateral dual‐plane group exhibited markedly superior long‐term efficacy, evidenced by mean VAS and ODI scores of 1.26 and 28.58, respectively, in comparison to 2.03 and 32.45 in the traditional group. Conclusions The unilateral dual‐plane puncture technique advances bone cement distribution within the vertebra, thereby reducing the risk of vertebral re‐collapse following PVP surgery and improving long‐term clinical outcomes for patients with OVCFs. Trajectory of the unilateral dual‐plane puncture. The sagittal CT scan after surgery clearly shows the puncture trajectory of the unilateral dual‐plane puncture. The bone cement simultaneously contacted both the upper and lower end plates.

Objective Lumbar disc degeneration (LDD) is a common cause of low back pain and disability, and its prevalence increases with age. The aim of this study is to investigate whether endplate Hounsfield unit (HU) values have an effect on lumbar disc degeneration (LDD) after transforaminal lumbar interbody fusion (TLIF) surgery in patients with degenerative lumbar stenosis. Methods This study was a retrospective analysis of patients who underwent TLIF surgery in January 2016 to October 2019. One hundred and fifty‐seven patients who underwent TLIF surgery for degenerative lumbar stenosis were enrolled in this study. Demographic data was recorded. VAS and ODI values were compared to assess the surgical outcomes in patients with or without process of LDD after TLIF surgery. Correlation analysis was performed to investigate associations between LDD and endplate HU value. Binary logistic regression analysis was carried out to study relationships between the DDD and the multiple risk factors. Results There was a statistically significant correlation between LDD, body mass index (BMI), age, paraspinal muscle atrophy, and total endplate scores (TEPS). Also, a strong and independent association between endplate HU value and LDD was found at every lumbar disc level (p < 0.01). After conditioning on matching factors, multivariate logistic regression analysis showed that higher endplate HU (odds ratio [OR]: 1.003, p = 0.003), higher TEPS (OR: 1.264, p = 0.002), higher BMI (odds ratio [OR]: 1.202, p = 0.002), a smaller cross‐sectional area (CSA) of the paraspinal muscle preoperatively (OR: 0.096, p < 0.001) were significant predictors of LDD development after TLIF surgery. Conclusions There is a significant association between LDD and endplate HU value after TLIF surgery in patients with degenerative lumbar stenosis. Beyond that, results from this study provide a mechanism by which high endplate HU value predisposes to LDD after TLIF surgery. Measurement of the Hounsfield units (HU) values of endplate. Locating the endplate in the sagittal plane then trailing edge of hyperintense area and recording the mean HU value in the coronal plane.

Osteosarcoma (OS) accounts for a large proportion of the types of bone tumors that are newly diagnosed, and is a relatively common bone tumor. However, there are still no effective treatments for this affliction. One interesting avenue is related to the mitochondrial NDUFA4L2 protein, which is encoded by the nuclear gene and is known to be a critical mediator in the regulation of cell survival. Thus, in this study, we aimed to investigate the effect of NDUFA4L2 upon the metastasis and epithelial–mesenchymal transition of OS. We found that NDUFA4L2 protein expression was upregulated in hypoxic conditions. We also used 2-ME and DMOG, which are HIF-1α inhibitors and agonists, respectively, to assess the effects related to decreasing or increasing HIF-1α expression. 2-ME caused a significant decrease of NDUFA4L2 expression and DMOG had the opposite effect. It was obvious that down-regulation of NDUFA4L2 had a direct interaction with the apoptosis of OS cells. Western blotting, wound healing analyses, Transwell invasion assays, and colony formation assays all indicated and supported the conclusion that NDUFA4L2 promoted OS cell migration, invasion, proliferation, and the epithelial–mesenchymal transition. During experiments, we incidentally discovered that autophagy and the ROS inhibitor could be used to facilitate the rescuing of tumor cells whose NDUFA4L2 was knocked down. Our findings will help to further elucidate the dynamics underlying the mechanism of OS cells and have provided a novel therapeutic target for the treatment of OS.

A healthy microenvironment of the intervertebral disc tissue is characterized by hypoxia owing to its sparse vascular distribution. Oxidative stress plays a pivotal role in the pathological development of intervertebral disc degeneration (IVDD). We found that the expression of prolyl endopeptidase (PREP) increased in degenerative nucleus pulposus (NP) tissues. The purpose of this study was to determine whether PREP is involved in oxidative-stress-induced IVDD. Tertbutyl hydroperoxide can inhibit the expression of PREP by activating the PI3K/AKT signaling pathway at low concentrations in NP cells. Knockdown of PREP protected NP cells from apoptosis induced by oxidative stress, whereas overexpression of PREP exacerbated the apoptosis of NP cells. We also investigated the connection between the PI3K/AKT signaling pathway and PREP and found that the activation of the PI3K/AKT signaling pathway downregulated the expression of PREP by inhibiting p53. As a crucial transcription factor, p53 binds to the PREP promoter region and promotes its transcription. Overexpression of PREP also impairs protein secretion in the extracellular matrix of NP cells. Furthermore, the in vivo knockout of PREP could attenuate puncture-induced IVDD. These findings suggested that the downregulation of PREP might maintain the viability of NP cells and attenuate IVDD under oxidative stress.