GDF5 as a rejuvenating treatment for age-related neuromuscular failure.

Sarcopenia involves a progressive loss of skeletal muscle force, quality and mass during ageing, which results in increased inability and death; however, no cure has been established thus far. Growth differentiation factor 5 (GDF5) has been described to modulate muscle mass maintenance in various contexts. For our proof of concept, we overexpressed GDF5 by AAV vector injection in Tibialis Anterior (TA) muscle of adult aged (20 months) mice and performed molecular and functional analysis of skeletal muscle. We analysed human Vastus Lateralis muscle biopsies from adult young (21-42 years) and aged (77-80 years) donors, quantifying the molecular markers modified by GDF5 overexpression (OE) in mouse muscle. We validated the major effects of GDF5 overexpression using human immortalized myotubes and Schwann Cells (SCs). We established a pre-clinical study by treating chronically (for 4 months) aged mice using recombinant GDF5 protein (rGDF5) in systemic administration and evaluated the long-term effect of this treatment on muscle mass and function. Here, we demonstrated that GDF5 OE in the old TAs promoted an increase of 16.5% of muscle weight (P = 0.0471) associated with a higher percentage of 5000-6000 µm2 large fibres (P = 0.0211), without the induction of muscle regeneration. Muscle mass gain was associated with an amelioration of 26.8% of rate of force generation (P = 0.0330) and a better neuromuscular connectivity (P = 0.0098). Moreover, GDF5 OE preserved neuromuscular junction (NMJ) morphology (38.5% of nerve terminal area increase, P < 0.0001) and stimulated the expression of re-innervation-related genes, in particular markers of SCs (fold change 3.19 for S100b gene expression, P = 0.0101). To further characterize the molecular events induced by GDF5 OE during ageing, we performed a genome-wide transcriptomic analysis of treated muscles and showed that this factor leads to a "rejuvenating" transcriptomic signature in aged mice, as 42% of the transcripts dysregulated by ageing reverted to youthful expression levels upon GDF5 OE (P < 0.05). Towards a pre-clinical approach, we performed a long-term systemic treatment using rGDF5 and showed its effectiveness in counteracting age-related muscle wasting, improving muscle function (17,8% of absolute maximal force increase, P = 0.0079), ensuring neuromuscular connectivity and preventing NMJ degeneration (7,96% of AchR area increase, P = 0.0125). In addition, in human muscle biopsies, we found the same age-related alterations than those observed in mice and improved by GDF5 and reproduced its major effects on human cells, suggesting this treatment as efficient in humans. Overall, these data provide a foundation to examine the curative potential of GDF5 drug in clinical trials for sarcopenia and, eventually, other neuromuscular diseases.

Tension regulates the cartilage phenotypic expression of endplate chondrocytes through the α-catenin/actin skeleton/Hippo pathway.

The study aimed to investigate the regulatory mechanism of intracellular tension signaling in endplate chondrocytes and its impact on extracellular matrix synthesis. Human endplate chondrocytes were subjected to tension load using Flexcell FX-5000™, and changes in phenotype, morphology, and the expression of Hippo signaling pathway and α-Catenin were assessed through various techniques. Through the overexpression of YAP and inhibition of α-Catenin, the study clarified the intracellular tension signaling pathway and its regulation of extracellular matrix synthesis in endplate cartilage. In vitro-cultured human endplate chondrocytes significantly suppressed phenotype-related genes and proteins, accompanied by distinct changes in cytoskeleton morphology. Tension activation resulted in the substantial activation of the Hippo pathway, increased phosphorylation of YAP, and reduced nuclear translocation of YAP. YAP overexpression alleviated the inhibitory effect of tension on extracellular matrix synthesis in endplate chondrocytes. Tension also upregulated the expression of α-Catenin in endplate chondrocytes, which was attenuated by inhibiting α-Catenin expression, thereby reducing the impact of tension on cytoskeletal morphology and YAP nuclear translocation. Taken together, the α-Catenin/actin skeleton/Hippo-coupled network is a crucial signaling pathway for tension signaling in endplate chondrocytes, providing potential therapeutic targets for the treatment of endplate cartilage degeneration.

LTF ameliorates cartilage endplate degeneration by suppressing calcification, senescence and matrix degradation through the JAK2/STAT3 pathway.

Intervertebral disc degeneration (IDD)-induced cervical and lumbar herniations are debilitating diseases. The function of intervertebral disc (IVD) mainly depends on the cartilage endplate (CEP), which provides support and waste removal. Therefore, IDD stems from the degeneration of CEP. Our study shows that the expression of lactotransferrin (LTF), an iron-binding protein, is significantly decreased in degenerated human and rat CEP tissues. In addition, we found that LTF knockdown promoted calcification, senescence, and extracellular matrix (ECM) degradation in human endplate chondrocytes. Furthermore, the in vivo experiment results confirmed that the JAK2/STAT3 pathway inhibitor AG490 significantly reversed these effects. In addition to investigating the role and mechanism of LTF in CEP degeneration, this study provides a theoretical basis and experimental evidence to improve IDD treatment.

Postnatal Pdzrn3 deficiency causes acute muscle atrophy without alterations in endplate morphology.

PDZ domain-containing RING finger family protein 3 (PDZRN3) is expressed in various tissues, including the skeletal muscle. Although PDZRN3 plays a crucial role in the terminal differentiation of myoblasts and synaptic growth/maturation in myogenesis, the role of this molecule in postnatal muscles is completely unknown despite its lifelong expression in myofibers. In this study, we aimed to elucidate the function of PDZRN3 in mature myofibers using myofiber-specific conditional knockout mice. After tamoxifen injection, PDZRN3 deficiency was confirmed in both fast and slow myofibers of Myf6-CreERT2; Pdzrn3flox/flox (Pdzrn3mcKO) mice. Transcriptome analysis of the skeletal muscles of Pdzrn3mcKO mice identified differentially expressed genes, including muscle atrophy-related genes such as Smox, Amd1/2, and Mt1/2, suggesting that PDZRN3 is involved in the homeostatic maintenance of postnatal muscles. PDZRN3 deficiency caused muscle atrophy, predominantly in fast-twitch (type II) myofibers, and reduced muscle strength. While myofiber-specific PDZRN3 deficiency did not influence endplate morphology or expression of neuromuscular synaptic formation-related genes in postnatal muscles, indicating that the relationship between PDZRN3 and neuromuscular junctions might be limited during muscle development. Considering that the expression of Pdzrn3 in skeletal muscles was significantly lower in aged mice than in mature adult mice, we speculated that the PDZRN3-mediated muscle maintenance system might be associated with the pathophysiology of age-related muscle decline, such as sarcopenia.

Qualitative and Quantitative MR Imaging of the Cartilaginous Endplate: A Review.

The cartilaginous endplate (CEP) plays a pivotal role in facilitating the supply of nutrients and, transport of metabolic waste, as well as providing mechanical support for the intervertebral disc (IVD). Recent technological advances have led to a surge in MR imaging studies focused on the CEP. This article describes the anatomy and functions of the CEP as well as MRI techniques for both qualitative and quantitative assessment of the CEP. Effective CEP MR imaging sequences require two key features: high spatial resolution and relatively short echo time. High spatial resolution spoiled gradient echo (SPGR) and ultrashort echo time (UTE) sequences, fulfilling these requirements, are the basis for most of the sequences employed in CEP imaging. This article reviews existing sequences for qualitative CEP imaging, such as the fat-suppressed SPGR and UTE, dual-echo subtraction UTE, inversion recovery prepared and fat-suppressed UTE, and dual inversion recovery prepared UTE sequences. These sequences are employed together with other techniques for quantitative CEP imaging, including measurements of T2*, T2, T1, T1ρ, magnetization transfer, perfusion, and diffusion tensor parameters. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Quantal size increase induced by the endocannabinoid 2-arachidonoylglycerol requires activation of CGRP receptors in mouse motor synapses.

In mouse motor synapses, the exogenous application of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG) increases acetylcholine (ACh) quantal size due to the activation of CB1 receptors and the stimulation of ACh vesicular uptake. In the present study, microelectrode recordings of miniature endplate potentials (MEPP) revealed that this effect of 2-AG is independent of brain-derived neurotrophic factor (BDNF) signaling but involves the activation of calcitonin gene-related peptide (CGRP) receptors along with CB1 receptors. Potentiation of MEPP amplitude in the presence of 2-AG was prevented by blockers of CGRP receptors and ryanodine receptors (RyR) and by inhibitors of phospholipase C (PLC) and Ca2+ /calmodulin-dependent protein kinase II (CaMKII). Therefore, we suggest a hypothetical chain of events, which starts from the activation of presynaptic CB1 receptors, involves PLC, RyR, and CaMKII, and results in CGRP release with the subsequent activation of presynaptic CGRP receptors. Activation of CGRP receptors is probably a part of a complex molecular cascade leading to the 2-AG-induced increase in ACh quantal size and MEPP amplitude. We propose that the same chain of events may also take place if 2-AG is endogenously produced in mouse motor synapses, because the increase in MEPP amplitude that follows after prolonged tetanic muscle contractions (30 Hz, 2 min) was prevented by the blocking of CB1 receptors. This work may help to unveil the previously unknown aspects of the functional interaction between ECs and peptide modulators aimed at the regulation of quantal size and synaptic transmission.

BDNF/TrkB signalling, in cooperation with muscarinic signalling, retrogradely regulates PKA pathway to phosphorylate SNAP-25 and Synapsin-1 at the neuromuscular junction.

BACKGROUND: Protein kinase A (PKA) enhances neurotransmission at the neuromuscular junction (NMJ), which is retrogradely regulated by nerve-induced muscle contraction to promote Acetylcholine (ACh) release through the phosphorylation of molecules involved in synaptic vesicle exocytosis (SNAP-25 and Synapsin-1). However, the molecular mechanism of the retrograde regulation of PKA subunits and its targets by BDNF/TrkB pathway and muscarinic signalling has not been demonstrated until now. At the NMJ, retrograde control is mainly associated with BDNF/TrkB signalling as muscle contraction enhances BDNF levels and controls specific kinases involved in the neurotransmission. Neurotransmission at the NMJ is also highly modulated by muscarinic receptors M1 and M2 (mAChRs), which are related to PKA and TrkB signallings. Here, we investigated the hypothesis that TrkB, in cooperation with mAChRs, regulates the activity-dependent dynamics of PKA subunits to phosphorylate SNAP-25 and Synapsin-1. METHODS: To explore this, we stimulated the rat phrenic nerve at 1Hz (30 minutes), with or without subsequent contraction (abolished by µ-conotoxin GIIIB). Pharmacological treatments were conducted with the anti-TrkB antibody clone 47/TrkB for TrkB inhibition and exogenous h-BDNF; muscarinic inhibition with Pirenzepine-dihydrochloride and Methoctramine-tetrahydrochloride for M1 and M2 mAChRs, respectively. Diaphragm protein levels and phosphorylation' changes were detected by Western blotting. Location of the target proteins was demonstrated using immunohistochemistry. RESULTS: While TrkB does not directly impact the levels of PKA catalytic subunits Cα and Cß, it regulates PKA regulatory subunits RIα and RIIß, facilitating the phosphorylation of critical exocytotic targets such as SNAP-25 and Synapsin-1. Furthermore, the muscarinic receptors pathway maintains a delicate balance in this regulatory process. These findings explain the dynamic interplay of PKA subunits influenced by BDNF/TrkB signalling, M1 and M2 mAChRs pathways, that are differently regulated by pre- and postsynaptic activity, demonstrating the specific roles of the BDNF/TrkB and muscarinic receptors pathway in retrograde regulation. CONCLUSION: This complex molecular interplay has the relevance of interrelating two fundamental pathways in PKA-synaptic modulation: one retrograde (neurotrophic) and the other autocrine (muscarinic). This deepens the fundamental understanding of neuromuscular physiology of neurotransmission that gives plasticity to synapses and holds the potential for identifying therapeutic strategies in conditions characterized by impaired neuromuscular communication.

Research Progress on the Role of Cartilage Endplate in Intervertebral Disc Degeneration.

Low back pain significantly impacts individuals' quality of life, with intervertebral disc degeneration (IDD) being a primary contributor to this condition. Currently, IDD treatment primarily focuses on symptom management and does not achieve a definitive cure. The cartilage endplate (CEP), a crucial nutrient-supplying tissue of the intervertebral disc, plays a pivotal role in disc degeneration. This review examines the mechanisms underlying CEP degeneration, summarizing recent advancements in understanding the structure and function of CEP, the involvement of various signaling pathways, and the roles of cartilage endplate stem cells (CESCs) and exosomes (Exos) in this process. The aim of this review is to provide a comprehensive reference for future research on CEP. Despite progress in understanding the role of CEP in IDD, the mechanisms underlying CEP degeneration remain incompletely elucidated. Future research poses significant challenges, necessitating further investigations to elucidate the complexities of CEP.

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission.

BACKGROUND: Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. MATERIALS AND METHODS: In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. RESULTS: We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. CONCLUSION: Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration.

CT-based surrogate parameters for MRI-based disc height and endplate degeneration in the lumbar spine.

PURPOSE: This study investigated potential use of computed tomography (CT)-based parameters in the lumbar spine as a surrogate for magnetic resonance imaging (MRI)-based findings. METHODS: In this retrospective study, all individuals, who had a lumbar spine CT scan and MRI between 2006 and 2012 were reviewed (n = 198). Disc height (DH) and endplate degeneration (ED) were evaluated between Th12/L1-L5/S1. Statistics consisted of Spearman correlation and univariate/multivariable regression (adjusting for age and gender). RESULTS: The mean CT-DH increased kranio-caudally (8.04 millimeters (mm) at T12/L1, 9.17 mm at L1/2, 10.59 mm at L2/3, 11.34 mm at L3/4, 11.42 mm at L4/5 and 10.47 mm at L5/S1). MRI-ED was observed in 58 (29%) individuals. CT-DH and MRI-DH had strong to very strong correlations (rho 0.781-0.904, p < .001). MRI-DH showed higher absolute values than CT-DH (mean of 1.76 mm). There was a significant association between CT-DH and MRI-ED at L2/3 (p = .006), L3/4 (p = .002), L4/5 (p < .001) and L5/S1 (p < .001). A calculated cut-off point was set at 11 mm. CONCLUSIONS: In the lumbar spine, there is a correlation between disc height on CT and MRI. This can be useful in trauma and emergency cases, where CT is readily available in the lack of an MRI. In addition, in the middle and lower part of the lumbar spine, loss of disc height on CT scans is associated with more pronounced endplate degeneration on MRIs. If the disc height on CT scans is lower than 11 mm, endplate degeneration on MRIs is likely more pronounced. LEVEL AND DESIGN: Level III, a retrospective study.

Novel Modic grading scoring system and its clinical validation: a preliminary investigation.

PURPOSE: To propose a novel Modic grading scoring system and explore the relationship between the Modic grading score and disc degeneration, disc herniation, disc height, and clinical symptom scores. METHOD: In total, 194 patients were included in the study. The new Modic grading scoring system included four indicators: invaded vertebral height, invaded endplate length, endplate morphology, and grade of endplate defects. The severity of Modic changes was visually quantified by numerical scores, and the kappa value was used to verify the interobserver and intraobserver reliability. Spearman correlation analysis was used to explore the relationship between the Modic grading score and intervertebral disc degeneration, disc herniation, disc height, and clinical symptom scores. RESULTS: The interobserver and intraobserver reliability showed substantial to almost perfect agreement in the new Modic grading scoring system. The Modic grading score was positively correlated with intervertebral disc degeneration (r = 0.757, p < 0.001) and negatively correlated with the intervertebral disc height index (r = - 0.231, p < 0.001). There was no significant correlation between the Modic grading scoring system and disc herniation (r = 0.369, p = 0.249). Additionally, there was no significant correlation between the Modic grading score and the Japanese Orthopaedic Association score (r = - 0.349, p = 0.25), Oswestry Disability Index score (r = 0.246, p = 0.11), or visual analogue scale score (r = 0.315, p = 0.35). CONCLUSION: The new Modic grading scoring system had good interobserver and intraobserver reliability. The Modic grading score was positively correlated with intervertebral disc degeneration and negatively correlated with the intervertebral disc height.

Endplate weakening during cage bed preparation significantly reduces endplate load capacity.

PURPOSE: To analyze the effect of endplate weakness prior to PLIF or TLIF cage implantation and compare it to the opposite intact endplate of the same vertebral body. In addition, the influence of bone quality on endplate resistance was investigated. METHODS: Twenty-two human lumbar vertebrae were tested in a ramp-to-failure test. One endplate of each vertebral body was tested intact and the other after weakening with a rasp (over an area of 200 mm2). Either a TLIF or PLIF cage was then placed and the compression load was applied across the cage until failure of the endplate. Failure was defined as the first local maximum of the force measurement. Bone quality was assessed by determining the Hounsfield units (HU) on CT images. RESULTS: With an intact endplate and a TLIF cage, the median force to failure was 1276.3N (693.1-1980.6N). Endplate weakening reduced axial endplate resistance to failure by 15% (0-23%). With an intact endplate and a PLIF cage, the median force to failure was 1057.2N (701.2-1735.5N). Endplate weakening reduced axial endplate resistance to failure by 36.6% (7-47.9%). Bone quality correlated linearly with the force at which endplate failure occurred. Intact and weakened endplates showed a strong positive correlation: intact-TLIF: r = 0.964, slope of the regression line (slope) = 11.8, p < 0.001; intact-PLIF: r = 0.909, slope = 11.2, p = 5.5E-05; weakened-TLIF: r = 0.973, slope = 12.5, p < 0.001; weakened-PLIF: r = 0.836, slope = 6, p = 0.003. CONCLUSION: Weakening of the endplate during cage bed preparation significantly reduces the resistance of the endplate to subsidence to failure: endplate load capacity is reduced by 15% with TLIF and 37% with PLIF. Bone quality correlates with the force at which endplate failure occurs.

New evidence on the controversy over the correlation between vertebral osteoporosis and intervertebral disc degeneration: a systematic review of relevant animal studies.

OBJECTIVE: The effect of vertebral osteoporosis on disc degeneration remains controversial. The aim of this study was to conduct a systematic review and meta-analysis of relevant animal studies to shed more light on the effects and mechanisms of vertebral osteoporosis on disc degeneration and to promote the resolution of the controversy. METHODS: The PubMed, Cochrane Library, and Embase databases were searched for studies that met the inclusion criteria. Basic information and data were extracted from the included studies and data were analyzed using STATA 15.1 software. This study was registered on INPLASY with the registration number INPLASY202370099 and https://doi.org/10.37766/inplasy2023.7.0099 . RESULTS: A total of 13 studies were included in our study. Both animals, rats and mice, were covered. Meta-analysis results showed in disc height index (DHI) (P < 0.001), histological score (P < 0.001), number of osteoblasts in the endplate (P = 0.043), number of osteoclasts in the endplate (P < 0.001), type I collagen (P < 0.001), type II collagen (P < 0.001), aggrecan (P < 0.001), recombinant a disintegrin and metalloproteinase with thrombospondin-4 (ADAMTS-4) (P < 0.001), matrix metalloproteinase-1 (MMP-1) (P < 0.001), MMP-3 (P < 0.001), MMP-13 (P < 0.001), the difference between the osteoporosis group and the control group was statistically significant. In terms of disc volume, the difference between the osteoporosis group and the control group was not statistically significant (P = 0.459). CONCLUSION: Our study shows that vertebral osteoporosis may exacerbate disc degeneration. Abnormal bone remodeling caused by vertebral osteoporosis disrupts the structural integrity of the endplate, leading to impaired nutrient supply to the disc, increased expression of catabolic factors, and decreased levels of type II collagen and aggrecan may be one of the potential mechanisms.

Development of a novel animal model of lumbar vertebral endplate lesion by intervertebral disk injection of monosodium iodoacetate in rats.

PURPOSE: Vertebral endplate lesions (EPLs) caused by severe disk degeneration are associated with low back pain. However, its pathophysiology remains unclear. In this study, we aimed to develop a vertebral EPL rat model mimicking severe intervertebral disk (IVD) degeneration by injecting monosodium iodoacetate (MIA) into the IVDs and evaluating it by assessing pain-related behavior, micro-computed tomography (CT) findings, and histological changes. METHODS: MIA was injected into the L4-5 and L5-6 IVDs of Sprague-Dawley rats. Their behavior was examined by measuring the total distance traveled and the total number of rearing in an open square arena. Bone alterations and volume around the vertebral endplate were assessed using micro-CT. Safranin-O staining, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining were performed for histological assessment. RESULTS: The total distance and number of rearing times in the open field were significantly reduced in a time-dependent manner. Micro-CT revealed intervertebral osteophytes and irregularities in the endplates at 12 weeks. The bone volume/tissue volume (BV/TV) around the endplates significantly increased from 6 weeks onward. Safranin-O staining revealed severe degeneration of IVDs and endplate disorders in a dose- and time-dependent manner. Calcitonin gene-related peptide-positive nerve fibers significantly increased from 6 weeks onward. However, the number of osteoclasts decreased over time. CONCLUSION: Our rat EPL model showed progressive morphological vertebral endplate changes in a time- and concentration-dependent manner, similar to the degenerative changes in human IVDs. This model can be used as an animal model of severe IVD degeneration to better understand the pathophysiology of EPL.

Discovery of circulating blood biomarkers in patients with and without Modic changes of the lumbar spine: a preliminary analysis.

PURPOSE: The following study aimed to determine the existence of blood biomarkers in symptomatic patients with or without lumbar Modic changes (MC). METHODS: A cross-sectional sub-analyses of a prospective cohort was performed. Fasting blood samples were collected from patients with and without lumbar MC who had undergone spinal fusion or microdiscectomy. An 80-plex panel and CCL5/RANTES were used to assess preoperative plasma cytokine concentrations. Patient demographics and imaging phenotypes were also assessed. RESULTS: Thirty-one subjects were analysed (n = 18 no MC; n = 13 MC). No significant differences were found in age, sex, body mass index, smoking and alcohol history, and surgical procedure (i.e. fusion, decompression) between the two groups (p > 0.05). Several statistically significant blood biomarkers in MC patients were identified, including elevated levels of C-C Motif Chemokine Ligand 5 (CCL5, p = 0.0006), while Macrophage Migration Inhibitory Factor (MIF) was significantly lower (p = 0.009). Additionally, C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 0.052), Pentraxin 3 (PTX3, p = 0.06) and Galectin-3 (Gal-3, p = 0.07) showed potential relevance. Moreover, MC patients exhibited significantly higher levels of disc degeneration (p = 0.0001) and displacement severity (p = 0.020). Based on multivariate analyses and controlling for disc degeneration/displacement, CCL5 (OR 1.02; 95% CI 1.002-1.033; p = 0.028) and MIF (OR 0.60; 95% CI 0.382-0.951; p = 0.030) were independently associated with MC patients. CONCLUSION: This "proof-of-concept" study is the first to identify specific and significantly circulating blood biomarkers associated with symptomatic patients with lumbar MC, independent of disc alterations of degeneration and/or bulges/herniations. Specifically, differences in CCL5 and MIF protein levels were significantly noted in MC patients compared to those without MC.

MRI-based endplate bone quality score independently predicts cage subsidence after anterior cervical corpectomy fusion.

BACKGROUND: To reduce the amount of radiation that patients receive during surgery, surgeons can evaluate the quality of the bone prior to surgery using computed tomography (CT) or dual-energy X-ray absorptiometry. Recently, lumbar spine vertebral bone quality has been evaluated using an MRI-based scoring system. However, few studies have investigated the connection between cage subsidence in patients following cervical interbody fusion and site-specific MRI bone evaluation. It is unknown how cage subsidence following anterior cervical corpectomy decompression and fusion is related to MRI-based endplate bone quality assessment. PURPOSE: To create a similar MRI-based cervical spine scoring system (C-EBQ) and to investigate the predictive value of the MRI cervical endplate bone quality (C-EBQ) score for cage subsidence after ACCF. METHODS: The patients' demographic, surgical, and radiological data were collected. Cage subsidence was defined as fusion segment height loss ≥ 3 mm. Multivariate logistic regression models were developed to determine correlations between potential risk factors and subsidence, and simple linear regression analyses of statistically significant indicators were performed. RESULTS: Among the patients who underwent single-level ACCF, 72 met the requirements for inclusion. The C-VBQ scores also improved from 2.28 ± 0.12, indicating no subsidence, to 3.27 ± 0.35, which indicated subsidence, and the C-EBQ scores improved in both the nonsubsidence group (1.95 ± 0.80) and the subsidence group (2.38 ± 0.54). There was a statistically significant difference (p < 0.05) among the groups. Higher C-EBQ scores were strongly correlated with subsidence in the multivariate analysis (odds ratio [OR] = 17.249, 95% CI = 2.269 to 7.537, P < 0.001), and the C-VBQ score was the major independent predictor of subsidence following ACCF ([OR] = 4.752, 95% CI = 3.824 to 8.781, P < 0.05). The C-EBQ score outperformed the C-VBQ score (75.6%) in terms of predictive accuracy, with a ROC curve indicating an 89.4% score. CONCLUSIONS: After ACCF, cage subsidence was strongly correlated with higher C-EBQ scores on preoperative MRI. Assessing C-EBQ before ACCF may be a useful way to estimate the likelihood of postoperative subsidence.

Prevalence and distribution of Schmorl node and endplate signal change, and correlation with disc degeneration in a population-based cohort: the Wakayama Spine Study.

PURPOSE: Degenerative spinal conditions, including disc degeneration (DD), Schmorl nodes (SN), and endplate signal changes (ESC), are pervasive age-associated phenomena that critically affect spinal health. Despite their prevalence, a comprehensive exploration of their distribution and correlations is lacking. This study examined the prevalence, distribution, and correlation of DD, SN, and ESC across the entire spine in a population-based cohort. METHODS: The Wakayama Spine Study included 975 participants (324 men, mean age 67.2 years; 651 women, mean age 66.0 years). Magnetic resonance imaging (MRI) was used to evaluate the intervertebral space from C2/3 to L5/S1. DD was classified using Pfirrmann's system, ESC was identified by diffuse high-intensity signal changes on the endplates, and SN was defined as a herniation pit with a hypointense signal. We assessed the prevalence and distribution of SN, ESC, and DD across the entire spine. The correlations among these factors were examined. RESULTS: Prevalence of ≥ 1 SN over the entire spine was 71% in men and 77% in women, while prevalence of ≥ 1 ESC was 57.9% in men and 56.3% in women. The prevalence of ESC and SN in the thoracic region was the highest among the three regions in both sexes. Positive linear correlations were observed between the number of SN and DD (r = 0.41, p < 0.001) and the number of ESC and DD (r = 0.40, p < 0.001), but weak correlations were found between the number of SN and ESC (r = 0.29, p < 0.001). CONCLUSION: The prevalence and distribution of SN and ESC over the entire spine were observed, and correlations between SN, ESC, and DD were established. This population-based cohort study provides a comprehensive analysis of these factors.

Oblique lumbar interbody fusion combined with anterolateral screw fixation and stress endplate augmentation for treating degenerative lumbar spondylolisthesis with osteoporosis.

PURPOSE: To evaluate the outcomes of Oblique lumbar interbody fusion (OLIF)combined with anterolateral screw fixation (AF) and Stress Endplate Augmentation(SEA) versus OLIF-AF in the treatment of degenerative lumbar spondylolisthesis (DLS)with osteoporosis (OP). METHODS: 30 patients underwent OLIF-AF-SEA (SEA group) were matched with 30 patients received OLIF-AF (control group), in terms of sex, age, body mass index (BMI) and bone mineral density (BMD). Clinical outcomes including visual analog scale (VAS) score of the lower back pain (VAS-LBP), leg pain (VAS-LP), and Oswestry Disability Index (ODI) were evaluated at different postoperative intervals and comparedwith their preoperative counterparts. Radiographic outcomes such as disk height (DH), slip distance (SD), lumbar lordosis (LL), segmental lordosis (SL), cage subsidence (CS) rate and fusion rate were evaluated at different postoperative intervals and compared with their preoperative counterparts. RESULTS: SEA group presented to be better at 3-month and 12-month follow-up, the VAS-LBP, VAS-LP and ODI scores of the SEA group were significantly lower than the control group (3-month SEA vs control: 2.30±0.70 vs 3.30±0.75, 2.03±0.72 vs 2.90±0.76,15.60±2.36 vs 23.23±3.07, respectively, all p<0.05. VAS-LBP and ODI 12-month SEA vs control: 1.27±0.74 vs 1.93±0.58, 12.20±1.88 vs 14.43±1.89,respectively, all p<0.05). At 24-month follow-up, both groups showed no difference in fusion rate (83.33% vs 90.00%, p=0.45), while SEA group showed a lower CS rate (13.33% vs 53.33%, p<0.05). CONCLUSION: OLIF-AF-SEA was safe with no adverse effects and resulted in lower CS rate and better sagittal balance. OLIF-AF-SEA is a promising surgical method for treating patients with DLS-OP.

A novel MRI-based Cervical-Endplate Bone Quality score independently predicts cage subsidence after Anterior Cervical Discectomy and Fusion.

INTRODUCTION: Postoperative cage subsidence after Anterior Cervical Discectomy and Fusion (ACDF) often has adverse clinical consequences and is closely related to Bone Mineral Density (BMD). Previous studies have shown that cage subsidence can be better predicted by measuring site-specific bone density. MRI-based Endplate Bone Quality (EBQ) scoring effectively predicts cage subsidence after lumbar interbody fusion. However, there is still a lack of studies on the practical application of EBQ scoring in the cervical spine. PURPOSE: To create a similar MRI-based scoring system for Cervical-EBQ (C-EBQ) and to assess the correlation of the C-EBQ with endplate Computed Tomography (CT)-Hounsfield Units (HU) and the ability of this scoring system to independently predict cage subsidence after ACDF, comparing the predictive ability of the C-EBQ with the Cervical-Vertebral Bone Quality (C-VBQ) score. METHODS: A total of 161 patients who underwent single-level ACDF for degenerative cervical spondylosis at our institution from 2012 to 2022 were included. Demographics, procedure-related data, and radiological data were collected, and Pearson correlation test was used to determine the correlation between C-EBQ and endplate HU values. Cage subsidence was defined as fusion segment height loss of ≥ 3 mm. Receiver operating characteristic analysis and area-under-the-curve values were used to assess the predictive ability of C-EBQ and C-VBQ. A multivariate logistic regression model was developed to identify potential risk factors associated with subsidence. RESULTS: Cage subsidence was present in 65 (40.4%) of 161 patients. The mean C-EBQ score was 1.81 ± 0.35 in the group without subsidence and 2.59 ± 0.58 in the group with subsidence (P < 0.001). Multivariate analysis showed that a higher C-EBQ score was significantly associated with subsidence (OR = 5.700; 95%CI = 3.435-8.193; P < 0.001), was the only independent predictor of cage subsidence after ACDF, had a predictive accuracy of 93.7%, which was superior to the C-VBQ score (89.2%), and was significantly negatively correlated with the endplate HU value (r = -0.58, P < 0.001). CONCLUSIONS: Higher C-EBQ scores were significantly associated with postoperative cage subsidence after ACDF. There was a significant negative correlation between C-EBQ and endplate HU values. The C-EBQ score may be a promising tool for assessing preoperative bone quality and postoperative cage subsidence and is superior to the C-VBQ.

Short-segment spinal fusion for chronic low back pain with bone marrow edema adjacent to the vertebral endplate in adult spinal deformity.

PURPOSE: Corrective long spinal fusion is a widely accepted surgical method for patients with adult spinal deformities. However, instrumented long fusion is associated with a significant risk of complications. Therefore, we aimed to assess the success of short-segment spinal fusion, particularly for bone marrow edema (BME) adjacent to the vertebral endplate, in patients with low back pain (LBP) and spinal deformity. METHODS: A prospective study was performed at multiple hospitals wherein we monitored patients with spinal deformities and accompanying LBP. Patients aged ≥ 50 years with a minimum LBP severity score of 40 mm on the visual analog scale (VAS) were included in the study. We also included patients with lumbar BME on magnetic resonance imaging. Short spinal fusion was performed on segments with BME. Clinical evaluations of LBP on VAS and Oswestry Disability Index (ODI), and radiological parameters for sagittal vertical axis (SVA), pelvic incidence (PI), lumbar lordosis (LL) and pelvic tilt (PT) were carried out. RESULTS: Overall, 35 patients (22 men and 13 women), with a mean age of 66.7 years and a mean follow-up period of 32 months, were included in the study. The mean VAS and ODI scores were 72.4 mm and 49.0% before surgery and 25.5 mm and 29.9% at the final follow-up, respectively; these parameters significantly improved after surgery. The SVA, PI-LL, and PT scores were 70.1 mm, 20.9°, and 22.8° before surgery and 85.4 mm, 13.8°, and 22.7° at the final follow-up, respectively. The spinal alignment parameters did not change significantly after surgery. CONCLUSIONS: Short-segment spinal fusion is effective for treating LBP and spinal deformity with BME adjacent to the vertebral endplate without spinal correction.