[Endoplasmic reticulum quality control system: a potential target for the treatment of intervertebral disc degeneration].

As the largest organelle in eukaryotic cells, the endoplasmic reticulum (ER) plays a crucial role in regulating intracellular protein folding, translation and assembly. Multiple quality control mechanisms in the ER ensure accurate modification of proteins in the ER lumen are accurately modified, thus maintaining calcium homeostasis, oxidative stress, cellular senescence and apoptosis. These mechanisms include ER stress (ERS), ER autophagy (ER-phagy, ERPA) and ER-associated degradation (ERAD). Intervertebral disc degeneration (IDD) is an age-related degenerative disease of the spine. Although the pathogenesis of IDD has not been fully elucidated, emerging evidence suggests that the ER quality control system may be involved in its progression. Previous studies have focused on mitochondrial quality control and its related mechanisms in diseases, with limited systematic summaries on the ER quality control system. In this paper, we comprehensively reviewed the molecular mechanisms of the ER quality control system and investigated its association with IDD. In addition, we summarized the potential therapeutic strategies targeting the ER quality control system to attenuate IDD progression, offering new insights into the pathogenesis and regenerative repair strategies of IDD.

Osteoporosis, spinal degenerative disorders, and their association with low back pain, activities of daily living, and physical performance in a general population.

Osteoporosis, vertebral fractures, and spinal degenerative diseases are common conditions that often coexist in older adults. This study aimed to determine the factors influencing low back pain and its impact on activities of daily living (ADL) and physical performance in older individuals with multiple comorbidities. This cross-sectional study was part of a large-scale population-based cohort study in Japan, involving 1009 participants who underwent spinal magnetic resonance imaging (MRI) to assess cervical cord compression, radiographic lumbar spinal stenosis, and lumbar disc degeneration. Vertebral fractures in the thoracolumbar spine were evaluated using sagittal MRI with a semi-quantitative method. Bone mineral density was measured using dual-energy X-ray absorptiometry. Low back pain, Oswestry Disability Index (ODI), and physical performance tests, such as one-leg standing time, five times chair-stand time, maximum walking speed, and maximum step length, were assessed. Using clinical conditions as objective variables and image evaluation parameters as explanatory variables, multiple regression analysis showed that vertebral fractures were significantly associated with low back pain and ODI. Vertebral fractures and osteoporosis significantly impacted physical performance, whereas osteoporosis alone did not affect low back pain or ODI. Our findings contribute to new insights into low back pain and its impact on ADL and physical performance.

Enzymatic denaturation versus excessive fatigue loading degeneration: Effects on the time-dependent response of the intervertebral disc.

Degenerative disc disease (DDD), regardless of its phenotype and clinical grade, is widely associated with low back pain (LBP), which remains the single leading cause of disability worldwide. This work provides a quantitative methodology for comparatively investigating artificial IVD degeneration via two popular approaches: enzymatic denaturation and fatigue loading. An in-vitro animal study was used to study the time-dependent responses of forty fresh juvenile porcine thoracic IVDs in conjunction with inverse and forward finite element (FE) simulations. The IVDs were dissected from 6-month-old-juvenile pigs and equally assigned to 5 groups (intact, denatured, low-level, medium-level, high-level fatigue loading). Upon preloading, a sinusoid cyclic load (Peak-to-peak/0.1-to-0.8 MPa) was applied (0.01-10 Hz), and dynamic-mechanical-analyses (DMA) was performed. The DMA outcomes were integrated with a robust meta-model analysis to quantify the poroelastic IVD characteristics, while specimen-specific FE models were developed to study the detailed responses. The results demonstrated that enzymatic denaturation had a more significantly pronounced effect on the resistive strength and shock attenuation capabilities of the intervertebral discs. This can be attributed to the simultaneous disruption of the collagen fibers and water-proteoglycan bonds induced by trypsin digestion. Fatigue loading, on the other hand, primarily influenced the disc's resistance to deformation in a frequency-dependent pattern, where alterations were most noticeable at low loading frequencies. This study confirms the intricate interplay between the biochemical changes induced by enzymatic processes and the mechanical behavior stemming from fatigue loading, suggesting the need for a comprehensive approach to closely mimic the interrelated multifaceted processes of human disc degeneration.

Biomechanical analysis of single and multi-level artificial disc replacement (ADR) in cervical spine using multi-scale loadings: A finite element study.

Artificial disc replacement (ADR) is a clinical procedure used to diagnose cervical degenerative disc disease, preserving range of motion (ROM) at the fixation level and preventing adjacent segment degeneration (ASD). This study analyzed the biomechanics of ADR by examining range of motion (ROM), stress levels in bone and implants, and strain in the bone-implant interface using multi-scale loadings. The study focused on single- and double-level patients across various loading scales during physiological motions within the cervical spine. Results showed increased ROM in single-level and double-level fixations during physiological loadings, while ROM decreased at the adjacent level of fixation with the intact cervical spine model. The Prodisc-Implant metal endplate experienced a maximum von Mises stress of 432 MPa during axial rotation, confirming the long durability and biomechanical performance of the bone-implant interface.

Biomechanics of annulus fibrosus: Elastic fiber simplification and degenerative impact on damage initiation and propagation.

This study addresses three primary objectives related to lumbar intervertebral disc (IVD) biomechanics under ramping quasi-static loading conditions. First, we explore the conditions justifying the simplification of axisymmetric elastic fiber families into single fiber bundles through discretized strain energy functions. Simulations reveal that a concentration factor exceeding 10 allows for a consistent deviation below 10% between simplified and non-simplified responses. Second, we investigate the impact of elastic fibers on the physiological stiffness in IVDs, revealing minimal influence on biological motions but significant effects on degeneration. Lastly, we examine the initiation and progression of annulus fibrosus (AF) damage. Our findings confirm the validity of simplifying elastic fiber families and underscore the necessity of considering elastic fiber damage in biomechanical studies of AF tissues. Elastic fibers contribute to increased biaxial stretch stiffness, and their damage significantly affects the loading capacity of the inner AF. Additionally, degeneration significantly alters the susceptibility to damage in the AF, with specific regions exhibiting higher vulnerability. Damage tends to extend circumferentially and radially, emphasizing the regional variations in collagen and elastic fiber properties. This study offers useful insights for refining biomechanical models, paving the way for a more comprehensive understanding of IVD responses and potential clinical implications.

Is the disappearance of the cervical flexion-relaxation phenomenon associated with cervical degeneration in healthy people?

PURPOSE: This study aims to explore the differences in cervical degeneration between healthy people with and without cervical flexion-relaxation phenomenon (FRP) and to identify whether the disappearance of cervical FRP is related to cervical degeneration. METHODS: According to the flexion relaxation ratio (FRR), healthy subjects were divided into the normal FRP group and the abnormal FRP group. Besides, MRI was used to evaluate the degeneration of the passive subsystem (vertebral body, intervertebral disc, cervical sagittal balance, etc.) and the active subsystem (deep flexors [DEs], deep extensors [DFs], and superficial extensors [SEs]). In addition, the correlation of the FRR with the cervical degeneration score, C2-7Cobb, Borden method, relative total cross-sectional area (rTCSA), relative functional cross-sectional area (rFCSA), and fatty infiltration ratio (FIR) was analyzed. RESULTS: A total of 128 healthy subjects were divided into the normal FRP group (n=52, 40.63%) and the abnormal FRP group (n=76, 59.38%). There were significant differences between the normal FRP group and the abnormal FRP group in the cervical degeneration score (z=-6.819, P<0.001), C2-7Cobb (t=2.994, P=0.004), Borden method (t=2.811, P=0.006), and FIR of DEs (t=-4.322, P<0.001). The FRR was significantly correlated with the cervical degeneration score (r=-0.457, P<0.001), C2-7Cobb (r=0.228, P=0.010), Borden method (r=0.197, P=0.026), and FIR of DEs (r=-0.253, P=0.004). CONCLUSION: The disappearance of cervical FRP is related to cervical degeneration. A new hypothesis mechanism for FRP is proposed. The cervical FRP test is an effective and noninvasive examination for the differential diagnosis of healthy people, people with potential NSNP, and patients with NSNP.

Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family.

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.

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 the 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 the standard treatment for degenerative cervical spondylosis. However, the selection of surgical methods and instruments in cases of skip-level cervical degenerative disk disease is still controversial. MATERIALS AND 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 disk 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 disks 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.

Different Load-Induced Alterations in Intervertebral Discs Between Low Back Pain Patients and Controls: A T2-map Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVE: Investigate load-induced effects in lumbar intervertebral discs (IVDs) and differences between low back pain (LBP) patients and controls. SUMMARY OF BACKGROUND DATA: T2-map values, obtained from quantitative MRI sequences, reflect IVD tissue composition and integrity. Feasibility studies with T2-mapping indicate different load-induced effects in entire IVDs and posterior IVD parts between LBP patients and controls. Larger studies are required to confirm these findings and increase the understanding of specific characteristics distinguishing IVD changes in LBP patients compared with controls. MATERIALS AND METHODS: Lumbar IVDs of 178 patients (mean age: 43.8 yr; range: 20-60 yr) with >3 months of LBP and 74 controls (mean age: 40.3 yr; range: 20-60 yr) were imaged with T2-map sequence in a 3T scanner in supine position without axial load, immediately followed by a repeated examination, using the same sequence, with axial load. On both examinations, mean T2-map values were obtained from entire IVDs and from central/posterior IVD parts on the three midsagittal slices in 855 patient IVDs and 366 control IVDs. Load-induced effect was compared with Fold-change ratio and adjusted for IVD-degeneration grade. RESULTS: Loading induced an increase in T2-map values in both patients and controls. Excluding most extreme values, the ranges varied between -15% and +35% in patients and -11% and +36% in controls (first to 99th percentile). Compared with controls, the T2-map value increase in patients was 2% smaller in entire IVDs (Fold-change: 0.98, P =0.031), and for central and posterior IVD parts 3% (Fold-change: 0.98, P =0.005), respectively, 2% (Fold-change: 0.9, P =0.015) smaller. CONCLUSIONS: This quantitative study confirmed diverse load-induced behaviors between LBP patients and controls, suggesting deviant biomechanical characteristics between IVDs in patients and controls not only attributed to the global grade of degeneration. These findings are an important step in the continuous work of identifying specific IVD phenotypes for LBP patients. LEVEL OF EVIDENCE: Level II.

Biomechanical investigation of a customized interspinous spacer system in the treatment of degenerative disc diseases: A finite element analysis.

BACKGROUND: A novel interspinous fixation system based on anatomical parameters and incorporating transfacetopedicular screws, was developed to treat degenerative disc diseases. The biomechanical characteristics of the novel system were evaluated using finite element analysis in comparison to other classical interspinous spacers. METHODS: The L1-S1 lumbar spine finite element models were surgically implanted with the novel system, Coflex and DIAM devices at the L4/L5 segment to assess the range of motion, the pression distribution of intervertebral disc, the peak stresses on the spinous process and implant during various motions. FINDINGS: Range of motions of the L4/L5 surgical segment were reduced by 29.13%, 61.27%, 77.35%, 33.33%, and the peak stresses of intervertebral disc were decreased by 36.82%, 67.31%, 73.00%, 69.57% for the novel system in flexion, extension, lateral bending, and axial rotation when compared with the Coflex, and they were declined by 34.53%, 57.86%, 75.81%, 25.21%; 36.22%, 67.31%, 75.01%, 71.40% compared with DIAM. The maximum stresses of the spinous process were 29.93 MPa, 24.66 MPa, 14.45 MPa, 24.37 MPa in the novel system, and those of Coflex and DIAM were 165.3 MPa, 109 MPa, 84.79 MPa, 47.66 MPa and 52.59 MPa, 48.78 MPa, 50.27 MPa, 44.16 MPa during the same condition. INTERPRETATION: Compared to other interspinous spacer devices, the novel interspinous fixation system demonstrated excellent stability, effectively distributing load on the intervertebral disc, and reducing the risk of spinous process fractures. The personalized design of the novel interspinous fixation system could be a viable option for treating degenerative disc diseases.

Biomechanical repercussion of sitting posture on lumbar intervertebral discs: A systematic review.

BACKGROUND: The static sitting position contributes to increased pressure on the lumbar intervertebral disc, which can lead to dehydration and decreased disc height. OBJECTIVE: To systematically investigate the of sitting posture on degeneration of the lumbar intervertebral disc. MATERIALS AND METHODS: One researcher carried out a systematic literature search of articles with no language or time limits. Studies from 2006 to 2018 were found. The searches in all databases were carried out on January 28, 2022, using the following databases: Pubmed, Scopus, Embase, Cochrane, and Physiotherapy Evidence Database (PEDro) databases, and for the grey literature: Google scholar, CAPES Thesis and Dissertation Bank, and Open Grey. The acronym PECOS was used to formulate the question focus of this study: P (population) - male and female subjects; E (exposure) - sitting posture; C (comparison) - other posture or sitting posture in different periods; O (outcomes) - height and degeneration of the lumbar intervertebral disc(s), imaging exam; and S (study) - cross-sectional and case control. RESULTS: The risk of bias was in its moderate totality in its outcome: height and degeneration of the lumbar intervertebral disc(s) - imaging. Of the four selected studies, three found a decrease in the height of the disc(s) in sitting posture. CONCLUSION: The individual data from the manuscripts suggest that the sitting posture causes a reduction in the height of the lumbar intervertebral disc. It was also concluded that there is a need for new primary studies with a more in-depth design and sample size.

Evolving role of VIADISC for chronic low back and discogenic pain: a narrative review.

INTRODUCTION: Chronic lower back pain is a leading cause of disability and healthcare spending worldwide. Discogenic pain, pain originating from the intervertebral disk, is a common etiology of chronic lower back pain. Currently, accepted treatments for chronic discogenic pain focus only on the management of symptoms, such as pain. There are no approved treatments that stop or reverse degenerating intervertebral discs. Biologic therapies promoting disc regeneration have been developed to expand treatment options. VIADISC™ NP, is a viable disc allograft supplementation that, in a recent trial, demonstrated a significant reduction in pain and increased function in patients suffering from symptomatic degenerative disc disease. AREAS COVERED: This manuscript summarizes the epidemiology and etiology of low back pain, the pathophysiology of degenerative disc disease, current treatments, and a need for newer therapies. The rationale behind intradiscal biologics for the treatment of symptomatic degenerative disc disease is also discussed. EXPERT OPINION: Characterization of the biology leading to disc degeneration has allowed for the development of intradiscal biologics. They may soon be capable of preventing and reversing disc degeneration. Clinical trials have shown promise, but further research into efficacy and safety is needed before these therapies are widely employed.

Update on the Correlation Between Mitochondrial Dysfunction and Intervertebral Disk Degeneration.

Low back pain (LBP) is a common disorder in orthopedic outpatients, affecting people of all ages, and some patients may develop chronic LBP. As a complex organelle, mitochondria are not only energy workstations but also regulate cell senescence, apoptosis, and homeostasis. Mitochondrial dysfunction promotes disk degeneration by affecting a variety of pathophysiological processes, including oxidative stress, mitophagy, mitochondrial homeostasis, cellular senescence, and cell death. We review the molecular mechanisms underlying the relationship between mitochondrial dysfunction and intervertebral disk degeneration (IDD) to provide a theoretical basis for IDD treatment using pharmacological or tissue-engineering approaches.

Rebalance of the Polyamine Metabolism Suppresses Oxidative Stress and Delays Senescence in Nucleus Pulposus Cells.

Intervertebral disk degeneration (IDD) is a major cause of low back pain that becomes a prevalent age-related disease. However, the pathophysiological processes behind IDD are rarely known. Here, we used bioinformatics analysis based on the microarray datasets (GSE34095) to identify the differentially expressed genes (DEGs) as biomarkers and therapeutic targets in degenerated discs. From the previous studies, oxidative stress has been notified as a positive inducement of IDD, which causes DNA damage and accelerates cell senescence. Polyamine oxidase (PAOX), a member of the observed 1057 DEGs, is involved in polyamine metabolism and influences the oxidative balance in cells. However, it is uncertain if the IDD is implicated in the dysregulation of PAOX and polyamine metabolism. This study firstly verified the PAOX upregulation in human degenerated disc samples and applied an IL-1ß-induced nucleus pulposus (NP) cell degeneration model to demonstrate that spermidine supplementation balanced polyamine metabolism and delayed NP cell senescence. Moreover, we confirmed that spermidine/N-acetylcysteine supplementation or Cdkn2a gene deletion stabilized the polyamine metabolism, suppressed oxidative stress, and therefore delayed the progress of IDD in older mice. Collectively, our study highlights the role of polyamine metabolism in IDD and foresees spermidine would be the advanced therapeutical drug for IDD.

G-Protein Coupled Receptor 35 Induces Intervertebral Disc Degeneration by Mediating the Influx of Calcium Ions and Upregulating Reactive Oxygen Species.

Intervertebral disc degeneration (IDD) is a chronic disease affecting millions of patients; however, its specific etiology is unknown. G protein-coupled receptors (GPRs) are a superfamily of integral membrane receptors in cells, and the receptors respond to a diverse range of stimuli and participate in multiple cellular activities. Here, using RNA-sequencing (RNA-seq) methods and immunohistochemistry, we revealed that G protein-coupled receptor 35 (GPR35) may have a relationship with IDD. Then, we demonstrated that the deletion of GPR35 in nucleus pulposus cells (NPCs) with siRNA or in Gpr35-/- mice significantly alleviated IDD caused by senescence or mechanical stress, further validating the pathological role of GPR35 in IDD. In addition, GPR35 induced the influx of Ca2+ and upregulation of reactive oxygen species (ROS) under mechanical stress in NPCs, which we believe to be the mechanism of GPR35-induced IDD. Finally, GPR35 caused upregulation of ROS in NPCs under mechanical stress, while excessive ROS stimulated the NPCs to express more GPR35 with a significant dose or time response. The u-regulated GPR35 could sense mechanical stress to produce more ROS and perpetuate this harmful cycle. In summary, our study shows that GPR35 plays a critical role in mediating IDD via mediating the influx of calcium ions and upregulating ROS, which implies a strong potential advantage of GPR35 as a prevention and treatment target in IDD.

Fundamentals of Intervertebral Disc Degeneration.

Lumbar disc degeneration is one of the leading causes of chronic low back pain. The degenerative cascade is often initiated by an imbalance between catabolic and anabolic processes in the intervertebral discs. As a consequence of extracellular matrix degradation, neoinnervation and neovascularization take place. Ultimately, this degenerative process results in disc bulging and loss of nucleus pulposus and water content and subsequent loss of disc height. Most patients respond to conservative management and surgical interventions well initially, yet a significant number of patients continue to suffer from chronic low back pain. Because of the high prevalence of long-term discogenic pain, regenerative biological therapies, including gene therapies, growth factors, cellular-based injections, and tissue-engineered constructs, have attracted significant attention in light of their potential to directly address the degenerative process. Understanding the pathophysiology of degenerative disc disease is important in both refining existing technologies and developing innovative techniques to reverse the degenerative processes in the discs. In this review, we aimed to cover the underlying pathophysiology of degenerative disc disease as well as its associated risk factors and give a comprehensive summary about the developmental, structural, radiological, and biomechanical properties of human intervertebral discs.

Challenges in the Development of Biological Approaches for the Treatment of Degenerative Disc Disease.

There are numerous innovative and promising approaches aimed at slowing, reversing, or healing degenerative disc disease. However, multiple treatment-specific impediments slow progress toward realizing the benefits of these therapies. First, the exact pathophysiology underlying degenerative disc disease remains complicated and challenging to study. In addition, the study of the spine and intervertebral disc in animal models is difficult to translate to humans, hindering the utility of preclinical research. Biological treatments are subject to the complex biomechanical environment in which native discs degenerate. The regulatory approval environment for these therapeutics will likely involve a high degree of scrutiny. Finally, patient selection and assessment of outcomes are a particular challenge in this clinical setting.

Innovative Biological Treatment Methods for Degenerative Disc Disease.

Low back pain is the leading cause of work absences and years lived with disability, and it is often associated with degenerative disc disease. In recent years, biological treatment approaches such as the use of growth factors, cell injections, annulus fibrosus (AF) repair, nucleus pulposus replacement, and tissue-engineered discs have been explored as means for preventing or reversing degenerative disc disease. Both animal and clinical studies have shown promising results for cell-based therapy on the grounds of its regenerative potential. Clinical data also indicate that stem cell injection is safe when appropriately performed, albeit its long-term safety and efficacy are yet to be explored. Numerous challenges also remain to be overcome, such as isolating, differentiating, and preconditioning the disc cells, as well as managing the nutrient-deficient and oxygen-deficient micromilieu of the intervertebral disc (IVD). AF repair methods including devices used in clinical trials have shown success in decreasing reherniation rates and improving overall clinical outcomes. In addition, recent studies that combined AF repair and nucleus pulposus replacement have shown improved biomechanical stability in IVDs after the combined treatment. Tissue-engineered IVDs for total disc replacement are still being developed, and future studies are necessary to overcome the challenges in their delivery, efficacy, and safety.

Single-Cell Transcriptome Profiling Reveals Multicellular Ecosystem of Nucleus Pulposus during Degeneration Progression.

Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, a comprehensive single-cell resolution transcript landscape of human NP is reported. Six novel human NP cells (NPCs) populations are identified by their distinct molecular signatures. The potential functional differences among NPC subpopulations are analyzed. Predictive transcripts, transcriptional factors, and signal pathways with respect to degeneration grades are explored. It is reported that fibroNPCs is the subpopulation for end-stage degeneration. CD90+NPCs are observed to be progenitor cells in degenerative NP tissues. NP-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid-derived suppressor cells (G-MDSCs). Integrin αM (CD11b) and oxidized low density lipoprotein receptor 1 (OLR1) as surface markers of NP-derived G-MDSCs are uncovered. The G-MDSCs are found to be enriched in mildly degenerated (grade II and III) NP tissues compared to severely degenerated (grade IV and V) NP tissues. Their immunosuppressive function and alleviation effects on NPCs' matrix degradation are revealed in vitro. Collectively, this study reveals the NPC-type complexity and phenotypic characteristics in NP, thereby providing new insights and clues for IVDD treatment.

Mechanical Stretch Induces Annulus Fibrosus Cell Senescence through Activation of the RhoA/ROCK Pathway.

BACKGROUND: Intervertebral disc is responsible for absorbing and transmitting mechanical compression. Under physiological conditions, the peripheral annulus fibrosus (AF) cells are subjected to different magnitudes of transverse mechanical stretch depending on the swelling of the central nucleus pulposus tissue. However, the biological behavior of AF cells under mechanical stretch is not well studied. OBJECTIVE: This study was performed to study the effects of mechanical tension on AF cell senescence and the potential signaling transduction pathway. METHODS: Rat AF cells were made to experience different magnitudes of mechanical stretch (2% elongation and 20% elongation for 4 hours every day at 1 Hz) in a 10-day experiment period. The inhibitor RKI-1447 of the Rho-associated coiled-coil-containing protein kinases (ROCK) was added along with culture medium to investigate its role. Cell proliferation, cell cycle, telomerase activity, and expression of senescence markers (p16 and p53) were analyzed. RESULTS: We found that 20% elongation significantly decreased cell proliferation, promoted G0/G1 cell cycle arrest, decreased telomerase activity, and upregulated mRNA/protein expression of p16 and p53. Moreover, the inhibitor RKI-1447 partly resisted effects of 20% elongation on these parameters of cell senescence. CONCLUSION: High mechanical stretch obviously induces AF cell senescence through the RhoA/ROCK pathway. This study provides us a deeper understanding on the AF cell's behavior under mechanical stretch.