Severe Intervertebral Disc Degeneration Research Articles

Osteopontin deficiency promotes cartilaginous endplate degeneration by enhancing the NF-κB signaling to recruit macrophages and activate the NLRP3 inflammasome

Intervertebral disc degeneration (IDD) is a major cause of discogenic pain, and is attributed to the dysfunction of nucleus pulposus, annulus fibrosus, and cartilaginous endplate (CEP). Osteopontin (OPN), a glycoprotein, is highly expressed in the CEP. However, little is known on how OPN regulates CEP homeostasis and degeneration, contributing to the pathogenesis of IDD. Here, we investigate the roles of OPN in CEP degeneration in a mouse IDD model induced by lumbar spine instability and its impact on the degeneration of endplate chondrocytes (EPCs) under pathological conditions. OPN is mainly expressed in the CEP and decreases with degeneration in mice and human patients with severe IDD. Conditional Spp1 knockout in EPCs of adult mice enhances age-related CEP degeneration and accelerates CEP remodeling during IDD. Mechanistically, OPN deficiency increases CCL2 and CCL5 production in EPCs to recruit macrophages and enhances the activation of NLRP3 inflammasome and NF-κB signaling by facilitating assembly of IRAK1-TRAF6 complex, deteriorating CEP degeneration in a spatiotemporal pattern. More importantly, pharmacological inhibition of the NF-κB/NLRP3 axis attenuates CEP degeneration in OPN-deficient IDD mice. Overall, this study highlights the importance of OPN in maintaining CEP and disc homeostasis, and proposes a promising therapeutic strategy for IDD by targeting the NF-κB/NLRP3 axis.

Radiographic and surgery-related predictive factors for increased segmental lumbar lordosis following lumbar fusion surgery in patients with degenerative lumbar spondylolisthesis.

This study aimed to evaluate preoperative (pre-op) radiographic characteristics and specific surgical interventions in patients with degenerative lumbar spondylolisthesis (DLS) who underwent lumbar fusion surgery (LFS), with a focus on analyzing predictors of postoperative restoration of segmental lumbar lordosis (SLL). A retrospective review at a single center identified consecutive single-level DLS patients who underwent LFS between 2016 and 2022. Radiographic measures included disc angle (DA), SLL, lumbar lordosis (LL), anterior/posterior disc height (ADH/PDH), spondylolisthesis percentage (SP), intervertebral disc degeneration, and paraspinal muscle quality. Surgery-related measures included cage position, screw insertion depth, spondylolisthesis reduction rate, and disc height restoration rate. A change in SLL ≥ 4° indicated increased segmental lumbar lordosis (ISLL), and unincreased segmental lumbar lordosis (UISLL) < 4°. Propensity score matching was employed for a 1:1 match between ISLL and UISLL patients based on age, gender, body mass index, smoking status, and osteoporosis condition. A total of 192 patients with an average follow-up of 20.9months were enrolled. Compared to UISLL patients, ISLL patients had significantly lower pre-op DA (6.78° vs. 11.84°), SLL (10.73° vs. 18.24°), LL (42.59° vs. 45.75°), and ADH (10.09mm vs. 12.21mm) (all, P < 0.05). ISLL patients were predisposed to more severe intervertebral disc degeneration (P = 0.047) and higher SP (21.30% vs. 19.39%, P = 0.019). The cage was positioned more anteriorly in ISLL patients (67.00% vs. 60.08%, P = 0.000), with more extensive reduction of spondylolisthesis (- 73.70% vs. - 56.16%, P = 0.000) and higher restoration of ADH (33.34% vs. 8.11%, P = 0.000). Multivariate regression showed that lower pre-op SLL (OR 0.750, P = 0.000), more anterior cage position (OR 1.269, P = 0.000), and a greater spondylolisthesis reduction rate (OR 0.965, P = 0.000) significantly impacted SLL restoration. Pre-op SLL, cage position, and spondylolisthesis reduction rate were identified as significant predictors of SLL restoration after LFS for DLS. Surgeons are advised to meticulously select patients based on pre-op SLL and strive to position the cage more anteriorly while minimizing spondylolisthesis to maximize SLL restoration.

Activation of Nuclear Factor Erythroid 2-Related Factor 2 Antagonizes the Reactive Oxygen Species Modulator 1-Induced Oxidative Stress in Nucleus Pulposus Cells

This study investigates the role of Reactive Oxygen Species Modulator 1 (ROMO1) in oxidative stress within nucleus pulposus (NP) cells and its potential regulation by Nuclear factor erythroid 2-related factor 2 (Nrf2). Intervertebral disc samples from patients were collected, and ROMO1, Nrf2, collagen I/II levels were analyzed to establish their potential connection. Human NP cells were cultured and exposed to H2O2 to induce oxidative stress. To elucidate ROMO1’s impact on NP cell metabolism, NP cells were transfected with ROMO1. Concurrently, Nrf2 activators and inhibitors were used to modulate Nrf2 expression during culturing. Oxidative stress was assessed through CAT and SOD1 gene expression analysis and measurement of cellular reactive oxygen species (ROS) production. NP cell status was determined by evaluating cell viability and collagen I/II expression. Results indicated elevated ROMO1 expression in severe intervertebral disc degeneration (IDD) and after H2O2 treatment. ROMO1 overexpression increased ROS production, suppressed CAT, SOD, and collagen II expression, while elevating collagen I and negatively affecting cell viability. However, Nrf2 activation effectively suppressed ROMO1 expression and protected NP cells from oxidative stress induced by H2O2 or ROMO1. In conclusion, ROMO1 exacerbates oxidative stress and contributes to NP cell degeneration, a process mitigated by Nrf2 activation.

Analysis of Factors Associated with Lumbar Degenerative Disease Complicated by Baastrup's Disease

ObjectiveTo investigate the factors associated with the occurrence of Baastrup's disease in patients with lumbar degenerative diseases. MethodsA retrospective analysis was conducted on 168 patients with lumbar degenerative diseases (including lumbar disc herniation, lumbar spinal stenosis, and lumbar spondylolisthesis) who were treated at our hospital from January 2020 to January 2023, comprising 95 males and 73 females, aged 48-84 years.Patients were divided into two groups based on the presence of Baastrup's disease: those with Baastrup's disease (Group A) and those without Baastrup's disease (Group B).Relevant patient factors were extracted, including age, gender, occupation, smoking history, alcohol consumption history, body mass index (BMI), bone density, presence of internal diseases (diabetes, hypertension), lumbar lordosis angle, endplate Modic changes, degree of intervertebral disc degeneration (Pfirrmann grading), and facet joint degeneration (Weishaupt grading).Statistical analysis was performed using SPSS 26.0 software to compare the differences in these factors between the two groups, and statistically significant results were included in a multivariate logistic regression analysis. ResultsUnivariate analysis indicated that there were no statistically significant differences between the two groups in terms of gender, smoking history, alcohol consumption history, bone density, presence of internal diseases (diabetes, hypertension), lumbar lordosis angle, and endplate Modic changes (P>0.05),whereas age, occupation, body mass index (BMI), degree of intervertebral disc degeneration, and degree of facet joint degeneration showed statistically significant differences (P<0.05).Multivariate logistic regression analysis revealed that age, degree of intervertebral disc degeneration, and degree of facet joint degeneration were independent risk factors for the occurrence of Baastrup's disease in patients with lumbar degenerative diseases (P<0.05). ConclusionBaastrup's disease is relatively common in patients with lumbar degenerative diseases, and advanced age, severe intervertebral disc degeneration, and facet joint degeneration are its independent risk factors.

Stepwise reduction of bony density in patients induces a higher risk of annular tears by deteriorating the local biomechanical environment

BACKGROUND CONTEXTThe relationship between osteoporosis and intervertebral disc degeneration (IDD) remains unclear. Considering that annular tear is the primary phenotype of IDD in the lumbar spine, the deteriorating local biomechanical environment may be the main trigger for annular tears. PURPOSETo investigate whether poor bone mineral density (BMD) in the vertebral bodies may increase the risk of annular tears via the degradation of the local biomechanical environment. STUDY DESIGNThis study was a retrospective investigation with relevant numerical mechanical simulations. PATIENT SAMPLEA total of 64 patients with low back pain (LBP) and the most severe IDD in the L4–L5 motion segment were enrolled. OUTCOME MEASURESAnnulus integration status was assessed using diffusion tensor fibre tractography (DTT). Hounsfield unit (HU) values of adjacent vertebral bodies were employed to determine BMD. Numerical simulations were conducted to compute stress values in the annulus of models with different BMDs and body positions. METHODSThe clinical data of the 64 patients with low back pain were collected retrospectively. The BMD of the vertebral bodies was measured using the HU values, and the annulus integration status was determined according to DTT. The data of the patients with and without annular tears were compared, and regression analysis was used to identify the independent risk factors for annular tears. Furthermore, finite element models of the L4–L5 motion segment were constructed and validated, followed by estimating the maximum stress on the post and postlateral interfaces between the superior and inferior bony endplates (BEPs) and the annulus. RESULTSPatients with lower HU values in their vertebral bodies had significantly higher incidence rates of annular tears, with decreased HU values being an independent risk factor for annular tears. Moreover, increased stress on the BEP-annulus interfaces was associated with a stepwise reduction of bony density (ie, elastic modulus) in the numerical models. CONCLUSIONSThe stepwise reduction of bony density in patients results in a higher risk of annular tears by deteriorating the local biomechanical environment. Thus, osteoporosis should be considered to be a potential risk factor for IDD biomechanically

TGF-β1 Inhibits Osteoclast Differentiation and Abnormal Angiogenesis in Intervertebral Disc Degeneration: Evidence from RNA Sequencing and Animal Studies.

Mechanisms involved in developing intervertebral disc degeneration (IDD) are poorly understood, thus making developing effective therapies difficult. This study aimed to suggest a possible molecular mechanism, based on transcriptome sequencing-identified transforming growth factor (TGF-β), underlying the effects on bone homeostasis in IDD. A mouse model for IDD was established. Transcriptome sequencing of nucleus pulposus tissue from mice (n = 3) identified differentially expressed mRNAs and key genes impacting bone homeostasis. A protein-protein interaction network pinpointed core genes. GO and KEGG analysis revealed gene functions. Expression levels of TGF-β1, tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were measured. Micro-CT evaluated vertebral structures and vascular imaging. Western Blot measured expression levels of Vegf, Opn, MMP3, and MMP13. Safranin O-Fast Green and TRAP staining were performed on intervertebral discs and endplates. Transcriptomic analysis found 1790 differentially expressed mRNAs in IDD mice. Twenty-eight genes related to bone homeostasis in IDD were identified. TGF-β1 was confirmed as the core gene. GO and KEGG showed TGF-β1 regulates osteoclast markers like CTSK and TRAP through pathways including NF-κB and MAPK. Experimental validation revealed lower TGF-β1 expression in IDD mice than controls, and increased TRAP and CTSK expression. Micro-CT showed decreased bone mass and intervertebral disc space in IDD mice. Vascular imaging showed increased vascular volume in IDD cartilaginous endplates. Western blot displayed increased VEGF and OPN levels, but decreased MMP3 and MMP13 in IDD mice. Safranin O-fast green staining revealed severe IDD degeneration. However, TGF-β1 injection improved bone parameters in IDD mice. In vitro experiments confirmed TGF-β1 inhibits bone marrow macrophages differentiation into osteoclasts. From our data, we conclude that TGF-β1 repressed osteoclast differentiation and aberrant bone-associated angiogenesis in cartilage endplates (EPs) to alleviate IDD, which may be instrumental for the therapeutic targeting of IDD.

Abdominal Fat is a Reliable Indicator of Lumbar Intervertebral Disc Degeneration than Body Mass Index

The objective of this study was to determine whether abdominal fat status correlates with low back pain (LBP) and lumbar intervertebral disc degeneration (IVDD) and to identify a new anthropometric index to predict the likelihood of developing LBP. Patients with chronic low back pain admitted to the Affiliated Hospital of Southwest Medical University from June 2022 to May 2023 were collected as the experimental group. Volunteers without LBP from June 2022 to May 2023 were also recruited as the control group. They underwent lumbar spine magnetic resonance imaging and had their body mass index (BMI) measured. Abdominal parameters were measured on T2-weighted median sagittal magnetic resonance imaging at the L3/4 level: abdominal diameter, sagittal abdominal diameter (SAD), and subcutaneous abdominal fat thickness (SAFT). Each lumbar IVDD was assessed using the Pfirrmann grading system. The differences in abdominal parameters and BMI between the experimental and control groups were compared, and the correlations between abdominal parameters, BMI, LBP, and IVDD were analyzed. Abdominal diameter, SAD, and SAFT had moderate-to-strong correlations with BMI. SAD was significantly associated with severe IVDD at L4-L5 and L5-S1 levels with odds ratio of 3.201 (95% confidence interval [CI]: 1.850-5.539, P<0.001) and 1.596 (95% CI: 1.072-2.378, P=0.021), respectively. BMI had no significant association with severe IVDD. In women, SAFT and BMI were significantly correlated with LBP; in men, only SAFT was significantly correlated with LBP. Appropriate cutoff values for men and women were 1.52cm (area under the curve=0.702, 95% CI: 0.615-0.789, P < 0.001) and 1.97cm (area under the curve=0.740, 95% CI: 0.662-0.818, P < 0.001), respectively. Men and women with SAFT of >1.52cm and >1.97cm, respectively, had significantly higher rates of LBP. SAD could predict severe IVDD better than BMI. SAFT is a better predictor of LBP than BMI, especially in men, and reliably distinguished patients with LBP from asymptomatic subjects with reliable cutoff values for men and women.

Fatty infiltration of the erector spinae at the upper lumbar spine could be a landmark for low back pain.

Intervertebral disc degeneration (IVDD), Modic changes, and fatty infiltration in the paraspinal muscles are possible causes of low back pain (LBP). Multifidus has been the most commonly blamed paraspinal muscle in the etiology of LBP. However, it contributes to 20% of the extensor moment on the lumbar spine. In the present study, we aimed to identify whether patients with LBP and asymptomatic subjects differed in terms of intervertebral discs, end-plates, and fatty infiltration in their paraspinal muscles. Consecutive women and men, who visited the spine outpatient clinics with chronic LBP and had lumbar spine MRI for their LBP without leg pain were included. Asymptomatic subjects without LBP/leg pain for the last year were recruited. Modic changes, IVDD, and fatty infiltration in the paraspinal muscles were evaluated on lumbar spine magnetic resonance imagings of the patients with LBP and age-, gender- and BMI-matched asymptomatic controls. Low back pain was closely associated with fatty infiltration in the paraspinal muscles at all lumbar levels whereas it had association with severe IVDD and Modic changes at lower lumbar levels. Multifidus at the lower lumbar levels was the fattiest paraspinal muscle in both asymptomatic subjects and patients with LBP. Patients with LBP had severe fatty infiltration in the erector spinae at the upper lumbar levels. Severe IVDD and Modic changes were more common at lower lumbar levels in patients with LBP. Both asymptomatic subjects and those with LBP had fatty multifidus at lower lumbar levels, whereas those with LBP had fatty infiltration in the erector spinae at upper lumbar levels. We suggest that fatty infiltration could have started in the multifidus. The erector spinae had greater contribution to the lumbar extension compared to the multifidus. Thus, LBP could develop when the quality of the erector spinae at the upper lumbar levels impairs due to fatty infiltration.

Relation of lumbar intervertebral disc height and severity of disc degeneration based on Pfirrmann scores

BackgroundDisc height (DH) change is considered one of the most critical factors in assessing intervertebral disc degeneration (IVD). Pfirrmann et al. developed a scoring system for disc degeneration evaluation based on changes in DH in magnetic resonance imaging (MRI). While the relationship between DH measurements and Pfirrmann scores for disc degeneration has been explored, the validity of different DH measuring techniques or their connection with disc degeneration is yet uncertain. The present study investigates intra-rater and inter-rater agreement and reliability of different DH measurement methods on MRI and evaluates the relationship between different DH measurement methods and Pfirrmann scores of IVD degeneration, as well as between different Pfirrmann scores and clinical outcomes. MethodsAdult patients with MRI scans of the lumbar spine were recruited. Eight DH measuring techniques were tested for intra-rater and inter-rater agreement and reliability. Bland and Altman's Limits of Agreement (LOA) was used to evaluate intra-rater and inter-rater agreements. Intra-rater and inter-rater reliability were evaluated using intra-class correlations (ICC) with 95 % confidence intervals (95 % CI). The association between DH and Pfirrmann scores was examined using one-way ANOVA. ResultsExcellent intra-rater reliability was reported for 332 participants on DH (ranging from 0.912 (0.901, 0.923) to 0.973 (0.964, 0.981) and from 0.902 (0.892, 0.915) to 0.975 (0.962, 0.985) by two independent raters). All measuring methods had high intra-rater agreement, except for methods 4 and 5. All methods had good-to-excellent of inter-rater reliability on DH (ICCs ranging from 0.812 (0.795, 0.828) to 0.995 (0.994, 0.995)) except for the posterior disc material length of method 5 (ICC 0.740 (0.718, 0.761)). Methods 1 to 6 for evaluating DH in patients with spondylolisthesis had poor inter-rater reliability. The IVD levels with grades IV and V in Pfirrmann scores had significantly lower DH than the IVD levels with grades I to III in Pfirrmann scores. IVD levels with grades IV and V in Pfirrmann scores had significantly higher VAS and ODI than IVD levels with grades I in Pfirrmann scores. ConclusionA good-to-excellent intra-rater and inter-rater reliability was achieved on most DH measuring methods on MRI following a standardized and structured protocol. However, small anatomical structures and different tissue borders could influence measurements. Additionally, DH can differentiate between grade IV and V Pfirrmann scores, and severe IVD degeneration (IV and V Pfirrmann) is linked to clinical outcomes.

Deep-learning-based biomarker of spinal cartilage endplate health using ultra-short echo time magnetic resonance imaging.

T2* relaxation times in the spinal cartilage endplate (CEP) measured using ultra-short echo time magnetic resonance imaging (UTE MRI) reflect aspects of biochemical composition that influence the CEP's permeability to nutrients. Deficits in CEP composition measured using T2* biomarkers from UTE MRI are associated with more severe intervertebral disc degeneration in patients with chronic low back pain (cLBP). The goal of this study was to develop an objective, accurate, and efficient deep-learning-based method for calculating biomarkers of CEP health using UTE images. Multi-echo UTE MRI of the lumbar spine was acquired from a prospectively enrolled cross-sectional and consecutive cohort of 83 subjects spanning a wide range of ages and cLBP-related conditions. CEPs from the L4-S1 levels were manually segmented on 6,972 UTE images and used to train neural networks utilizing the u-net architecture. CEP segmentations and mean CEP T2* values derived from manually- and model-generated segmentations were compared using Dice scores, sensitivity, specificity, Bland-Altman, and receiver-operator characteristic (ROC) analysis. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated and related to model performance. Compared with manual CEP segmentations, model-generated segmentations achieved sensitives of 0.80-0.91, specificities of 0.99, Dice scores of 0.77-0.85, area under the receiver-operating characteristic curve values of 0.99, and precision-recall (PR) AUC values of 0.56-0.77, depending on spinal level and sagittal image position. Mean CEP T2* values and principal CEP angles derived from the model-predicted segmentations had low bias in an unseen test dataset (T2* bias =0.33±2.37 ms, angle bias =0.36±2.65°). To simulate a hypothetical clinical scenario, the predicted segmentations were used to stratify CEPs into high, medium, and low T2* groups. Group predictions had diagnostic sensitivities of 0.77-0.86 and specificities of 0.86-0.95. Model performance was positively associated with image SNR and CNR. The trained deep learning models enable accurate, automated CEP segmentations and T2* biomarker computations that are statistically similar to those from manual segmentations. These models address limitations with inefficiency and subjectivity associated with manual methods. Such techniques could be used to elucidate the role of CEP composition in disc degeneration etiology and guide emerging therapies for cLBP.

Are serum thyroid hormone, parathormone, calcium, and vitamin D levels associated with lumbar spine degeneration? A cross-sectional observational clinical study.

Low back pain (LBP) impairs the quality of life and rises healthcare costs. The association of spine degeneration and LBP with metabolic disorders have been reported, previously. However, metabolic processes related with spine degeneration remained unclear. We aimed to analyze whether serum thyroid hormones, parathormone, calcium, and vitamin D levels were associated with lumbar intervertebral disc degeneration (IVDD), Modic changes, and fatty infiltration in the paraspinal muscles. We cross-sectionally analyzed a retrospective database. Patients who visited internal medicine outpatient clinics with suspect of endocrine disorders and chronic LBP were searched. Patients with biochemistry results within 1week before lumbar spine magnetic resonance imaging (MRI) were included. Age- and gender-matched cohorts were made-up and analyzed. Patients with higher serum free thyroxine levels were more likely to have severe IVDD. They were also more likely to have fattier multifidus and erector spinae at upper lumbar levels, less fatty psoas and less Modic changes at lower lumbar levels. Higher PTH levels were observed in patients with severe IVDD at L4-L5 level. Patients with lower serum vitamin D and calcium levels had more Modic changes and fattier paraspinal muscles at upper lumbar levels. Serum hormone, vitamin D, and calcium levels were associated with not only IVDD and Modic changes but also with fatty infiltration in the paraspinal muscles, mainly at upper lumbar levels in patients with symptomatic backache presenting to a tertiary care center. Complex inflammatory, metabolic, and mechanical factors present in the backstage of spine degeneration.

SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD.

Correlation between intervertebral disc degeneration and bone mineral density difference: a retrospective study of postmenopausal women using an eight-level MRI-based disc degeneration grading system

PurposeTo explore the correlation between intervertebral disc degeneration (IDD) and bone mineral density (BMD) difference between adjacent vertebrae.MethodsA retrospective analysis of 114 postmenopausal women who were treated in our hospital from January 2021 to December 2021. The degree of lumbar(L)1–5 IDD was scored according to an 8-grade scoring system. The lumbar vertebrae BMD was detected, and the BMD difference was calculated. The subjects were grouped according to age and whether the disc was severe IDD. Data were collected for statistical analysis.ResultsThe prevalence of osteoporosis in the 51–60-year-old group was lower than that in the other groups, while the prevalence of modic changes in the 71–80-year-old group was higher than that in the 51–70-year-old group (P < 0.05). At the L1/2 level, the prevalence of severe IDD in the 81-90y group was higher than that in the 51-70y group (P < 0.05). At the L2/3 level, the prevalence of severe IDD in the 71-90y group was higher than that in the 51-60y group, and the prevalence of severe IDD in the 71-80y group was higher than that in the 61-70y group (P < 0.05). The L2/3 disc score was positively correlated with the L3-L2 BMD difference (P < 0.05). At the level of L1-2, the BMD difference in the non-severe IDD group was smaller than that in the severe IDD group (P < 0.05).ConclusionFor postmenopausal women, an increase in BMD difference is correlated with IDD. Osteoporosis is more common in people over 60 years old, and the possibility of modic change in 71-80y is higher than in other age groups. The incidence of severe IDD also increases with aging, especially for the L1/2 and L2/3 discs.

Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration

Abnormal mechanical load is a main risk factor of intervertebral disc degeneration (IDD), and cellular senescence is a pathological change in IDD. In addition, extracellular matrix (ECM) stiffness promotes human nucleus pulposus cells (hNPCs) senescence. However, the molecular mechanism underlying mechano-induced cellular senescence and IDD progression is not yet fully elucidated. First, we demonstrated that mechano-stress promoted hNPCs senescence via NF-κB signaling. Subsequently, we identified periostin as the main mechano-responsive molecule in hNPCs through unbiased sequencing, which was transcriptionally upregulated by NF-κB p65; moreover, secreted periostin by senescent hNPCs further promoted senescence and upregulated the catabolic process in hNPCs through activating NF-κB, forming a positive loop. Both Postn (encoding periostin) knockdown via siRNA and periostin inactivation via neutralizing antibodies alleviated IDD and NPCs senescence. Furthermore, we found that mechano-stress initiated the positive feedback of NF-κB and periostin via PIEZO1. PIEZO1 activation by Yoda1 induced severe IDD in rat tails without compression, and Postn knockdown alleviated the Yoda1-induced IDD invivo. Here, we reported for the first time that self-amplifying loop of NF-κB and periostin initiated via PIEZO1 under mechano-stress accelerated NPCs senescence, leading to IDD. Furthermore, periostin neutralizing antibodies, which may serve as potential therapeutic agents for IDD, interrupted this loop.

Mechanisms and clinical implications of intervertebral disc calcification.

Low back pain is a leading cause of disability worldwide. Intervertebral disc (IVD) degeneration is often associated with low back pain but is sometimes asymptomatic. IVD calcification is an often overlooked disc phenotype that might have considerable clinical impact. IVD calcification is not a rare finding in ageing or in degenerative and scoliotic spinal conditions, but is often ignored and under-reported. IVD calcification may lead to stiffer IVDs and altered segmental biomechanics, more severe IVD degeneration, inflammation and low back pain. Calcification is not restricted to the IVD but is also observed in the degeneration of other cartilaginous tissues, such as joint cartilage, and is involved in the tissue inflammatory process. Furthermore, IVD calcification may also affect the vertebral endplate, leading to Modic changes (non-neoplastic subchondral vertebral bone marrow lesions) and the generation of pain. Such effects in the spine might develop in similar ways to the development of subchondral marrow lesions of the knee, which are associated with osteoarthritis-related pain. We propose that IVD calcification is a phenotypic biomarker of clinically relevant disc degeneration and endplate changes. As IVD calcification has implications for the management and prognosis of degenerative spinal changes and could affect targeted therapeutics and regenerative approaches for the spine, awareness of IVD calcification should be raised in the spine community.

Intervertebral Disc Degeneration and Low Back Pain Depends on Duration and Magnitude of Axial Compression.

Purpose The pathological role of axial stress in intervertebral disc degeneration (IDD) is controversial, and there was no quantified study until now. Here, we tried to clarify the correlation between IDD or low back pain (LBP) and axial stress at different duration and magnitude in vitro and in vivo. Method In vitro, the gene expression of aggrecan, matrix metalloproteinase-3 (MMP3), calcitonin gene-related peptide (CGRP), and substance P (SP) was measured when nucleus pulposus cells (NPCs) were compressed under gradual severity. In vivo, a measurable Ilizarov-type compression apparatus was established for single coccygeal (Co) intervertebral disc (IVD) compression of Co7-8 in mouse. Gradient stress was placed at 0.4 Mpa (mild), 0.8 Mpa (moderate), and 1.2 Mpa (severe) for three days to investigate the effect of the magnitude of axial stress. Additionally, mild compression with 3, 7, and 14 days was used to determine the effect of the duration of axial stress. Subsequently, we evaluated the severity of IDD and LBP by radiological X-ray film; histological examination with H&E staining; immunohistochemical analysis with collagen II, aggrecan, and CGRP staining; and western blot analysis with collagen II, aggrecan, MMP-3, and interleukin-1β (IL-1β). Results When NPCs suffered gradual increased mechanical stress, the cells exhibited gradual downregulated expression of extracellular matrix (ECM)-related gene of aggrecan, upregulated expression of IDD-related gene of MMP3, and LBP-related gene of CGRP and SP. In the meantime, with different magnitudes of axial stress, the IVD showed progressively severe IDD and LBP, with gradual narrowing intervertebral height, destruction of IVD anatomy, decreased ECM, and increased catabolic factors and proalgesic peptides. Conclusion Axial compression is one of the critical pathological factors to cause IDD and LBP, and there was a strong positive correlation depended on the duration and magnitude of compression.

Schmorl’s nodes could be associated with intervertebral disc degeneration at upper lumbar levels and end-plate disease at lower lumbar level in patients with low back pain

Schmorl’s nodes (SNs) have increasingly been recognized on vertebral end-plates using advanced imaging techniques. Even though vertebral end-plates are the closest structures to discs, their pathologies are underestimated in the etiology of low back pain (LBP). We aimed to detect the prevalence of SNs and other end-plate defects in subjects with/without LBP and to understand whether SNs were associated with LBP and spinal degeneration. Subjects were evaluated in terms of end-plate defects, intervertebral disc degeneration (IVDD), and vertebral end-plate changes (Modic changes) at all lumbar levels on lumbar spine magnetic resonance imagings (MRI). Control subjects were compared to patients with LBP. Higher Pfirrmann scores (OR: 2.696) and higher SN scores (OR: 8.076) were significantly associated with Modic changes at L4-L5 disc level. Patients with higher SN scores at L1-L2 or L2-L3 levels had approximately 7-fold increased risk of severe IVDD at the corresponding levels. The most significant factor associated with presence of SNs was body weight of the patients (OR: 1.417). The most significant factor associated with intensity of LBP was severe IVDD at L5-S1 level (OR: 3.670). Having higher total SN score had an OR of 1.230 (95% CI: 1.003–1.509; p = 0.047) for predicting LBP. Schmorl’s nodes were seen in 33.1% of patients and 11.5% of asymptomatic subjects. Body weight was the most significant factor associated with SNs. The most significant factor associated with LBP was severe IVDD at L5-S1 level.

At what speed does spinal degeneration gear up?: Aging Paradigm in patients with Low Back Pain

ObjectiveAging is a cause of spinal degeneration. However, the natural history of degeneration process is unclear. We aimed to analyze change of intervertebral disc degeneration (IVDD) and Modic changes in Caucasians with LBP decade by decade. We also aimed to find out breaking points of having severe IVDD and Modic changes throughout human life. Patients and methodsWe conducted a cross-sectional analysis of a retrospective database in patients aged between 10 and 100 years. All patients were evaluated in terms of IVDD and Modic changes. Optimal binning was conveyed to group age of the patients in terms of major changes in percentages of severe IVDD and Modic changes. ResultsWe evaluated 2434 patients (female: 1328 and male: 1106; mean age: 47.2 ± 17.2 years; age range = 10–98 years). In all patients, 50.5% and 23.6% had severe IVDD and Modic changes at any lumbar level, respectively. Women were significantly more likely to have severe IVDD than men. Frequency of Modic changes at any lumbar level significantly increased in 40 s and 60 s, whereas frequency of severe IVDD at any lumbar level significantly increased in 20 s, 30 s, 50 s and 70 s ConclusionSpinal degeneration had specific gear-up periods in human life. Age groups of future spine studies could be defined according to the new defined change periods of severe IVDD and Modic changes in human life.

Hsa_circ_0134111 promotes intervertebral disc degeneration via sponging miR-578

Intervertebral disc degeneration (IDD) is a chronic degenerative and age-dependent process characterized by aberrant apoptosis, proliferation, synthesis, and catabolism of the extracellular matrix of the nucleus pulposus (NP) cells. Recently, studies showed that circular RNAs play important roles in the development of many diseases. However, the role of circRNAs in IDD development remains unknown. We showed that circ_0134111 level was overexpressed in IDD tissue samples as compar-ed to control tissues. The upregulation of circ_0134111 was more drastic in the moderate and severe IDD cases than in those with mild IDD. In addition, we showed that interleukin-1β and tumor necrosis factor-α exposure significantly enhanced circ_0134111 expression in NP cells. Furthermore, ectopic expression of circ_0134111 induced proliferation, pro-inflammatory cytokine secretion, and ECM degradation in the NP cells. We also showed that circ_0134111 directly interacted with microRNA (miR)-578 in NP cells where elevated expression of circ_0134111 enhanced the ADAMTS-5 and MMP-9 expression. Moreover, miR-578 expression was significantly decreased in IDD patients and the miR-578 expression was negatively correlated with circ_0134111 expression in the IDD samples. Interleukin-1β and tumor necrosis factor-α exposure significantly decreased miR-578 levels in NP cells, in which ectopic miR-578 expression inhibited cell growth, pro-inflammatory cytokine expression, and ECM degradation. Finally, we showed that circ_0134111 overexpression induced the IDD-related phenotypic changes through inhibiting miR-578. These data suggested that circ_0134111 could promote the progression of IDD through enhancing aberrant NP cell growth, inflammation, and ECM degradation partly via regulating miR-578.

Discectomy decreases facet joint distance and increases the instability of the spine: A finite element study

The L4-L5 spinal segment is mostly associated with the development of lumbar back pain (LBP). Lumbar disc herniation (LDH), intervertebral disc degeneration (IVDD), or degeneration of the facet joints (FJs) can lead to LBP. Although the surgical gold standard for treating LDH is well established, consequences from this surgery on the biomechanics of the spine are still a matter of discussion. Using a finite element model of the L4-L5 spinal segment, this study aimed (1) to determine the changes in FJ distance during physiological motions of a lumbar spine in a healthy-normal condition, after conservative and aggressive percutaneous transforaminal endoscopic discectomy (PTED) to correct LDH, and during mild and severe IVDD; (2) to determine spine instability and endplate stresses under various physiological motions. Aggressive-PTED in a healthy disc decreased facet distances in axial rotation, lateral bending, and flexion by ∼25%, ∼10%, and 8%, respectively. Mild and severe disc degeneration increased the stiffness of the spine, resulting in a decrease in the range of motion (ROM) for all conditions. Severe disc degeneration decreased ROM as high as 57% for lateral bending, while a 13% decrease was observed for mild degeneration. High and abnormal endplate stress distributions were observed due to PTED and IVDD. PTED and IVDD, individually and collectively, change spine kinematics potentially leading to LBP and other associated negative outcomes. An increase in spine instability and a decrease in distance between superior and inferior facets resulting from PTED might lead to facet degeneration.