Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration.

BACKGROUND: Extracellular matrix stiffness is emerging as a crucial mechanical cue that drives the progression of various diseases, such as cancer, fibrosis, and inflammation. The matrix stiffness of the nucleus pulposus (NP) tissues increase gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In addition, mitochondrial dynamics play a key role in various cellular functions. An in-depth investigation of the pathogenesis of IDD can provide new insights for the development of effective therapies. In this study, we aim to investigate the effects of matrix stiffness on mitochondrial dynamics in IDD. METHODS: To build the gradient stiffness model, NP cells were cultured on polystyrene plates with different stiffness. Western blot analysis, and immunofluorescence staining were used to detect the expression of mitochondrial dynamics-related proteins. Flow cytometry was used to detect the mitochondrial membrane potential and intracellular Ca2+ levels. Apoptosis related proteins, ROS level, and TUNEL staining were performed to assess the effect of substrate stiffness on NP cells. RESULTS: Stiff substrate increased phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 by activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which promoted mitochondrial fission and apoptosis in NP cells. Furthermore, Piezo1 activation was involved in the regulation of the post-translational modifications of Drp1 and mitochondrial fission caused by matrix stiffness. Inhibition of Piezo1 and ERK1/2 can effectively reduce stiffness-induced ROS elevation and apoptosis in NP cells. CONCLUSIONS: Our results revealed that stiff substrate causes Piezo1 activation and Ca2+ influx, results in ERK1/2 activation and phosphorylation of Drp1 at S616, and finally leads to mitochondrial fission and apoptosis in NP cells. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for treating IDD.

Bone Repairment via Mechanosensation of Piezo1 Using Wearable Pulsed Triboelectric Nanogenerator.

Bone repair in real time is a challenging medical issue for elderly patients; this is mainly because aged bone marrow mesenchymal stem cells (BMSCs) possess limited osteogenesis potential and repair capacity. In this study, triboelectric stimulation technology is used to achieve bone repair via mechanosensation of Piezo1 by fabricating a wearable pulsed triboelectric nanogenerator (WP-TENG) driven by human body movement. A peak value of 30 µA has the optimal effects to rejuvenate aged BMSCs, enhance their osteogenic differentiation, and promote human umbilical vein endothelial cell tube formation. Further, previous studies demonstrate that triboelectric stimulation of a WP-TENG can reinforce osteogenesis of BMSCs and promote the angiogenesis of human umbilical vein endothelial cells (HUVECs). Mechanistically, aged BMSCs are rejuvenated by triboelectric stimulation via the mechanosensitive ion channel Piezo1. Thus, the osteogenesis potential of BMSCs is enhanced and the tube formation capacity of HUVECs is improved, which is further confirmed by augmented bone repair and regeneration in in vivo investigations. This study provides a potential signal transduction mechanism for rejuvenating aged BMSCs and a theoretical basis for bone regeneration using triboelectric stimulation generated by a WP-TENG.

Vasorin-containing small extracellular vesicles retard intervertebral disc degeneration utilizing an injectable thermoresponsive delivery system.

Intervertebral disc degeneration (IDD) is the pathological reason of back pain and the therapeutic approaches are still unsatisfactory. Recently, mesenchymal stem cell-derived small extracellular vesicles (EVs) have emerged as the novel regenerative method for IDD. In this study, we intensively investigated the therapeutic mechanism of small EVs, and found that vasorin protein enriched in EVs promoted the proliferation and extracellular matrix anabolism of nucleus pulposus cells via the Notch1 signaling pathway. Then, we fabricated a thermoresponsive gel which composed of Pluronic F127 and decellularized extracellular matrix (FEC) for the delivery and sustained release of EVs. Besides, ex vivo and in vivo results showed that EVs embedded in FEC (EVs@FEC) ameliorate the disc degeneration efficiently and achieve better therapeutic effects than one-off EVs delivery. Collectively, these findings deepen the understanding of EVs mechanism in treating intervertebral disc degeneration, and also illustrate the promising capacity of sustained EVs release system for intervertebral disc regeneration.

Preoperative management and postoperative complications associated with transoral decompression for the upper cervical spine.

PURPOSE: This review aimed to describe the preoperative management and postoperative complications associated with transoral decompression of the upper cervical spine, and to clarify the risk factors, related issues and complication management. METHODS: Studies on transoral decompression for the upper cervical spine were reviewed systematically. The preoperative management and postoperative complications associated with transoral decompression for upper cervical deformities were analyzed. RESULTS: Evidence suggests that preoperative management in patients undergoing transoral decompression for the upper cervical spine is closely related to the occurrence of postoperative complications. Hence, preoperative surgical planning, preoperative preparation, and oral nursing care should be seriously considered in these patients. Moreover, while being established as an effective and safe method, transoral decompression is associated with several postoperative complications, which could be prevented by elaborate preoperative management, improved surgical skills, and appropriate precautionary measures. CONCLUSIONS: The effectiveness and safety of transoral decompression has been improved by the constant development of operative techniques and advanced auxiliary diagnostic and therapeutic methods, with the understanding of the anatomical structure of the craniocervical joint. Therefore, the incidence rates of postoperative complications have decreased. The application of individualized anterior implants and less-invasive endoscopic endonasal approach has improved the effectiveness of transoral decompression and reduced the associated complications.

Distal adding-on after surgery in Lenke 5C adolescent idiopathic scoliosis: clinical and radiological outcomes.

BACKGROUND: To evaluate the incidence and risk factors of postoperative distal adding-on in patients with Lenke 5C adolescent idiopathic scoliosis (AIS). More accurate selection criteria for the lower instrumented vertebra (LIV) should be confirmed to prevent distal adding-on. METHODS: Forty-six patients with Lenke 5C AIS who underwent posterior fusion were enrolled in the study. Patients were allocated into adding-on and no adding-on groups. Demographic data, clinical data, and radiographic parameters were recorded and compared. RESULTS: Postoperative distal adding-on occurred in eight patients (17.4%) during follow-up. Demographic data, clinical data, and baseline radiographic parameters of the two groups were not significantly different. The postoperative thoracolumbar (TL) or lumbar (L) Cobb angle, LIV translation, and LIV + 1 translation were higher in the adding-on group than those in the no adding-on group, while the postoperative coronal imbalance of the adding-on group was lower than that of the no adding-on group. The level difference of last barely touched vertebra (LBTV) and last substantial touched vertebra (LSTV) with LIV were higher in the adding-on group than in the no adding-on group. CONCLUSION: Postoperative TL/L curve, postoperative LIV translation, postoperative LIV + 1 translation, and postoperative coronal imbalance were determined as risk factors for postoperative distal adding-on in patients with Lenke 5C AIS. Moreover, LIV selection of LBTV-1 or LSTV-1 may cause a higher risk of postoperative distal adding-on.

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.

Angiotensin (1-7) Alleviates Postresuscitation Myocardial Dysfunction by Suppressing Oxidative Stress Through the Phosphoinositide 3-Kinase, Protein Kinase B, and Endothelial Nitric Oxide Synthase Signaling Pathway.

ABSTRACT: There is increasing evidence that angiotensin (1-7) [Ang (1-7)] is an endogenous biologically active component of the renin-angiotensin system. However, the role of the Ang (1-7)-MasR axis in postresuscitation myocardial dysfunction (PRMD) and its associated mechanism are still unclear. In this study, we investigated the effect of the Ang (1-7)-MasR axis on myocardial injury after cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation. We established a model of oxygen/glucose deprivation-reperfusion in myocardial cells in vitro and a rat model of cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation in vivo. The cell apoptosis rate and the expression of the superoxide anion 3-nitrotyrosine were decreased in the Ang (1-7) group in vitro and in vivo. The mean arterial pressure was decreased, whereas +LVdp/dtmax and -LVdp/dtmax were increased in rats in the Ang (1-7) group. The mRNA and protein levels of Ang II type 1 receptor, MasR, phosphoinositide 3-kinase, protein kinase B, and endothelial nitric oxide synthase were increased in the Ang (1-7) group in vivo. These results indicate that the Ang (1-7)-MasR axis can alleviate PRMD by reducing myocardial tissue damage and oxidative stress through activation of the phosphoinositide 3-kinase-protein kinase B-endothelial nitric oxide synthase signaling pathway and provide a new direction for the clinical treatment of PRMD.

lncRNA HOTAIR upregulates autophagy to promote apoptosis and senescence of nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is a complex and chronic disease that involves disc cell senescence, death, and extracellular matrix (ECM) degradation. HOTAIR, a long non-coding RNA (lncRNA) is reportedly associated with autophagy, whereas autophagy is shown to promote IDD. However, how it affects nucleus pulposus (NP) cells, the primary component of intervertebral discs is still unclear. We hypothesized that HOTAIR promotes NP cell apoptosis and senescence through upregulating autophagy. Thus, silencing HOTAIR should inhibit autophagy and exert a therapeutic effect on IDD. Our in vitro experiments in human NP cells revealed that HOTAIR expression positively correlated with IDD grade, and overexpression enhanced autophagy. Autophagy inhibition via 3-methyladenine reversed HOTAIR stimulatory effects on apoptosis, senescence, and ECM catabolism, while the AMP-activated protein kinase (AMPK) inhibitor Compound C suppressed HOTAIR-induced autophagy through regulating AMPK/mTOR/ULK1 pathways. Our in vivo experiment then illustrated that silencing HOTAIR ameliorates IDD in rats. Collectively, we demonstrated that HOTAIR stimulates autophagy to promote NP cell apoptosis, senescence, and ECM catabolism. Therefore, silencing HOTAIR has the potential to become a treatment option for IDD.

Comparison of lumbar endoscopic unilateral laminotomy bilateral decompression and minimally invasive surgery transforaminal lumbar interbody fusion for one-level lumbar spinal stenosis.

BACKGROUND: The aim of the present study is to compare the clinical outcomes and postoperative complications of lumbar endoscopic unilateral laminotomy bilateral decompression (LE-ULBD) and minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF) to treat one-level lumbar spinal stenosis (LSS) without degenerative spondylolisthesis or deformity. METHODS: A retrospective analysis of 112 consecutive patients of one-level LSS undergoing either LE-ULBD or MIS-TLIF was performed. Patient demographics, operation time, estimated blood loss, time to ambulation, length of hospitalization, intraoperative and postoperative complications were recorded. The visual analog scale (VAS) score for leg and back pain, the Oswestry Disability Index (ODI) score, and the Macnab criteria were used to evaluate the clinical outcomes. The healthcare cost was also recorded. RESULTS: The operation time, estimated blood loss, time to ambulation and length of hospitalization of LE-ULBD group were shorter than MIS-TLIF group. The postoperative mean VAS and ODI scores decreased significantly in both groups. According to the modified Macnab criteria, the outcomes rated as excellent/good rate were 90.6 and 93.8% in the two groups. The mean VAS scores, ODI scores and outcomes of the modified Macnab criteria of both groups were of no significant difference. The healthcare cost of LE-ULBD group was lower than MIS-TLIF group. Two cases of intraoperative epineurium injury were observed in the LE-ULBD group. One case of cauda equina injury was observed in the LE-ULBD group. No nerve injury, dural injury or cauda equina syndrome was observed in MIS-TLIF group. However, one case with transient urinary retention, one case with pleural effusion, one case with incision infection and one case with implant dislodgement were observed in MIS-TLIF group. CONCLUSIONS: Both LE-ULBD and MIS-TLIF are safe and effective to treat one-level LSS without degenerative spondylolisthesis or deformity. LE-ULBD is a more minimally invasive option and of less economic burden compared with MIS-TLIF. Decompression plus instrumented fusion may be not necessary for one-level LSS without degenerative spondylolisthesis or deformity.

The efficacy of allograft bone using titanium mesh in the posterior-only surgical treatment of thoracic and thoracolumbar spinal tuberculosis.

BACKGROUND: The bony fusion of allograft bone using titanium mesh in the posterior-only surgical treatment of thoracic and thoracolumbar spinal tuberculosis has not been explained in detail. We aimed to analyze the efficacy of bony fusion of allograft bone using titanium mesh in the posterior-only surgical treatment of thoracic and thoracolumbar spinal tuberculosis. METHODS: We treated 32 thoracic or thoracolumbar tuberculosis patients by one-stage posterior debridement, allograft bone graft using titanium mesh, posterior instrumentation, and fusion from May 2011 to September 2015. The American Spinal Injury Association neurological classification, visual analog scale, and Oswestry disability index scores were analyzed preoperatively, postoperatively, and at final follow-up. The Cobb angles were recorded to evaluate the kyphosis correction and the loss of correction. The bony fusion was evaluated by X-ray and computed tomography images, and the bony fusion classifications were recorded. RESULTS: All patients had pain relief. The erythrocyte sedimentation rate, C-response protein, and hepatorenal function were normal at final follow-up. The American Spinal Injury Association neurological classification, visual analog scale, and Oswestry disability index scores were improved in all the patients. All patients achieved bone fusion. Twenty-eight patients achieved complete fusion (Grade I), whereas only four patients achieved partial fusion (Grade II). The preoperative Cobb angle was 33.6 ± 9.3°. The Cobb angle was reduced to 10.6 ± 2.6° postoperatively and was found to be 11.4 ± 3.1° at the final follow-up. The mean angle correction was 23.0 ± 8.9°, and the correction rate was 66.2 ± 12.2%. The mean angle lost was 0.8 ± 0.9°, and the lost rate was 5.8 ± 5.4% at the final follow-up. CONCLUSIONS: Allograft bone using titanium mesh in the posterior-only surgical treatment is effective for patients with thoracic and thoracolumbar spinal tuberculosis. It can correct kyphosis, and most patients can achieve complete bony fusion.

Biomechanical Comparison of Different Surgical Strategies for Skip-level Cervical Degenerative Disc Disease: A Finite Element Study.

STUDY DESIGN: We constructed finite element (FE) models of the cervical spine consisting of C2-C7 and predicted the biomechanical effects of different surgical procedures and instruments on adjacent segments, internal fixation systems, and the overall cervical spine through FE analysis. OBJECTIVE: To compare the biomechanical effects between zero-profile device and cage-plate device in skip-level multistage anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is often considered as the standard treatment for degenerative cervical spondylosis. However, the selection of surgical methods and instruments in cases of skip-level cervical degenerative disc disease is still controversial. METHODS: Three FE models were constructed, which used noncontiguous 2-level Zero-P (NCZP) devices for C3/4 and C5/6, a noncontiguous 2-level cage-plate (NCCP) for C3/4 and C5/6, and a contiguous 3-level cage-plate (CCP) for C3/6. Simulate daily activities in ABAQUS. The range of motion (ROM), von Mises stress distribution of the endplate and internal fixation system, and intervertebral disc pressure (IDP) of each model were recorded and compared. RESULTS: Similar to the stress of the cortical bone, the maximum stress of the Zero-P device was higher than that of the CP device for most activities. The ROM increments of the superior, inferior, and intermediate segments of the NCZP model were lower than those of the NCCP and CCP models in many actions. In terms of the IDP, the increment value of stress for the NCZP model was the smallest, whereas those of the NCCP and CCP models were larger. Similarly, the increment value of stress on the endplate also shows the minimum in the NCZP model. CONCLUSIONS: Noncontiguous ACDF with zero-profile can reduce the stress on adjacent intervertebral discs and endplates, resulting in a reduced risk of adjacent segment disease development. However, the high cortical bone stress caused by the Zero-P device may influence the risk of fractures.

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration.

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia-mutated and Rad3-related protein (ATR) deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS/STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanistically, disassembly of the ATR-tripartite motif-containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Biomechanical Comparison of Different Surgical Approaches for the Treatment of Adjacent Segment Diseases after Primary Transforaminal Lumbar Interbody Fusion: A Finite Element Analysis.

BACKGROUND AND OBJECTIVE: Adjacent segment disease (ASD) is a well-known complication after interbody fusion. Revision surgery is necessary for symptomatic ASD to further decompress and fix the affected segment. However, no optimal construct is accepted as a standard in treating ASD. The purpose of this study was to compare the biomechanical effects of different surgical approaches for the treatment of ASD after primary transforaminal lumbar interbody fusion (TLIF). METHODS: A finite element model of the L1-S1 was conducted based on computed tomography scan images. The primary surgery model was developed with a single-level TLIF at L4-L5 segment. The revision surgical models were developed with anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), or TLIF at L3-L4 segment. The range of motion (ROM), intradiscal pressure (IDP), and the stress in cages were compared to investigate the biomechanical influences of different surgical approaches. RESULTS: The results indicated that all the three surgical approaches can stabilize the spinal segment by reducing the ROM at revision level. The ROM and IDP at adjacent segments of revision model of TLIF was greater than those of other revision models. While revision surgery with ALIF and LLIF had similar effects on the ROM and IDP of adjacent segments. Compared among all the surgical models, cage stress in revision model of TLIF was the maximum in extension and axial rotation. CONCLUSION: The IDP at adjacent segments and stress in cages of revision model of TLIF was greater than those of ALIF and LLIF. This may be that direct extension of the surgical segment in the same direction results in stress concentration.

3D Printed Biomimetic Metamaterials with Graded Porosity and Tapering Topology for Improved Cell Seeding and Bone Regeneration.

Biomimetic metallic biomaterials prepared for bone scaffolds have drawn more and more attention in recent years. However, the topological design of scaffolds is critical to cater to multi-physical requirements for efficient cell seeding and bone regeneration, yet remains a big scientific challenge owing to the coupling of mechanical and mass-transport properties in conventional scaffolds that lead to poor control towards favorable modulus and permeability combinations. Herein, inspired by the microstructure of natural sea urchin spines, biomimetic scaffolds constructed by pentamode metamaterials (PMs) with hierarchical structural tunability were additively manufactured via selective laser melting. The mechanical and mass-transport properties of scaffolds could be simultaneously tuned by the graded porosity (B/T ratio) and the tapering level (D/d ratio). Compared with traditional metallic biomaterials, our biomimetic PM scaffolds possess graded pore distribution, suitable strength, and significant improvements to cell seeding efficiency, permeability, and impact-tolerant capacity, and they also promote in vivo osteogenesis, indicating promising application for cell proliferation and bone regeneration using a structural innovation.

Lysine methylation of PPP1CA by the methyltransferase SUV39H2 disrupts TFEB-dependent autophagy and promotes intervertebral disc degeneration.

Impaired transcription factor EB (TFEB) function and deficient autophagy activity have been shown to aggravate intervertebral disc (IVD) degeneration (IDD), yet the underlying mechanisms remain less clear. Protein posttranslational modifications (PTMs) are critical for determining TFEB trafficking and transcriptional activity. Here, we demonstrate that TFEB activity is controlled by protein methylation in degenerated nucleus pulposus cells (NPCs), even though TFEB itself is incapable of undergoing methylation. Specifically, protein phosphatase 1 catalytic subunit alpha (PPP1CA), newly identified to dephosphorylate TFEB, contains a K141 mono-methylated site. In degenerated NPCs, increased K141-methylation of PPP1CA disrupts its interaction with TEFB and subsequently blocks TEFB dephosphorylation and nuclear translocation, which eventually leads to autophagy deficiency and NPC senescence. In addition, we found that the PPP1CA-mediated targeting of TFEB is facilitated by the protein phosphatase 1 regulatory subunit 9B (PPP1R9B), which binds with PPP1CA and is also manipulated by K141 methylation. Further proteomic analysis revealed that the protein lysine methyltransferase suppressor of variegation 3-9 homologue 2 (SUV39H2) is responsible for the K141 mono-methylation of PPP1CA. Targeting SUV39H2 effectively mitigates NPC senescence and IDD progression, providing a potential therapeutic strategy for IDD intervention.

Stiff Substrate Induces Nucleus Pulposus Cell Ferroptosis via YAP and N-Cadherin Mediated Mechanotransduction.

Increased tissue stiffness is associated with various pathological processes, such as fibrosis, inflammation, and aging. The matrix stiffness of the nucleus pulposus (NP) tissues increases gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In this study, the results indicate that ferroptosis is involved in stiff substrate-induced NP cell death. The expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) increases in NP cells of the stiff group, which mediates lipid peroxidation and ferroptosis in NP cells. In addition, stiff substrate activates the hippo signaling cascade and induces the nuclear translocation of yes-associated protein (YAP). Interestingly, inhibition of YAP is efficient to reverse the increase of ACSL4 expression caused by matrix stiffness. Furthermore, stiff substrate suppresses the expression of N-cadherin in NP cells. N-cadherin overexpression can inhibit YAP nuclear translocation via the formation of the N-cadherin/ß-catenin/YAP complex, and reverse matrix stiffness-induced ferroptosis in NP cells. Finally, the effects of YAP inhibition and N-cadherin overexpression on IDD progression are further illustrated in animal models. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for the treatment of IDD.

Evaluation of the Radiographic Risk Factors of Postoperative Shoulder Imbalance in Adult Scoliosis.

Objective: This study aimed to evaluate the radiographic risk factors of postoperative shoulder imbalance (PSI) after adult scoliosis (AS) correction surgery. Methods: Seventy-nine patients with AS undergoing correction surgery at a single institution were reviewed. The mean follow-up was 28 months. Patients were divided into two groups based on their radiographic shoulder height (RSH): (1) the balanced group (RSH <10 mm) and (2) the unbalanced group (RSH ≥10 mm). The preoperative and postoperative Cobb angles of the proximal thoracic (PT), main thoracic (MT), thoracolumbar/lumbar (TL/L) and upper instrumented vertebra (UIV) were measured. Results: No significant difference was found between the balanced and unbalanced groups when the UIV was T1-2, T3-4, or below T4. Univariate analysis indicated that the unbalanced group had significantly higher postoperative RSH, lower percentage PT correction, and greater percentage MT correction. The classification and regression tree analysis revealed that when the correction percentage of PT curve was more than 55.3%, 84.4% of patients acquired shoulder balance. However, when the correction percentage of PT curve was less than 55.3%, and the correction percentage of MT curve was more than 56%, 65.7% of the patients developed PSI. Conclusions: In AS correction surgery, a lower percentage correction of the PT curve and greater percentage correction of the MT curve were independent radiographic risk factors of PSI, regardless of the UIV level. Sufficient PT correction is required to achieve postoperative shoulder balance in AS correction surgery when the MT curve is overcorrected.

Case Report: Transvertebral transposition of the spinal cord for recovery after paraplegia during kyphoscoliosis surgery.

Introduction: Neurological impairment during spinal deformity surgery is the most serious possible complication. When confronting intraoperative neurophysiological monitoring alerts, various surgical management methods such as the release of implants and decompression of the spinal cord are always performed. Transvertebral transposition of the spinal cord is rarely performed, and its role in the management of acute paraplegia is seldom reported. Case description: The authors present two patients with kyphoscoliosis who experienced neurological deficits and abnormal neurological monitoring intraoperatively or post-operatively that were detected during correction surgery. Acute paraplegia was confirmed by a wake-up test. Subsequent spinal cord transposition was performed. Intraoperative neurophysiological monitoring motor-evoked potentials (MEPs) and somatosensory-evoked potentials (SEPs) were performed to detect the changes during the process. After transvertebral transposition of the spinal cord, the MEPs and SEPs were significantly improved in both patients during surgery. The spinal cord function was restored post-operatively and recovered to normal at the final follow-up in two patients. Conclusion: This case demonstrated that instead of decreasing the correction ratio of kyphoscoliosis, transvertebral transposition of the spinal cord under intraoperative neurophysiological monitoring may be an alternative therapeutic strategy for acute spinal cord dysfunction caused by deformity correction surgeries.

Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis.

Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with a high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death and the development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as a damage-associated molecular pattern (DAMP) that is monitored by the cGAS-STING axis to trigger the immune response in many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis is a type of inflammatory programmed death that promotes a chronic inflammatory response and tissue degeneration. However, the relationship between the cGAS-STING axis and NLRP3 inflammasome-induced pyroptosis in the pathogenesis of IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) and histopathology to demonstrate that cGAS, STING, and NLRP3 are associated with the degree of IVD degeneration. Oxidative stress induced cGAS-STING axis activation and NLRP3 inflammasome-mediated pyroptosis in a STING-dependent manner in human NP cells. Interestingly, the canonical morphological and functional characteristics of mitochondrial permeability transition pore (mPTP) opening with the cytosolic escape of mitochondrial DNA (mtDNA) were observed in human NP cells under oxidative stress. Furthermore, the administration of a specific pharmacological inhibitor of mPTP and self-mtDNA cytosolic leakage effectively reduced NLRP3 inflammasome-mediated pyroptotic NP cell death and microenvironmental inflammation in vitro and degenerative progression in a rat disc needle puncture model. Collectively, these data highlight the critical roles of the cGAS-STING-NLRP3 axis and pyroptosis in the progression of IVD degeneration and provide promising therapeutic approaches for discogenic LBP.

WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration.

N6-methyladenosine (m6A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m6A regulation in intervertebral disc degeneration (IVDD) remains elusive. Here, we show that methylation of the lncRNA NORAD significantly increases in senescent nucleus pulposus cells (NPCs) by m6A sequencing. Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent NPCs due to an epigenetic increase in H3K4me3 of the promoter mediated by KDM5a, and significantly promotes NORAD m6A modification. Furthermore, YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1/2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. Here, we show interruption of NORAD m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.