O-GlcNAc transferase regulates intervertebral disc degeneration by targeting FAM134B-mediated ER-phagy.

Both O-linked ß-N-acetylglucosaminylation (O-GlcNAcylation) and endoplasmic reticulum-phagy (ER-phagy) are well-characterized conserved adaptive regulatory mechanisms that maintain cellular homeostasis and function in response to various stress conditions. Abnormalities in O-GlcNAcylation and ER-phagy have been documented in a wide variety of human pathologies. However, whether O-GlcNAcylation or ER-phagy is involved in the pathogenesis of intervertebral disc degeneration (IDD) is largely unknown. In this study, we investigated the function of O-GlcNAcylation and ER-phagy and the related underlying mechanisms in IDD. We found that the expression profiles of O-GlcNAcylation and O-GlcNAc transferase (OGT) were notably increased in degenerated NP tissues and nutrient-deprived nucleus pulposus (NP) cells. By modulating the O-GlcNAc level through genetic manipulation and specific pharmacological intervention, we revealed that increasing O-GlcNAcylation abundance substantially enhanced cell function and facilitated cell survival under nutrient deprivation (ND) conditions. Moreover, FAM134B-mediated ER-phagy activation was regulated by O-GlcNAcylation, and suppression of ER-phagy by FAM134B knockdown considerably counteracted the protective effects of amplified O-GlcNAcylation. Mechanistically, FAM134B was determined to be a potential target of OGT, and O-GlcNAcylation of FAM134B notably reduced FAM134B ubiquitination-mediated degradation. Correspondingly, the protection conferred by modulating O-GlcNAcylation homeostasis was verified in a rat IDD model. Our data demonstrated that OGT directly associates with and stabilizes FAM134B and subsequently enhances FAM134B-mediated ER-phagy to enhance the adaptive capability of cells in response to nutrient deficiency. These findings may provide a new option for O-GlcNAcylation-based therapeutics in IDD prevention.

Clinically suspected fibrocartilaginous embolism: a case report and literature review.

Spinal cord infarction (SCI) occurs rarely and is characterized by abrupt onset of neck or back pain and neurologic deterioration. Fibrocartilaginous embolism (FCE) of the spinal cord is a rare but possible cause of acutely progressive spinal cord symptoms. Here, we report the case of an older woman who developed acute paraplegia with SCI on the 10th day after thoracic spine surgery. Although definitive FCE diagnosis can be confirmed only histologically, the characteristic clinical and radiological features were highly suggestive of FCE. Furthermore, 40 clinically suspected cases of FCE are reviewed.

Biomechanical Evaluation of Different Surgical Approaches for the Treatment of Adjacent Segment Diseases After Primary Anterior Cervical Discectomy and Fusion: A Finite Element Analysis.

Symptomatic adjacent segment disease (ASD) is a common challenge after anterior cervical discectomy and fusion (ACDF). The objective of this study was to compare the biomechanical effects of a second ACDF and laminoplasty for the treatment of ASD after primary ACDF. We developed a finite element (FE) model of the C2-T1 based on computed tomography images. The FE models of revision surgeries of ACDF and laminoplasty were simulated to treat one-level and two-level ASD after primary ACDF. The range of motion (ROM) and intradiscal pressure (IDP) of the adjacent segments, and stress in the cord were analyzed to investigate the biomechanical effects of the second ACDF and laminoplasty. The results indicated that revision surgery of one-level ACDF increased the ROM and IDP at the C2-C3 segment, whereas two-level ACDF significantly increased the ROM and IDP at the C2-C3 and C7-T1 segments. Furthermore, no significant changes in the ROM and IDP of the laminoplasty models were observed. The stress in the cord of the re-laminoplasty model decreased to some extent, which was higher than that of the re-ACDF model. In conclusion, both ACDF and laminoplasty can relieve the high level of stress in the spinal cord caused by ASD after primary ACDF, whereas ACDF can achieve better decompression effect. Revision surgery of the superior ACDF or the superior and inferior ACDF after the primary ACDF increased the ROM and IDP at the adjacent segments, which may be the reason for the high incidence of recurrent ASD after second ACDF.

FAM134B-Mediated ER-phagy Upregulation Attenuates AGEs-Induced Apoptosis and Senescence in Human Nucleus Pulposus Cells.

Previous studies have established the pathogenic role of advanced glycation end products (AGEs) accumulation in intervertebral disc degeneration (IDD). Emerging evidence indicates that ER-phagy serves as a crucial cellular adaptive mechanism during stress conditions. This study is aimed at investigating the role of FAM134B-mediated ER-phagy in human nucleus pulposus (NP) cells upon AGEs treatment and exploring its regulatory mechanisms. We observed that AGEs treatment resulted in significantly increased apoptosis, senescence, and ROS accumulation in human NP cells; meanwhile, the enhanced apoptosis and senescence by AGEs treatment could be partially alleviated with the classic ROS scavenger NAC administration. Furthermore, we confirmed that FAM134B-mediated ER-phagy was activated under AGEs stimulation via ROS pathway. Importantly, it was also found that FAM134B overexpression could efficiently relieve intracellular ROS accumulation, apoptosis, and senescence upon AGEs treatment; conversely, FAM134B knockdown markedly resulted in opposite effects. In conclusion, our data demonstrate that FAM134B-mediated ER-phagy plays a vital role in AGEs-induced apoptosis and senescence through modulating cellular ROS accumulation, and targeting FAM134B-mediated ER-phagy could be a promising therapeutic strategy for IDD treatment.

Mitochondrial quality control in intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is a common and early-onset pathogenesis in the human lifespan that can increase the risk of low back pain. More clarification of the molecular mechanisms associated with the onset and progression of IDD is likely to help establish novel preventive and therapeutic strategies. Recently, mitochondria have been increasingly recognized as participants in regulating glycolytic metabolism, which has historically been regarded as the main metabolic pathway in intervertebral discs due to their avascular properties. Indeed, mitochondrial structural and functional disruption has been observed in degenerated nucleus pulposus (NP) cells and intervertebral discs. Multilevel and well-orchestrated strategies, namely, mitochondrial quality control (MQC), are involved in the maintenance of mitochondrial integrity, mitochondrial proteostasis, the mitochondrial antioxidant system, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis. Here, we address the key evidence and current knowledge of the role of mitochondrial function in the IDD process and consider how MQC strategies contribute to the protective and detrimental properties of mitochondria in NP cell function. The relevant potential therapeutic treatments targeting MQC for IDD intervention are also summarized. Further clarification of the functional and synergistic mechanisms among MQC mechanisms may provide useful clues for use in developing novel IDD treatments.

Metformin facilitates mesenchymal stem cell-derived extracellular nanovesicles release and optimizes therapeutic efficacy in intervertebral disc degeneration.

Extracellular vesicles (EVs) are extracellular nanovesicles that deliver diverse cargoes to the cell and participate in cell communication. Mesenchymal stem cell (MSCs)-derived EVs are considered a therapeutic approach in musculoskeletal degenerative diseases, including intervertebral disc degeneration. However, limited production yield and unstable quality have impeded the clinical application of EVs. In the present study, it is indicated that metformin promotes EVs release and alters the protein profile of EVs. Metformin enhances EVs production via an autophagy-related pathway, concomitantly with the phosphorylation of synaptosome-associated protein 29. More than quantity, quality of MSCs-derived EVs is influenced by metformin treatment. Proteomics analysis reveals that metformin increases the protein content of EVs involved in cell growth. It is shown that EVs derived from metformin-treated MSCs ameliorate intervertebral disc cells senescence in vitro and in vivo. Collectively, these findings demonstrate the great promise of metformin in EVs-based intervertebral disc regeneration.

Ferroportin-Dependent Iron Homeostasis Protects against Oxidative Stress-Induced Nucleus Pulposus Cell Ferroptosis and Ameliorates Intervertebral Disc Degeneration In Vivo.

Ferroptosis is a specialized form of regulated cell death that is charactered by iron-dependent lethal lipid peroxidation, a process associated with multiple diseases. However, its role in the pathogenesis of intervertebral disc degeneration (IVDD) is rarely investigated. This study is aimed at investigating the role of ferroptosis in oxidative stress- (OS-) induced nucleus pulposus cell (NPC) decline and the pathogenesis of IVDD and determine the underlying regulatory mechanisms. We used tert-butyl hydroperoxide (TBHP) to simulate OS conditions around human NPCs. Flow cytometry and transmission electron microscopy were used to identify ferroptosis, while iron assay kit, Perl's staining, and western blotting were performed to assay the intracellular iron levels. A ferroportin- (FPN-) lentivirus and FPN-siRNA were constructed and used to explore the relationship between FPN, intracellular iron homeostasis, and ferroptosis. Furthermore, hinokitiol, a bioactive compound known to specifically resist OS and restore FPN function, was evaluated for its therapeutic role in IVDD both in vitro and in vivo. The results indicated that intercellular iron overload plays an essential role in TBHP-induced ferroptosis of human NPCs. Mechanistically, FPN dysregulation is responsible for intercellular iron overload under OS. The increase in nuclear translocation of metal-regulatory transcription factor 1 (MTF1) restored the function of FPN, abolished the intercellular iron overload, and protected cells against ferroptosis. Additionally, hinokitiol enhanced the nuclear translocation of MTF1 by suppressing the JNK pathway and ameliorated the progression of IVDD in vivo. Taken together, our results demonstrate that ferroptosis and FPN dysfunction are involved in the NPC depletion and the pathogenesis of IVDD under OS. To the best of our knowledge, this is the first study to demonstrate the protective role of FPN in ferroptosis of NPCs, suggesting its potential used as a novel therapeutic target against IVDD.

Mechanosensitive Ion Channel Piezo1 Activated by Matrix Stiffness Regulates Oxidative Stress-Induced Senescence and Apoptosis in Human Intervertebral Disc Degeneration.

Mechanical stimulation plays a crucial part in the development of intervertebral disc degeneration (IDD). Extracellular matrix (ECM) stiffness, which is a crucial mechanical microenvironment of the nucleus pulposus (NP) tissue, contributes to the pathogenesis of IDD. The mechanosensitive ion channel Piezo1 mediates mechanical transduction. This study purposed to investigate the function of Piezo1 in human NP cells under ECM stiffness. The expression of Piezo1 and the ECM elasticity modulus increased in degenerative NP tissues. Stiff ECM activated the Piezo1 channel and increased intracellular Ca2+ levels. Moreover, the activation of Piezo1 increased intracellular reactive oxygen species (ROS) levels and the expression of GRP78 and CHOP, which contribute to oxidative stress and endoplasmic reticulum (ER) stress. Furthermore, stiff ECM aggravated oxidative stress-induced senescence and apoptosis in human NP cells. Piezo1 inhibition alleviated oxidative stress-induced senescence and apoptosis, caused by the increase in ECM stiffness. Finally, Piezo1 silencing ameliorated IDD in an in vivo rat model and decreased the elasticity modulus of rat NP tissues. In conclusion, we identified the mechanosensitive ion channel Piezo1 in human NP cells as a mechanical transduction mediator for stiff ECM stimulation. Our results provide novel insights into the mechanism of mechanical transduction in NP cells, with potential for treating IDD.

The distinct roles of myosin IIA and IIB under compression stress in nucleus pulposus cells.

OBJECTIVES: Inappropriate or excessive compression applied to intervertebral disc (IVD) contributes substantially to IVD degeneration. The actomyosin system plays a leading role in responding to mechanical stimuli. In the present study, we investigated the roles of myosin II isoforms in the compression stress-induced senescence of nucleus pulposus (NP) cells. MATERIAL AND METHODS: Nucleus pulposus cells were exposed to 1.0 MPa compression for 0, 12, 24 or 36 hours. Immunofluorescence and co-immunoprecipitation analysis were used to measure the interaction of myosin IIA and IIB with actin. Western blot analysis and immunofluorescence staining were used to detect nuclear expression and nuclear localization of MRTF-A. In addition, the expression levels of p-RhoA/RhoA, ROCK1/2 and p-MLC/MLC were measured in human NP cells under compression stress and in degenerative IVD tissues. RESULTS: Compression stress increased the interaction of myosin IIA and actin, while the interaction of myosin IIB and actin was reduced. The actomyosin cytoskeleton remodelling was involved in the compression stress-induced fibrotic phenotype mediated by MRTF-A nuclear translocation and inhibition of proliferation in NP cells. Furthermore, RhoA/ROCK1 pathway activation mediated compression stress-induced human NP cells senescence by regulating the interaction of myosin IIA and IIB with actin. CONCLUSIONS: We for the first time investigated the regulation of actomyosin cytoskeleton in human NP cells under compression stress. It provided new insights into the development of therapy for effectively inhibiting IVD degeneration.

Allicin Attenuated Advanced Oxidation Protein Product-Induced Oxidative Stress and Mitochondrial Apoptosis in Human Nucleus Pulposus Cells.

Intervertebral disc degeneration (IDD) is one of the most common chronic degenerative musculoskeletal disorders. Oxidative stress-induced apoptosis of the nucleus pulposus (NP) cells plays a key role during IDD progression. Advanced oxidation protein products (AOPP), novel biomarkers of oxidative stress, have been reported to function in various diseases due to their potential for disrupting the redox balance. The current study is aimed at investigating the function of AOPP in the oxidative stress-induced apoptosis of human NP cells and the alleviative effects of allicin during this process which was known for its antioxidant properties. AOPP were demonstrated to hamper the viability and proliferation of NP cells in a time- and concentration-dependent manner and cause cell apoptosis markedly. High levels of reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were detected in NP cells after AOPP stimulation, which resulted in depolarized mitochondrial transmembrane potential (MTP). Correspondingly, higher levels of AOPP were discovered in the human degenerative intervertebral discs (IVD). It was also found that allicin could protect NP cells against AOPP-mediated oxidative stress and mitochondrial dysfunction via suppressing the p38-MAPK pathway. These results disclosed a significant role of AOPP in the oxidative stress-induced apoptosis of NP cells, which could be involved in the primary pathogenesis of IDD. It was also revealed that allicin could be a promising therapeutic approach against AOPP-mediated oxidative stress during IDD progression.

CircCOG8 Downregulation Contributes to the Compression-Induced Intervertebral Disk Degeneration by Targeting miR-182-5p and FOXO3.

Circular RNAs (circRNAs) have been increasingly demonstrated to play critical roles in the pathogenesis of various human diseases. Intervertebral disk degeneration (IDD) is recognized as the major contributor to lower back pain, and mechanical stress is a predominant trigger for IDD. However, little is known about the part that circRNAs play in the involvement of mechanical stress during IDD development. In the present study, we identified a novel circRNA and examined the role of this circRNA in a compression loading-induced IDD process. We detected the expression pattern of circCOG8 and observed its function in disk NP cells under mechanical stress. We conducted bioinformatics analysis, RNA immunoprecipitation experiment, and reporter gene assay to unveil the mechanism of the circCOG8 downregulation mediated IVD degeneration. Results showed that the circCOG8 expression was obviously down-regulated by the mechanical stress in disk NP cells. CircCOG8 attenuated NP cells apoptosis, intracellular ROS accumulation, and ECM degradation in vitro and ex vivo. CircCOG8 directly interacted with miR-182-5p and, thus, modulated the FOXO3 expression to affect the compression-induced IDD progression. Altogether, the present study revealed that the circCOG8/miR-182-5p/FOXO3 pathway was an important underlying mechanism in the involvement of compression during the IDD progression. Intervention of circCOG8 is a new therapeutic strategy for IDD treatment.

Biomechanical evaluation of anterior and posterior lumbar surgical approaches on the adjacent segment: a finite element analysis.

The purpose of this study was to use models of spine to compare range of motion and intradiscal pressure of adjacent segments performing anterior and/or posterior lumbar surgical approaches and predict potential risk of adjacent segment degeneration. A previously validated finite element model of the intact L1-S1 segments was used. Three different anterior and one posterior surgical fixation approaches for tuberculosis were performed in L3-L5. Three different anterior surgical models were constructed according to the anterior approaches involving debridement, bone graft with or without titanium mesh, and internal fixation with different number of screws and rods. The posterior surgical approach involved transforaminal lumbar interbody debridement, bone graft, and internal fixation. Range of motion and intradiscal pressure of segments adjacent to the fusion were assessed, and biomechanical influences were compared. Intradiscal pressure and range of motion of the adjacent L2/3 and L5/S1 increased during different physiological movements after anterior and/or posterior surgical approaches as compared to baseline values. Comparison between the biomechanical values assessed after different anterior surgical approaches yielded no significant difference. After anterior and posterior surgical approaches were performed on the same model, there were no significant differences in intradiscal pressure and range of motion of the adjacent L2/3 and L5/S1. Anterior and/or posterior lumbar surgical approaches increased range of motion and intradiscal pressure in L2/3 and L5/S1, suggesting each lumbar surgical approach assessed has the potential risk of adjacent segment degeneration. However, there were no significant differences between the biomechanical measurements across the different surgical approaches evaluated.

Minimally Invasive Surgery Oblique Lumbar Interbody Debridement and Fusion for the Treatment of Lumbar Spondylodiscitis.

OBJECTIVE: To evaluate the efficacy and feasibility of minimally invasive oblique lumbar interbody debridement and fusion for the treatment of conservatively ineffective lumbar spondylodiscitis. METHODS: This is a retrospective study. Between December 2016 and November 2017, a total of 14 consecutive patients (eight males and six females, with an average age of 49.1 years, range from 42 to 74 years) with single-level lumbar spondylodiscitis were included in the study. The inclusion criteria include single-level spondylodiscitis without spinal deformity or epidural abscess, ineffective conservative treatment (continuously aggravated clinical symptoms and uncontrollable infective symptoms treated with antibiotics for more than 6 weeks), minimally invasive oblique lumbar interbody fusion surgery (Mis-OLIF) and iliac graft for the treatment of lumbar spondylodiscitis, and postoperative follow-up >12 months. Each patient was treated Mis-OLIF. Clinical outcomes including demographic characteristics, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analog scale (VAS), the Oswestry Disability Index (ODI), American Spinal Injury Association neurological classification, and lordotic angle were analyzed. RESULTS: The infectious levels included L1/2 (one patient), L2/3 (two patients), L3/4 (eight patients), and L4/5 (three patients). The pathogens found in these patients included Staphylococcus aureus (5), brucellosis (6), and enterobacterium (2). The pathogen was undefined in one patient. The mean duration of the surgery, mean blood loss, and mean follow-up were 89.3 ± 17.5 min, 155.0 ± 49.4 mL, and 16.8 ± 4.2 months, respectively. The ESR and CRP decreased after Mis-OLIF and antibiotic administration. The average preoperative VAS score was 6.9 ± 0.9, then decreased to 3.0 ± 1.0 (t = 14.18, P < 0.001) and 0.6 ± 0.7 (t = 20.68, P < 0.001) before discharge and at final follow-up, respectively. The average preoperative ODI score was 58.4 ± 13.0, then decreased to 28.3 ± 6.1 (t = 18.6, P < 0.001) and 8.0 ± 4.6 (t = 22.7, P < 0.001) before discharge and at final follow-up, respectively. None of the patients developed postoperative ileus, vascular injury, nerve injury, and ureteral injury. One patient suffered incision-related complication that healed by debridement and dressing change. One patient developed subsidence of autologous iliac bone before discharge and achieved complete bony fusion after staying in bed and fixing it with a brace at 3 months follow-up. All patients achieved bony fusion at final follow-up. CONCLUSION: Mis-OLIF without anterior or posterior instrumentation and iliac graft is an effective and viable approach for the treatment of conservatively ineffective lumbar spondylodiscitis without spinal deformity or epidural abscess.

Percutaneous posterior full-endoscopic cervical foraminotomy and discectomy: a finite element analysis and radiological assessment.

Percutaneous posterior full-endoscopic cervical foraminotomy and discectomy (PECFD) is recognized as a safe, effective, and minimally invasive treatment for cervical spondylotic radiculopathy (CSR). However, the potential mechanisms of the degenerative changes and postoperative recurrence after PECFD are unclear. In this study, a finite element (FE) analysis and radiological assessment were performed to evaluate the biomechanical effects after PECFD. The FE model indicated that the ROM and IDP of C5-C6 increased significantly after PECFD in the extension loading. The radiological evaluation revealed that the extension ROM of C2-C7 and the operative level increased significantly at the one-year follow-up compared with that obtained preoperatively. Combining the FE results and radiological changes, we conclude that the increase in the ROM and IDP at the operative level in the extension loading is the potential cause of the degenerative changes and recurrences after PECFD surgery.

Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy.

N6 methyladenosine (m6A) is one of the most prevalent epitranscriptomic modifications of mRNAs, and plays a critical role in various bioprocesses. Bone-derived mesenchymal stem cells (BMSCs) can attenuate apoptosis of nucleus pulposus cells (NPCs) under compression; however, the underlying mechanisms are poorly understood. This study showed that the level of m6A mRNA modifications was decreased, and the autophagic flux was increased in NPCs under compression when they were cocultured with BMSCs. We report that under coculture conditions, RNA demethylase ALKBH5-mediated FIP200 mRNA demethylation enhanced autophagic flux and attenuated the apoptosis of NPCs under compression. Specific silencing of ALKBH5 results in impaired autophagic flux and a higher proportion of apoptotic NPCs under compression, even when cocultured with BMSCs. Mechanistically, we further identify that the m6A "reader" YTHDF2 is likely to be involved in the regulation of autophagy, and lower m6A levels in the coding region of FIP200 lead to a reduction in YTHDF2-mediated mRNA degradation of FIP200, a core molecular component of the ULK1 complex that participates in the initiating process of autophagy. Taken together, our study reveals the roles of ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis in NPCs when cocultured with BMSCs.

Keyhole Foraminotomy via a Percutaneous Posterior Full-endoscopic Approach for Cervical Radiculopathy: An Advanced Procedure and Clinical Study.

Endoscopic cervical foraminotomy is increasingly used for cervical spondylotic radiculopathy (CSR), but there is great concern about radiation exposure because of the heavy dependence of this surgical method on fluoroscopy. The objective of this study was to introduce in detail an advanced surgical technique of keyhole foraminotomy via a percutaneous posterior full-endoscopic approach as a treatment for CSR and investigate its clinical outcomes. We retrospectively reviewed 33 consecutive patients with CSR who underwent keyhole foraminotomy via a percutaneous posterior full-endoscopic approach from October 2015 to April 2017. The patients' general characteristics, including operative time, blood loss, hospital stay, complications, and recurrence, were obtained. Clinical outcomes were evaluated using the visual analogue scale (VAS) for radicular pain, the neck disability index (NDI) for functional assessment, and the modified MacNab criteria for patient satisfaction. All operations were successfully performed (mean operation time, 62 min), with no measurable blood loss or severe related complications. The mean follow-up was 25 months. The VAS and NDI scores were significantly improved as compared with those in the preoperative period (preoperative vs. final follow-up: 7.6±1.6 vs. 3.83±7.34 for VAS, P<0.01; 69.5%±10.5% vs. 17.54%±13.40% for NDI, P<0.01). Of the 33 patients, 32 (97.0%) had good-to-excellent global outcomes and all patients obtained symptomatic improvement. In conclusion, keyhole foraminotomy via a percutaneous posterior full-endoscopic approach is an efficient, safe, and feasible procedure for the treatment of CSR. Its simplified single-step blunt incision for localization appears to decrease radiation exposure risks.

Biomechanical Evaluation of the Sacral Slope on the Adjacent Segment in Transforaminal Lumbar Interbody Fusion: A Finite Element Analysis.

BACKGROUND: Spinopelvic sagittal parameters have a significant influence on adjacent segment degeneration (ASD) after fusion surgery. The association between ASD and sagittal balance is not well understood. The purpose of this study was to investigate the biomechanical influence of various sacral slope (SS) degrees on adjacent segments after transforaminal lumbar interbody fusion (TLIF) at the L4-L5 level. METHODS: We conducted a finite element model of the L1-S1 based on computed tomography scan images. The L1-S1 model with L4-L5 TLIF was modified with various SS degrees (33°, 38°, 43°, and 48°) to investigate the biomechanical influence of SS on adjacent segments. The range of motion (ROM) and intradiscal pressure (IDP) of the adjacent segments (L3-L4 and L5-S1) were compared among models using various SS angles. RESULTS: When the SS angle increased, the ROM and IDP in L5-S1 decreased gradually after TLIF at the L4-L5 level in all motion patterns. Nevertheless, the ROM and IDP in L3-L4 were not significantly different among various SS angles. CONCLUSIONS: Decreased SS after lumbar fusion surgery may pose a higher risk of ASD. Therefore, restoring appropriate SS should be considered during decision-making prior to fusion surgery to reduce the risk of degenerative changes.

Impaired calcium homeostasis via advanced glycation end products promotes apoptosis through endoplasmic reticulum stress in human nucleus pulposus cells and exacerbates intervertebral disc degeneration in rats.

Previous studies identified advanced glycation end products (AGEs) accumulation in the intervertebral disc (IVD) as an essential risk factor associated with IVD degeneration via accelerated cell apoptosis and impeded extracellular-matrix metabolism; however, the underlying mechanisms have not been fully elucidated. Here, we investigated the effects and mechanisms of AGEs-mediated apoptosis in vitro and in vivo. We evaluated the effects of AGEs on endoplasmic reticulum (ER) stress, apoptosis, and subcellular calcium (Ca2+ ) redistribution. Our data indicated time- and concentration-dependent upregulation of ER-stress responses in AGEs-treated nucleus pulposus (NP) cells. Additionally, we observed marked suppression of AGEs-mediated apoptosis following the inhibition of ER stress using 4-phenylbutyric acid. Moreover, AGEs-induced sustained cytosolic Ca2+ ([Ca2+ ]c) elevation and ER luminal Ca2+ ([Ca2+ ]er) depletion in a concentration- and time-dependent manner in NP cells. Furthermore, we observed significant increases and decreases in levels of the ER-resident Ca2+ -release channels inositol 1,4,5-triphosphate receptor and ryanodine receptor and ER Ca2+ -reuptake pumps sarco/endoplasmic reticulum Ca2+ -ATPase, respectively. Pharmacologically blocking ER Ca2+ release using Ca2+ antagonists significantly ameliorated Ca2+ dyshomeostasis, ER stress, and subsequent apoptosis in NP cells and partially attenuated the progression of IVD degeneration in vivo. These results demonstrated that impaired Ca2+ homeostasis plays an essential role in AGEs-mediated ER stress and subsequent apoptosis in NP cells, with blockage of ER Ca2+ release partially ameliorating subcellular Ca2+ redistribution, ER stress, and apoptosis. Our findings provide novel mechanistic insight into the role of AGEs in the pathogenesis of IVD degeneration and a potential therapeutic strategy.

Berberine ameliorates oxidative stress-induced apoptosis by modulating ER stress and autophagy in human nucleus pulposus cells.

AIM: Nucleus pulposus (NP) cell apoptosis induced by oxidative stress is known to be closely involved in the pathogenesis of intervertebral disc (IVD) degeneration. Berberine, a small molecule derived from Rhizoma coptidis, has been found to exert antioxidative activity and preserve cell viability. The present study aims to investigate whether berberine can prevent NP cell apoptosis under oxidative damage and the potential underlying mechanisms. METHODS AND MATERIALS: The effects of berberine on IVD degeneration were investigated both in vitro and in vivo. KEY FINDINGS: Our results showed that berberine significantly mitigated oxidative stress-decreased cell viability as well as apoptosis in human NP cells. Berberine treatment could attenuate oxidative stress-induced ER stress and autophagy in a concentration-dependent manner. With 4-PBA (ER stress specific inhibitor) and 3-MA (autophagy specific inhibitor) administration, we demonstrated that berberine inhibited oxidative stress-induced apoptosis by modulating the ER stress and autophagy pathway. We also found that the IRE1/JNK pathway was involved in the induction of ER stress-dependent autophagy. With Ca2+ chelator BAPTA-AM utilization, we revealed that oxidative stress-mediated ER stress and autophagy repressed by berberine could be restored by inducing intracellular Ca2+ dysregulation. Furthermore, in vivo study provided evidence that berberine treatment could retard the process of puncture-induced IVD degeneration in a rat model. SIGNIFICANCE: Our results indicate that berberine could prevent oxidative stress-induced apoptosis by modulating ER stress and autophagy, thus offering a novel potential pharmacological treatment strategy for IVD degeneration.

Biomechanical Evaluation of Transforaminal Lumbar Interbody Fusion and Oblique Lumbar Interbody Fusion on the Adjacent Segment: A Finite Element Analysis.

OBJECTIVE: To analyze the biomechanical changes of lumbar adjacent segment by comparing the biomechanics after the surgery of transforaminal lumbar interbody fusion (TLIF) and oblique lumbar interbody fusion (OLIF). METHODS: The finite element model of the L1-S1 was reconstructed via computed tomography scan images. The models of TLIF and OLIF were constructed and analyzed. A 400-N vertical axial pre-load was imposed on the superior surface of L1 and a 10-N·m moment was applied on the L1 superior surface along the radial direction to simulate 4 different physiological motions: flexion, extension, bending, and torsion. The range of motion (ROM) and the intradiscal pressure (IDP) were evaluated and compared with investigate the biomechanical influences of TLIF and OLIF on the adjacent segments (L3-L4 and L5-S1). RESULTS: Compared with the normal model, TLIF and OLIF in all motion patterns increased the ROM and the IDP of adjacent segments. However, the ROM and the IDP between TLIF and OLIF had no significant difference. CONCLUSIONS: The biomechanical analysis showed that both TLIF and OLIF can increase ROM and IDP. It indicates that TLIF and OLIF probably increase the potential risk of adjacent segment degeneration similarly.