Severity Of Intervertebral Disc Degeneration Research Articles

The role of melatonergic system in intervertebral disc degeneration and its association with low back pain: a clinical study.

The mechanisms of intervertebral disc degeneration (IVDD) in low back pain (LBP) patients are multiples. In this study, we attempt to investigate whether melatonergic system plays a potential role in IVDD patients with LBP by analyzing their clinical specimens. The fucus will be given to the correlation between the melatonin receptor expression and intervertebral disc tissue apoptosis. In this clinical study, 107 lumbar intervertebral disc nucleus pulposus (NP) specimens from patients with LBP were collected with patients' consents. The disc height (DH) discrepancy ratio, range of motion and sagittal parameters of the pathological plane were measured and Pfirrmann grade was used to classified the grades of IVDD level. Discs at grades 1-3 were served as normal control and grades 4-5 were considered as IVDD. The expression levels of melatonin receptor 1A (MT1) and 1B (MT2) were measured by immunohistochemistry. The apoptosis of NP was assessed using TUNEL staining. Their potential associations among MT1/2, DH, apoptosis, sagittal parameters with IVDD and LBP were evaluated with statistical analysis. The incidence of IVDD was positively associated with age and negatively related to VAS scores for LBP (p<0.001). Patients with higher degree of IVDD also have higher DH discrepancy ratio (p<0.001), higher prevalence of lumbar instability (p=0.003) and higher cell apoptosis compared to the control. Nevertheless, no statistically significant correlation was identified between Pfirrmann grade and lumbar sagittal parameters. MT1 and MT2 both were highly expressed in the NP tissues. Importantly, MT1 expression but not MT2 was significantly increased in the intervertebral disc tissue of patients with IVDD and its level correlated well with cell apoptosis level and the severity of IVDD as well as lower VAS scores for LBP. The highly elevated MT1 expression was found in NP tissues of patients with IVDD and LBP compared to the control. This phenomenon probably reflects the compensating response of the body to the pathological alteration of the IVDD and LBP. Therefore, these findings provide the novel information to use selective agonists of MT1 to target IVDD and LBP clinically.

MINK1 deficiency stimulates nucleus pulposus cell pyroptosis and exacerbates intervertebral disc degeneration

Intervertebral disc (IVD) degeneration, induced by aging and irregular mechanical strain, is highly prevalent in the elderly population, serving as a leading cause of chronic low back pain and disability. Evolving evidence has revealed the involvement of nucleus pulposus (NP) pyroptosis in the pathogenesis of IVD degeneration, while the precise regulatory mechanisms of NP pyroptosis remain obscure. Misshapen/Nck-interacting kinase (NIK)-related kinase 1 (MINK1), a serine-threonine protein kinase, has the potential to modulate the activation of NLRP3 inflammasome, indicating its pivotal role in governing pyroptosis. In this study, to assess the significance of MINK1 in NP pyroptosis and IVD degeneration, NP tissues from patients with varying degrees of IVD degeneration, and IVD tissues from both aging-induced and lumbar spine instability (LSI) surgery-induced IVD degeneration mouse models, with or without MINK1 ablation, were meticulously evaluated. Our findings indicated a notable decline in MINK1 expression in NP tissues of patients with IVD degeneration and both mouse models as degeneration progresses, accompanied by heightened matrix degradation and increased NP pyroptosis. Moreover, MINK1 ablation led to substantial activation of NP pyroptosis in both mouse models, and accelerating ECM degradation and intensifying the degeneration phenotype in mechanically stress-induced mice. Mechanistically, MINK1 deficiency triggered NF-κB signaling in NP tissues. Overall, our data illustrate an inverse correlation between MINK1 expression and severity of IVD degeneration, and the absence of MINK1 stimulates NP pyroptosis, exacerbating IVD degeneration by activating NF-κB signaling, highlighting a potential innovative therapeutic target in treating IVD degeneration.

POSTN knockdown suppresses IL‐1β‐induced inflammation and apoptosis of nucleus pulposus cells via inhibiting the NF‐κB pathway and alleviates intervertebral disc degeneration

AbstractThe aim of this study is to investigate the effects of POSTN on IL‐1β induced inflammation, apoptosis, NF‐κB pathway and intervertebral disc degeneration (IVDD) in Nucleus pulposus (NP) cells (NPCs). NP tissue samples with different Pfirrmann grades were collected from patients with different degrees of IVDD. Western blot and immunohistochemical staining were used to compare the expression of POSTN protein in NP tissues. Using the IL‐1β‐induced IVDD model, NPCs were transfected with lentivirus‐coated si‐POSTN to down‐regulate the expression of POSTN and treated with CU‐T12‐9 to evaluate the involvement of NF‐κB pathway. Western blot, immunofluorescence, and TUNEL staining were used to detect the expression changes of inflammation, apoptosis and NF‐κB pathway‐related proteins in NPCs. To investigate the role of POSTN in vivo, a rat IVDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus‐coated si‐POSTN, and H&amp;E staining and immunohistochemical staining were performed. POSTN expression is positively correlated with the severity of IVDD in human. POSTN expression was significantly increased in the IL‐1β‐induced NPCs degeneration model. Downregulation of POSTN protects NPCs from IL‐1β‐induced inflammation and apoptosis. CU‐T12‐9 treatment reversed the protective effect of si‐POSTN on NPCs. Furthermore, lentivirus‐coated si‐POSTN injection partially reversed NP tissue damage in the IVDD model in vivo. POSTN knockdown reduces inflammation and apoptosis of NPCs by inhibiting NF‐κB pathway, and ultimately prevents IVDD. Therefore, POSTN may be an effective target for the treatment of IVDD.

Mast Cells and Their Related Gene HK-1 are Closely Associated with Discogenic Low Back Pain: A Bioinformatics and Clinical Sample Study.

Low back pain (LBP) is primarily caused by intervertebral disc degeneration (IVDD). Immune cells penetrating nucleus pulposus (NP) tissues may play an important role in generating IVDD and LBP. The clinical data from 100 cases of IVDD patients was initially analyzed retrospectively. Subsequently, peripheral blood and NP tissues from 41 IVDD patients were gathered for a validated investigation. Among them, ribosome-removed-RNA sequencing (RNA-seq) was performed on 10 cases of NP tissues of specific classifications (VAS 3 and Pfirrmann 3 were used as the controls, while patients with VAS 6 and Pfirrmann 5 were used as the experimental group). Differentially expressed genes (DEGs) were identified for the subsequent bioinformatics analysis. Further methods to confirm the underlying cause of discogenic LBP included mast cell immunohistochemistry (IHC), 12 cytokine detection, Western blot (WB), and real-time polymerase chain reaction (RT-PCR). Discogenic LBP and IVDD severity are strongly associated, and immunological cell infiltration has been demonstrated to be a significant factor in LBP by bioanalytical research. Tryptase-positive mast cells were found to be significantly more abundant in the VAS 6 NP tissues of IVDD patients than in the VAS 3 NP tissues. It was initially demonstrated that IVDD and LBP were significantly impacted by hemokinin-1 (HK-1), the mast cell-related gene. Furthermore, blood levels of interleukin 12 p70 (IL-12P70) are noticeably elevated and strongly correlated with HK-1, indicating that HK-1 may be involved in the regulation of mast cell activity and IL-12P70 production. The severity of LBP was observed to be positively correlated with the IVDD Pfirrmann grading. Further research indicates that patients with IVDD may experience persistent low back pain due to HK-1 activation of mast cells and the release of the cytokine IL12P70. This work will offer new insights into the diagnosis and treatment of discogenic LBP.

Sympathetic Neurotransmitter, VIP, Delays Intervertebral Disc Degeneration via FGF18/FGFR2-Mediated Activation of Akt Signaling Pathway.

Neuromodulation-related intervertebral disc degeneration (IVDD) is a novel IVDD pattern and are proposed recently. However, the mechanistic basis of neuromodulation and intervertebral disc (IVD) homeostasis remains unclear. Here, this study aimed to investigate the expression of postganglionic sympathetic nerve fiber-derived vasoactive intestinal peptide (VIP) system in human IVD tissue, and to assess the role of VIP-related neuromodulation in IVDD. Patient samples and in vitro cell experiments showed that the expression of receptors for VIP is negatively correlated with the severity of IVDD, and the administration of exogenous VIP can ameliorate interleukin 1β-induced nucleus pulposus (NP) cell apoptosis and inflammation. Further mRNA-seq analysis revealed that fibroblast growth factor 18- (FGF18)-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway is involved in the protective effects of VIP on inflammation-induced NP cell degeneration. Further analysis identified VIP via its receptor vasoactive intestinal peptide receptor 2 can directly result in decreased expression of miR-15a-5p, which targeted FGF18. Finally, in vivo mice lumbar IVDD model confirmed that focally exogenous administration of VIP can effectively ameliorated the progression of IVDD, as shown by the radiological and histological analysis. In conclusion, these results indicated that sympathetic neurotransmitter, VIP, delayed IVDD via FGF18/FGFR2-mediated activation of V-akt murine thymoma viral oncogene homolog signaling pathway, which will broaden the horizon concerning how the neuromodulation correlates with IVDD and shed new light on novel therapeutical alternatives to IVDD.

Histopathological spectrum of lumbar disc changes in obesity: analysis of intervertebral discs in lumbar hernia patients in Zenica-Doboj Canton, Bosnia and Herzegovina

&amp;lt;p&amp;gt;&amp;lt;strong&amp;gt;Aim&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;To investigate the correlation of body mass index (BMI) with severity of intervertebral disc degeneration.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Methods &amp;lt;br /&amp;gt;&amp;lt;/strong&amp;gt;The study enrolled patients who had undergone surgical intervention for a herniated disc at the Department of Neurosurgery of the Cantonal Hospital Zenica. Patients underwent thorough preoperative evaluation, including medical history, neurological and physical assessments, and radiological analysis. The surgical intervention consisted of a posterior lumbar discectomy, and the excised disc material was preserved and subjected to histopathological analysis based on Histopathologic Degeneration Score (HDS). Patients were divided in two groups according to Body Mass Index (BMI): study group with BMI&amp;amp;ge;25 and control group with BMI&amp;amp;lt;25.&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Results&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;Among 69 patients with herniated IVD, 26 (37.7%) were with BMI&amp;amp;ge;25 (study group), and 43 (62.3%) were with BMI&amp;amp;lt;25&amp;lt;br /&amp;gt;(controls). The study group displayed substantial increase in height, 1.80&amp;amp;plusmn;0.06 m compared to controls, 1.74&amp;amp;plusmn;0.06 m (p=0.001). Weight and BMI were significantly higher in the study group of patients (weight: 91.60&amp;amp;plusmn;10.22 vs. 67.37&amp;amp;plusmn;9.20 kg, BMI: 28&amp;amp;plusmn;2 vs. 22&amp;amp;plusmn;2; p&amp;amp;lt;0.001). Differences were confirmed in HDS values in the study group comparing to the control group (p&amp;amp;lt;0.001). The study group exhibited significant differences in chondrocyte proliferation, tears and clefts, granular changes, and mucous degeneration (p&amp;amp;lt;0.05), and positive correlations were found between BMI and&amp;lt;br /&amp;gt;these alterations found in the herniated discs (p&amp;amp;lt;0.05). Therefore, HDS showed positive correlations with BMI (R=0.599; p&amp;amp;lt;0.001) and weight (R=0.696; p&amp;amp;lt;0.001).&amp;lt;br /&amp;gt;&amp;lt;strong&amp;gt;Conclusion&amp;lt;/strong&amp;gt; &amp;lt;br /&amp;gt;The study&amp;#039;s findings confirmed that BMI has a significant impact on intervertebral disc degeneration, emphasizing the&amp;lt;br /&amp;gt;importance of weight management in preventing disc degeneration.&amp;lt;/p&amp;gt;

Impact of dyslipidemia on the severity of symptomatic lumbar spine degeneration: A retrospective clinical study.

Lumbar intervertebral disc degeneration (IVDD) is an important cause of low back pain or sciatica, and metabolic factors play an important role. However, little is known about the relationship of dyslipidemia to the risk of intervertebral disc degeneration (IVDD). This study aimed to assess the impact of serum lipid levels on the severity of lumbar disc degeneration and to investigate its association with endplate inflammation. We conducted a case retrospective study in which a total of 302 hospitalized Chinese patients were recruited, of whom 188 (112 males and 76 females; mean age: 51.66 years) were without underlying disease, while the remaining 114 patients (51 males and 63 females; mean age: 62.75 years) had underlying diseases. We examined fasting serum lipid levels for total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Magnetic resonance imaging (MRI) was used to determine endplate inflammation. Pfirrmann grading and Weishaupt grading were used to evaluate the severity of intervertebral disc degeneration and facet joint degeneration, respectively. There was no difference in age, gender, and general BMI between the two groups (P > 0.05), but there were significantly high levels in TC, LDL-C, and LDL-C/HDL-C (P = 0.04, P = 0.013, P = 0.01, respectively). TG and HDL-C showed no significant difference (P = 0.064, P = 0.336, respectively). The multivariate logistic regression model showed that age was a risk factor for the occurrence of endplate inflammation. In the group without underlying diseases, age, but not other indicators, was a risk factor for the occurrence of endplate inflammation (P < 0.01), In the group with underlying diseases, none of the patient indicators was directly related to the occurrence of endplate inflammation (P > 0.05). A nonlinear machine learning model was used to measure the contribution of each factor to the disease outcome and to analyze the effect between the top three contributing factors and the outcome variables. In patients without underlying diseases, the top three factors contributing to the severity grading of intervertebral disc degeneration were age (32.9%), high-density lipoproteins (20.7%), and triglycerides (11.8%). For the severity grading of facet joint degeneration, the top three contributing factors were age (27.7%), high-density lipoproteins (19.4%), and triglycerides (14.6%). For patients with underlying diseases, the top three factors contributing to intervertebral disc degeneration were age (25.4%), BMI (15.3%), and low-density lipoprotein/high-density lipoprotein ratio (13.9%). In terms of degree classification for facet joint degeneration, the top three contributing factors were age (17.5%), BMI (17.2%), and total cholesterol (16.7%). This study shows that age, high-density lipoprotein, and triglycerides affect the degree of degeneration in patients with symptomatic lumbar degeneration without underlying diseases. Age and BMI are two major factors affecting the severity of degeneration in patients with underlying diseases, and dyslipidemia is a secondary factor. However, there is no clear association between dyslipidemia and the occurrence of endplate inflammation in either group.

Visual acupotomy intervention mitigates pain reaction by improving intervertebral disc degeneration and inhibiting apoptosis of nucleus pulposus cells in rabbits with cervical spondylosis

To investigate the effect of visual acupotomy intervention on intervertebral disc degeneration, nucleus pulposus cell apoptosis and expression of apoptosis related proteins in rabbits with cervical spondylosis (CS), so as to explore its mechanism underlying improvement of CS. A total of 48 male New Zealand rabbits were randomly divided into blank control, model, acupotomy and medication (meloxicam) groups, with 12 rabbits in each group. The neck type CS model was established by forcing the rabbit to make a neck flexion for 5 hours in a restrained chamber, once daily for 12 weeks. Rabbits of the medication group received an intramuscular injection of meloxicam (0.35 mg/kg), once daily for 4 consecutive weeks, and those of the acupotomy group received ultrasound-guided acupotomy intervention, once a week for 4 weeks. The pain threshold (PT) was measured by using a VonFrey electronic pain detector. The levels of prostaglandin E2 (PGE2), 5-hydroxytryptamine (5-HT) and substance P (SP) in serum were detected by ELISA. The severity of intervertebral disc degeneration was observed by using magnetic resonance imaging (MRI) and given scores in accordance with Suzuki's and colleague's "new classification system of cervical disk degeneration". The apoptosis of nucleus pulposus cells was analyzed by TUNEL staining. The protein expression levels of apoptosis-related protein Fas, cysteinyl aspartate-specific protease-3 (Caspase-3), B-cell lymphoma-2 asso-ciated X protein (Bax) and B-cell lymphoma-2 protein (Bcl-2) were measured by Western blot. Compared with the blank control group, the PT and Bcl-2 expression and MRI score were significantly down-regulated (P<0.01, P<0.001), whereas the contents of serum PGE2, 5-HT and SP, ratios of TUNEL-positive cells, and expression of Fas, Caspase-3 and Bax were considerably up-regulated (P<0.001, P<0.05, P<0.01) in the model group. In contrast to the model group, both the medication and acupotomy groups had an obvious increase in the levels of PT and Bcl-2 expression and MRI score (P<0.05, P<0.01), and a significant decrease in the contents of serum PGE2, 5-HT, SP, ratios of TUNEL-positive cells, and expression of Fas, Caspase-3 and Bax proteins (P<0.05). No significant differences were found between the medication and acupotomy groups in all the indexes mentioned above (P>0.05). Visual acupotomy intervention can mitigate the pain state of CS rabbits, which may be related to its functions in improving the intervertebral disc degeneration, reducing inflammatory reactions and apoptosis of nucleus pulposus cells.

Preoperative Lymphocyte to Monocyte Ratio as a Predictive Biomarker for Disease Severity and Spinal Fusion Failure in Lumbar Degenerative Diseases Patients Undergoing Lumbar Fusion

ObjectiveThis study was designed to determine whether lymphocyte to monocyte ratio (LMR) correlated with the intervertebral disc degeneration (IDD) severity and the postoperative spinal fusion rate in patients with lumbar disc disease.Methods303 patients undergoing posterior lumbar decompression and fusion were retrospectively analyzed. An examination of the blood count was performed before surgery. The cumulative grade was calculated by summing the pfirrmann grades of all lumbar discs. Grouping was based on the 50th percentile of cumulative grade and spinal fusion. The relationship between LMR and IDD severity and spinal fusion was explored using correlation analyses and logistic regression models. The receiver operating characteristic (ROC) curve was performed to measure model discrimination, and Hosmer-Lemeshow (H-L) test was used to measure calibration. Meanwhile, the ROC curve evaluated the discrimination ability of LMR in predicting severe degeneration and fusion failure.ResultsLMR was significantly lower in the severe degeneration group (cumulative grade > 18) than in the mild to moderate degeneration group (cumulative grade ≤ 18). Furthermore, the LMR of the fusion group was significantly higher than that of the non-fusion group. The multivariate binary logistic models revealed that LMR was an independently influencing factor of the severe degeneration and fusion failure (OR: 0.793, 95% CI: 0.638–0.987, p = 0.038; OR: 0.371, 95% CI: 0.258–0.532, p < 0.001). The models showed excellent discrimination and calibration. The area under the curve (AUC) of severe degeneration and fusion failure identified by LMR were 0.635 and 0.643, respectively, and the corresponding cut-off values were 3.16 and 3.90.ConclusionLMR is significantly associated with the risk of severe disc degeneration and spinal fusion failure.

Is intervertebral disc degeneration associated with reduction in serum ferritin?

Ferritin autophagy is characterized by intracellular ferroptosis and selective ferritin degradation. However, the role of ferritin in the development of intervertebral disc degeneration (IDD) has not been elucidated. The study aimed to investigate the role of serum iron metabolism markers, especially serum ferritin (SF), in IDD. 217 patients who came to the spine surgery department of our hospital for low back pain were recruited, and blood samples were collected for routine examination after admission. The cumulative grade was also calculated by summing up the Pfirrmann grade of all lumbar discs. Correlation analysis showed that cumulative grade was correlated with SF (r = -0.185, p = 0.006), not with serum iron (SI), transferrin saturation (TS), unsaturated iron-binding capacity (UIBC) and total iron-binding capacity (TIBC) (all p > 0.05). In addition, SF levels in the low severity IDD were significantly higher than high severity IDD in cumulative grade (p = 0.003) and single disc grade. No statistically significant difference was found in the other four indicators. A statistically significant difference was observed between the high (cumulative grade > 17) and low score (cumulative grade ≤ 17) groups in terms of age. According to the ROC curve, the cut-off value of SF levels was 170.5. Patients with SF < 170.5ng/mL had severe disc degeneration. The sensitivity and specificity were 0.635 and 0.602, respectively. This study preliminarily showed that SF was negatively correlated with the degree of IDD and can be used to predict IDD severity.

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.

Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation.

Intervertebral disc degeneration (IVDD) is a main cause of low back pain, and inflammatory factors play key roles in its pathogenesis. Gremlin-1 (Grem1) was reported to induce an inflammatory response in other fields. This study aimed to investigate the mechanisms of Grem1 in the degenerative process of intervertebral discs. Dysregulated genes were determined by analyzing microarray profiles. The expression of Grem1 in 17 human disc samples (male:female = 9:8) and rat models (n = 5 each group) was measured by western blotting (WB), real-time quantitative PCR (RT-qPCR), and immunohistochemistry (IHC). The regulatory effects of Grem1 on apoptosis were examined using siRNAs, flow cytometry, immunofluorescence (IF), and WB. The therapeutic effect was evaluated by locally injecting specific Grem1 siRNA into IVDD rats. The expression of Grem1 was significantly increased in human degenerative intervertebral discs; furthermore, the expression of Grem1 positively correlated with the level of intervertebral disc degeneration. Grem1 was significantly overexpressed in tumor necrosis factor (TNF)-α-induced degenerative NP cells. Apoptosis in degenerative NP cells transfected with siRNA targeting Grem1 was significantly lower than that in the control group. Specific Grem1 siRNA markedly repressed the development of IVDD in surgery-induced IVDD rats. These results indicated that the expression of Grem1 was positively correlated with the severity of intervertebral disc degeneration, and Grem1 siRNA could inhibit Grem1-induced apoptosis and extracellular matrix alterations by mediating the TGF-β/Smad signaling pathway. This study may provide a therapeutic strategy for alleviating inflammation-induced apoptosis associated with intervertebral disc degeneration.

Analysis of intervertebral disc degeneration in patients with ossification of the posterior longitudinal ligament.

As degenerative disease with nerve compression, little is known about the relationship between cervical ossification of the posterior longitudinal ligament (OPLL) and intervertebral disc degeneration (IVDD). This study investigates the effect of ossification of ligaments on IVDD in patients with cervical OPLL. We focus on the ossification-related segment in patients diagnosed with OPLL, which is characterized by ossification that crosses intervertebral space or occurs concurrently in the upper and lower vertebrae. A total of 92 ossification-related segments from 40 patients were involved in the study. X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) were used to evaluate the ossification thickness, disc height, cervical range of motion (ROM) of the segment, Kang's grade, and disc signal loss. We conducted correlation analysis and subgroup comparisons to analyze the type of ossification, ossification thickness, disc height, disc signal loss, ROM and Kang's grade. The specific ossification thickness was negatively correlated with the disc signal loss (P<0.05). Specific ossification thickness and specific disc height were positively correlated (P<0.05). Segments were divided into the nude group (ossification not crossing the intervertebral space) and the covered group (ossification crossing the intervertebral space). The nude group presented smaller ossification thickness and disc height, and a higher grade of disc signal loss and ROM (P<0.05). The formation of OPLL may be interrelated with the alleviation of IVDD at the same segment. Furthermore, IVDD is not only related to the limited ROM caused by ossification, but also the size and shape of the ossified mass. A negative correlation exists between the ossification thickness and the severity of IVDD in OPLL patients. Ossification that crosses the interverbal space is associated with lower ROM, a thicker ossified mass, and better disc signal. For patients with nude ossification-related segments, a fusion surgery to restore intervertebral stabilization deserves serious consideration.

Restoring the dampened expression of the core clock molecule BMAL1 protects against compression-induced intervertebral disc degeneration

The circadian clock participates in maintaining homeostasis in peripheral tissues, including intervertebral discs (IVDs). Abnormal mechanical loading is a known risk factor for intervertebral disc degeneration (IDD). Based on the rhythmic daily loading pattern of rest and activity, we hypothesized that abnormal mechanical loading could dampen the IVD clock, contributing to IDD. Here, we investigated the effects of abnormal loading on the IVD clock and aimed to inhibit compression-induced IDD by targeting the core clock molecule brain and muscle Arnt-like protein-1 (BMAL1). In this study, we showed that BMAL1 KO mice exhibit radiographic features similar to those of human IDD and that BMAL1 expression was negatively correlated with IDD severity by systematic analysis based on 149 human IVD samples. The intrinsic circadian clock in the IVD was dampened by excessive loading, and BMAL1 overexpression by lentivirus attenuated compression-induced IDD. Inhibition of the RhoA/ROCK pathway by Y-27632 or melatonin attenuated the compression-induced decrease in BMAL1 expression. Finally, the two drugs partially restored BMAL1 expression and alleviated IDD in a diurnal compression model. Our results first show that excessive loading dampens the circadian clock of nucleus pulposus tissues via the RhoA/ROCK pathway, the inhibition of which potentially protects against compression-induced IDD by preserving BMAL1 expression. These findings underline the importance of the circadian clock for IVD homeostasis and provide a potentially effective therapeutic strategy for IDD.

Is There Any Relationship between Plasma IL-6 and TNF-α Levels and Lumbar Disc Degeneration? A Retrospective Single-Center Study.

Intervertebral disc degeneration (IDD) is one of the most common degenerative diseases all over the world. A growing number of studies have proved that large amounts of cytokines are produced during the development of IDD, and the inflammatory responses induced by these cytokines aggravate the occurrence and development of the disc degeneration. In this retrospective single-center study, a total of 182 lumbar spine cases were retrospectively reviewed between July 2020 and October 2021. An appropriate cutoff value was found for discriminating severity of IDD by William rank-sum test and locally weighted scatterplot smoothing algorithm. The cumulative grade was also calculated by summing Pfirrmann grades for all lumbar spine intervertebral discs. It was found that high-score group (total score > 18) plasma interleukin-6 (IL-6) concentration was significantly higher than that of the low-score group (total score ≤ 18) (9.6 ± 1.75 vs. 5.40 ± 0.61 pg/ml, p = 0.002), tumor necrosis factor-α (TNF-α) following the same trend (5.27 ± 1.48 vs. 2.97 ± 0.23, p = 0.006), which was most pronounced in the upper lumbar intervertebral discs (L1-3). In the entire sample, preoperative IL-6 concentration was significantly higher than that of the postoperation (p < 0.001), while the TNF-α was the opposite (p = 0.039). It was also found that there were significant differences in the two groups with respect to age and hypertension (p < 0.001 and p = 0.037). In conclusion, this study preliminarily indicated the relationship between IL-6 and TNF-α and the severity of lumbar disc degeneration.

Expression of ANGPTL4 in Nucleus Pulposus Tissues Is Associated with Intervertebral Disc Degeneration.

Objective Angiopoietin-like protein 4 (ANGPTL4), encoding a glycosylated secreted protein, has been reported to be closely related to many kinds of diseases, including diabetes, tumor, and some musculoskeletal pathologies, such as rheumatoid arthritis, osteoarthritis, and osteoporosis. The aim of the current study is to investigate the role of ANGPTL4 in intervertebral disc degeneration and analyze the association of ANGPTL4 expression with Pfirrmann grades. Methods A total of 162 nucleus pulposus tissues were collected from lumbar intervertebral disc herniation patients undergoing interforaminal endoscopic surgery. Real-time quantitative PCR and western blot were performed to determine the mRNA and protein expression of ANGPTL4 in nucleus pulposus samples. Statistical analysis was performed to analyze the association of ANGPTL4 expression with Pfirrmann grades. Results Based on the clinical data of 162 patients, results showed that Pfirrmann grades were significantly associated with patients' age (r = 0.162, P = 0.047) and were not significantly associated with patients' gender (P > 0.05). RT-qPCR and western blot results showed that the mRNA (r = 0.287, P < 0.05) and protein (r = 0.356, P < 0.05) expressions of ANGPTL4 were both closely associated with Pfirrmann grades. The expression of ANGPTL4 was remarkably increased in the groups of high IVDD Pfirrmann grades. Conclusion The results demonstrated that ANGPTL4 expression was positively associated with the Pfirrmann grades and the severity of intervertebral disc degeneration. ANGPTL4 may be served as a candidate biomarker for intervertebral disc degeneration.

MicroRNA-338-3p as a novel therapeutic target for intervertebral disc degeneration

Recent studies have demonstrated the pivotal role played by microRNAs (miRNAs) in the etiopathogenesis of intervertebral disc degeneration (IDD). The study of miRNA intervention in IDD models may promote the advancement of miRNA-based therapeutic strategies. The aim of the current study was to investigate whether intradiscal delivery of miRNA can attenuate IDD development. Our results showed that miR-338-3p expression was significantly increased in the nucleus pulposus (NP) of patients with IDD. Moreover, there was a statistically significant positive correlation between the expression level of miR-338-3p and the severity of IDD. Our functional studies showed that miR-338-3p significantly influenced the expression of extracellular matrix synthesis genes, as well as the proliferation and apoptosis of NP cells. Mechanistically, miR-338-3p aggravated IDD progression by directly targeting SIRT6, a negative regulator of the MAPK/ERK pathway. Intradiscal injection of antagomir-338-3p significantly decelerated IDD development in mouse models. Our study is the first to identify miR-338-3p as a mediator of IDD and thus may be a promising target for rescuing IDD.

Protective role of the alpha-1-antitrypsin in intervertebral disc degeneration

BackgroundIntervertebral disc degeneration is a complex disease with high prevalence. It suggests that cell death, senescence, and extracellular matrix degradation are involved in the pathogenesis. Alpha-1 antitrypsin (AAT), a serine protease inhibitor, was previously correlated with inflammation-related diseases. However, its function on intervertebral disc degeneration remains unclear.MethodsA latex-enhanced immunoturbidimetric assay measured the serum level of AAT. Real-time polymerase chain reaction (RT-qPCR) and western blot were used to testify the expression of RNA and proteins related to cell apoptosis and the Wnt/β-catenin pathway. The animal model for intervertebral disc degeneration was built by disc puncture. The degeneration grades were analyzed by safranin o staining.ResultsWe showed that alpha-1 antitrypsin could ameliorate intervertebral disc degeneration in vitro and in vivo. We also found that the serum alpha-1 antitrypsin level in Intervertebral disc degeneration patients is negative related to the severity of intervertebral disc degeneration. Moreover, alpha-1 antitrypsin was also showed to suppress tumor necrosis factor-alpha (TNF-α) induced WNT/β-catenin signaling pathway activation in human nucleus pulposus cells.ConclusionsOur study provides evidence for AAT to serve as a potential therapeutic reagent for the treatment of intervertebral disc degeneration.

Development of a standardized histopathology scoring system for intervertebral disc degeneration in rat models: An initiative of the ORS spine section.

BackgroundRats are a widely accepted preclinical model for evaluating intervertebral disc (IVD) degeneration and regeneration. IVD morphology is commonly assessed using histology, which forms the foundation for quantifying the state of IVD degeneration. IVD degeneration severity is evaluated using different grading systems that focus on distinct degenerative features. A standard grading system would facilitate more accurate comparison across laboratories and more robust comparisons of different models and interventions.AimsThis study aimed to develop a histology grading system to quantify IVD degeneration for different rat models.Materials & MethodsThis study involved a literature review, a survey of experts in the field, and a validation study using 25 slides that were scored by 15 graders from different international institutes to determine inter‐ and intra‐rater reliability.ResultsA new IVD degeneration grading system was established and it consists of eight significant degenerative features, including nucleus pulposus (NP) shape, NP area, NP cell number, NP cell morphology, annulus fibrosus (AF) lamellar organization, AF tears/fissures/disruptions, NP‐AF border appearance, as well as endplate disruptions/microfractures and osteophyte/ossification. The validation study indicated this system was easily adopted, and able to discern different severities of degenerative changes from different rat IVD degeneration models with high reproducibility for both experienced and inexperienced graders. In addition, a widely‐accepted protocol for histological preparation of rat IVD samples based on the survey findings include paraffin embedding, sagittal orientation, section thickness < 10 μm, and staining using H&E and/or SO/FG to facilitate comparison across laboratories.ConclusionThe proposed histological preparation protocol and grading system provide a platform for more precise comparisons and more robust evaluation of rat IVD degeneration models and interventions across laboratories.

Is the Distribution Pattern of Modic Changes in Vertebral End-plates Associated With the Severity of Intervertebral Disc Degeneration?: A Cross-sectional Analysis of 527 Caucasians

Low back pain (LBP) is one of the most common disorders, with many possible causes including intervertebral disc degeneration (IVDD) and Modic changes. In this study we aimed to analyze whether the distribution pattern of Modic changes in the vertebral end-plates was associated with the severity of IVDD. We conducted a cross-sectional analysis of a retrospective database. Patients with constant LBP were evaluated in terms of IVDD and Modic changes on lumbar spine magnetic resonance imaging. Statistical analyses were specifically performed for the lower lumbar levels. We evaluated 527 patients. Modic changes were detected in 25% of the patients. Severe IVDD was detected in 90% and 88% of patients with Modic changes through the whole end-plates at L4-L5 and L5-S1 levels, respectively. Patients with Modic changes at L5-S1 level had significantly lower lumbar lordosis. Presence of severe IVDD at L4-L5 and L5-S1 levels was associated with 2.7- and 2.9-times higher risk of more widely distributed Modic changes in those vertebral end-plates, respectively. Severe IVDD was significantly more common in patients with Modic changes through the whole end-plate and in those with Modic type I changes.