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Adjacent segment degeneration is commonly observed in patients after fusion surgery. Among the associated risk factors is the preoperative presence of adjacent disc degeneration (ADD). The risk factors and other spine phenotypes associated with preoperative ADD is critical to understand the pathological process and better prognosis postsurgery. Current study aims to assess and compare the magnetic resonance imaging (MRI) spinal phenotype of herniated level with and without ADD. Preoperative T2W sagittal lumbar MRI images of 155 lumbar disc herniated patients were analyzed for the presence of ADD (Pfirrmann grade III and above). The herniated disc level was assessed for the presence and absence of vertebral endplate (VEP) defects, Modic changes, and high intensity zone (HIZ). Mean age of patients was 38 ± 2 years, almost 62% were males. ADD was found in 57%, VEP defects were seen in 62% of the herniated level, 24.5% showed Modic changes, 3.8% showed spondylolishthesis, and 15.5% revealed HIZ. Age and other demographic factors did not have any significant effect on the presence of ADD, the patients with extruded and sequestered discs had more ADD (p = 0.02). VEP defects were significantly higher in levels with ADD (p = 0.02). Patients with ADD had significantly VEP defect scores (p = 0.01), Modic score (p = 0.002), HIZ score (0.02), and posterior bulge score (p < 0.001). Findings suggest that affected levels with VEP defects and severe grade of disc herniation have the greater likelihood of having ADD. Once developed this ADD may also affect the other spinal levels, and also can affect postoperative prognosis., (© 2023 Orthopaedic Research Society.)

Lumbar disc herniation (LDH) is rare in juveniles. LDH occurring at age 20 years or younger is referred to as juvenile disc herniation (JDH). While adult LDH is regarded as an advanced stage of disc degeneration, it remains unclear why intervertebral discs rupture in youth. This study aimed to characterize magnetic resonance imaging (MRI) findings of JDH and investigate possible etiological factors. From 2013 to 2020, JDH patients and controls were identified and interviewed to assess demographics, general lifestyles, and family histories. MRIs were evaluated for disc degeneration, epiphyseal ring separation, Modic changes and endplate lesions. The relationships between JDH and suspected risk factors were examined. A total of 297 JDH patients (199 boys and 98 girls, age 17.3 ± 2.1 years) and 185 controls (age 17.1 ± 2.4 years) were studied. Age, body mass index, exposures to daily physical labor, regular exercise, and daily sitting time were similar between JDH cases and controls. A family medical history of serious back pain was more common in JDH patients than in controls (59.4% vs. 26.5%, p < 0.001), as well as family history of clinically established LDH (45.0% vs. 12.4%, p < 0.001). Epiphyseal ring separation was identified in 102 (29.2%) herniated discs in 91 (36.4%) JDH patients, while occurring in only 5 (1.4%) control participants (p < 0.001). Overall, severe disc degeneration was not a prominent finding in JDH patients. In conclusion, epiphyseal ring separation was a common magnetic resonance feature in JDH. Findings suggest a genetically mediated developmental model of JDH, rather than a model of premature disc degeneration., (© 2023 Orthopaedic Research Society.)

Macrophage infiltration and polarization during lumbar intervertebral disc herniation (LDH) have attracted increased attention but their role remains unclear. To explore macrophage polarization in herniated nucleus pulposus (NP) tissue of patients with LDH and investigate the association between cell frequency and different clinical characteristics or symptoms, we conducted a retrospective study by analyzing NP tissue samples from 79 patients. Clinical features and symptoms, using the visual analog scale (VAS) and Oswestry disability index (ODI), were collected. The macrophage markers CD68, CCR7, CD163, and CD206; pro-inflammatory cytokine TNF-α; and anti-inflammatory factor IL-4 were analyzed by immunohistochemistry. The frequency of polarized macrophages and positivity rate of pro- and anti-inflammatory cytokines showed significant differences in some of clinical characteristics. Specifically, higher CCR7 + and TNF-α + proportions were identified in the high-intensity zone (HIZ) and the type of extrusion and sequestration NP tissue than in non-HIZ and protrude NP tissue. Higher CD206 + and IL-4+ proportion were detected in Modic changes. However, no differences in gender, age, smoking status, Pfirrmann grade, analgesic use, leg pain duration, and segments were found between groups. CD68 + , CCR7 + , and CD206 + cell proportions, and TNF-α and IL-4 showed positive associations with VAS scores preoperation. Associations between ODI and the macrophages markers were weak/insignificant. Our results indicated that macrophage polarization or macrophage-like cells contribute to LDH pathological features. Macrophage populations displaying significant associations with VAS score reflected continuous M1/M2 transition contributing to pain during LDH. These findings may contribute to enhanced/personalized pharmacological interventions for patients with LDH considering pain heterogeneity., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Low back pain is a very common symptom and the leading cause of disability throughout the world. Several degenerative imaging findings seen on magnetic resonance imaging are associated with low back pain but none of them is specific for the presence of low back pain as abnormal findings are prevalent among asymptomatic subjects as well. The purpose of this population-based study was to investigate if more specific magnetic resonance imaging predictors of low back pain could be found via texture analysis and machine learning. We used this methodology to classify T 2 -weighted magnetic resonance images from the Northern Finland Birth Cohort 1966 data to symptomatic and asymptomatic groups. Lumbar spine magnetic resonance imaging was performed using a fast spin-echo sequence at 1.5 T. Texture analysis pipeline consisting of textural feature extraction, principal component analysis, and logistic regression classifier was applied to the data to classify them into symptomatic (clinically relevant pain with frequency ≥30 days and intensity ≥6/10) and asymptomatic (frequency ≤7 days, intensity ≤3/10, and no previous pain episodes in the follow-up period) groups. Best classification results were observed applying texture analysis to the two lowest intervertebral discs (L4-L5 and L5-S1), with accuracy of 83%, specificity of 83%, sensitivity of 82%, negative predictive value of 94%, precision of 56%, and receiver operating characteristic area-under-curve of 0.91. To conclude, textural features from T 2 -weighted magnetic resonance images can be applied in low back pain classification., (© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Mechanical characterization of the intervertebral disc involves labor-intensive and destructive experimental methodology. Contrast-enhanced micro-computed tomography is a nondestructive imaging modality for high-resolution visualization and glycosaminoglycan quantification of cartilaginous tissues. The purpose of this study was to determine whether anionic and cationic contrast-enhanced micro-computed tomography of the intervertebral disc can be used to indirectly assess disc mechanical properties in an ex vivo model of disc degeneration. L3/L4 motion segments were dissected from female Lewis rats. To deplete glycosaminoglycan, samples were treated with 0 U/ml (Control) or 5 U/ml papain. Contrast-enhanced micro-computed tomography was performed following incubation in 40% Hexabrix (anionic) or 30 mg I/ml CA 4+ (cationic) for 24 h (n = 10/contrast agent/digestion group). Motion segments underwent cyclic mechanical testing to determine compressive and tensile modulus, stiffness, and hysteresis. Glycosaminoglycan content was determined using the dimethylmethylene blue assay. Correlations between glycosaminoglycan content, contrast-enhanced micro-computed tomography attenuation, and mechanical properties were assessed via the Pearson correlation. The predictive accuracy of attenuation on compressive properties was assessed via repeated random sub-sampling cross validation. Papain digestion produced significant decreases in glycosaminoglycan content and corresponding differences in attenuation and mechanical properties. Attenuation correlated significantly to glycosaminoglycan content and to all compressive mechanical properties using both Hexabrix and CA 4+ . Predictive linear regression models demonstrated a predictive accuracy of attenuation on compressive modulus and stiffness of 79.8-86.0%. Contrast-enhanced micro-computed tomography was highly predictive of compressive mechanical properties in an ex vivo simulation of disc degeneration and may represent an effective modality for indirectly assessing disc compressive properties. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2030-2038, 2018., (© 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Damage at the intervertebral disc-vertebra interface associates with back pain and disc herniation. However, the structural and biomechanical properties of the disc-vertebra interface remain underexplored. We sought to measure mechanical properties and failure mechanisms, quantify architectural features, and assess structure-function relationships at this vulnerable location. Vertebra-disc-vertebra specimens from human cadaver thoracic spines were scanned with micro-computed tomography (μCT), surface speckle-coated, and loaded to failure in uniaxial tension. Digital image correlation (DIC) was used to calculate local surface strains. Failure surfaces were scanned using scanning electron microscopy (SEM), and adjacent sagittal slices were analyzed with histology and SEM. Seventy-one percent of specimens failed initially at the cartilage endplate-bone interface of the inner annulus region. Histology and SEM both indicated a lack of structural integration between the cartilage endplate (CEP) and bone. The interface failure strength was increased in samples with higher trabecular bone volume fraction in the vertebral endplates. Furthermore, failure strength decreased with degeneration, and in discs with thicker CEPs. Our findings indicate that poor structural connectivity between the CEP and vertebra may explain the structural weakness at this region, and provide insight into structural features that may contribute to risk for disc-vertebra interface injury. The disc-vertebra interface is the site of failure in the majority of herniation injuries. Here we show new structure-function relationships at this interface that may motivate the development of diagnostics, prevention strategies, and treatments to improve the prognosis for many low back pain patients with disc-vertebra interface injuries. © 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:192-201, 2018., (© 2017 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society.)

Intervertebral disc (IVD) degeneration is responsible for various spine pathologies and present clinical treatments are insufficient. Concurrently, the mechanisms behind IVD degeneration are still not completely understood, so as to allow development of efficient tissue engineering approaches. A model of rat IVD degeneration directly coupled to herniation is here proposed in a pilot study. Disc injury is induced by needle puncture, using two different needles gauges: a low caliber 25-G needle and a high caliber 21-G needle. Histological, biochemical, and radiographic degeneration was evaluated at 2 and 6 weeks post-injury. We show that the larger caliber needle results in a more extended histological and radiographic degeneration within the IVD, compared to the smaller one. TUNEL quantification indicates also increased cell death in the 21-G group. Analyses of collagen type I (Picrosirius red staining), collagen type II (immunofluorescence), and GAG content (Blyscan assay) indicate that degeneration features spontaneously recover from 2 to 6 weeks, for both needle types. Moreover, we show the occurrence of hernia proportional to the needle gauge. The number of CD68+ macrophages present, as well as cell apoptosis within the herniated tissue are both proportional to hernia volume. Moreover, hernias formed after lesion tend to spontaneously diminish in volume after 6 weeks. Finally, MMP3 is increased in the hernia in the 21-G group at 2 weeks. This model, by uniquely combining IVD degeneration and IVD herniation in the same animal, may help to understand mechanisms behind IVD pathophysiology, such as hernia formation and spontaneous regression. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:258-268, 2017., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The extracellular matrix (ECM) of the human intervertebral disc is rich in molecules that interact with cells through integrin-mediated attachments. Porcine nucleus pulposus (NP) cells have been shown to interact with laminin (LM) isoforms LM-111 and LM-511 through select integrins that regulate biosynthesis and cell attachment. Since human NP cells lose many phenotypic characteristics with age, attachment and interaction with the ECM may be altered. Expression of LM-binding integrins was quantified for human NP cells using flow cytometry. The cell-ECM attachment mechanism was determined by quantifying cell attachment to LM-111, LM-511, or type II collagen after functionally blocking specific integrin subunits. Human NP cells express integrins β1, α3, and α5, with over 70% of cells positive for each subunit. Blocking subunit β1 inhibited NP cell attachment to all substrates. Blocking subunits α1, α2, α3, and α5 simultaneously, but not individually, inhibits NP cell attachment to laminins. While integrin α6β1 mediated porcine NP cell attachment to LM-111, we found integrins α3, α5, and β1 instead contributed to human NP cell attachment. These findings identify integrin subunits that may mediate interactions with the ECM for human NP cells and could be used to promote cell attachment, survival, and biosynthesis in cell-based therapeutics., (Copyright © 2013 Orthopaedic Research Society.)

Back pain and intervertebral disc degeneration have a growing socioeconomic healthcare impact. Information on mitochondrial function in human intervertebral disc cells, however, is surprisingly sparse. We assessed mitochondrial bioenergetics, mass, and ultrastructure in annulus cells cultured from human discs of varying degenerative stages. Citrate synthase activity (reflecting mitochondrial mass) declined significantly with increasing Thompson grade (p < 0.0001). Both mitochondrial (p = 0.009) and non-mitochondrial (p = 0.0029) respiration showed significant changes with increasing stages of disc degeneration. No significant relationships were found for the association of respiration data with herniated or non-herniated status, or with subject age. Examination of mitochondrial ultrastructure in cultured annulus cells revealed unusual features which included mitochondrial inclusion bodies, poorly defined cristae and dark staining. Findings reported here are novel and document biochemical, metabolic, and morphologic abnormalities in mitochondria in cells from more degenerated annulus cells. Data suggest that the disc degenerative, not age, is a major factor associated with mitochondrial impairment, and also implicate oxidative stress, driven by mitochondrial dysfunction, as a major component within the degenerating disc. Findings have relevance to advancements in cell-based therapies to treat disc degeneration., (Copyright © 2013 Orthopaedic Research Society.)

Thymic stromal lymphopoietin (TSLP), an IL-7-like cytokine, is highly expressed in herniated disc (HD) tissue and may act as a key molecule for the initiation of macrophage recruitment into the tissue and natural resorption of HD. However, it remains unclear how TSLP expression is regulated in the intervertebral discs. This study showed that expression of TSLP and phosphorylated NF-κB in HD tissue samples was inversely correlated with expression of phosphorylated Smad2/3 (an indicator of active TGF-β signaling) and vice versa in posterior lumbar spinal fusion samples. The pharmacological blockades of endogenous TGF-β activity induced TSLP expression in mouse intervertebral disc tissue culture, which was inhibited by NF-κB inhibitors. Additionally, phosphorylation of Smad2/3 was constitutively detected in mouse intervertebral disc tissue in the steady states. Collectively, these results suggest that endogenous TGF-β activity limits TSLP expression in intervertebral disc tissue in the steady states by suppressing NF-κB activation. The findings reveal a regulatory mechanism how TSLP expression is induced in the intervertebral disc tissue and suggest a novel role of TGF-β in maintaining the homeostasis of intervertebral disc tissue., (Copyright © 2013 Orthopaedic Research Society.)

This study evaluated how dynamic compression induced changes in gene expression, tissue composition, and structural properties of the intervertebral disc using a rat tail model. We hypothesized that daily exposure to dynamic compression for short durations would result in anabolic remodeling with increased matrix protein expression and proteoglycan content, and that increased daily load exposure time and experiment duration would retain these changes but also accumulate changes representative of mild degeneration. Sprague-Dawley rats (n = 100) were instrumented with an Ilizarov-type device and divided into three dynamic compression (2 week-1.5 h/day, 2 week-8 h/day, 8 week-8 h/day at 1 MPa and 1 Hz) and two sham (2 week, 8 week) groups. Dynamic compression resulted in anabolic remodeling with increased matrix mRNA expression, minimal changes in catabolic genes or disc structure and stiffness, and increased glysosaminoglycans (GAG) content in the nucleus pulposus. Some accumulation of mild degeneration with 8 week-8 h included loss of annulus fibrosus GAG and disc height although 8-week shams also had loss of disc height, water content, and minor structural alterations. We conclude that dynamic compression is consistent with a notion of "healthy" loading that is able to maintain or promote matrix biosynthesis without substantially disrupting disc structural integrity. A slow accumulation of changes similar to human disc degeneration occurred when dynamic compression was applied for excessive durations, but this degenerative shift was mild when compared to static compression, bending, or other interventions that create greater structural disruption., ((c) 2009 Orthopaedic Research Society.)

Many of the therapeutic interventions for intervertebral disc degeneration attempt to repopulate the nucleus pulposus (NP) tissue; however, NP cells are heterogeneous and not well characterized. To address this, we have investigated the morphology, extracellular gene and protein expression, and apoptosis changes in NP explants cultured in vitro with or without chondrogenic reagents for different periods. We also compared the susceptibility of the explants to different treatments by comparing: treatment of NP explants with GDF5 protein, transfection of NP explants with GDF5 plasmid, and infection of NP explants with GDF5 adenovirus vector. We found that expression levels of two of the major extracellular proteins found in NP tissue, that is, collagen II and aggrecan, could be maintained in an NP explant culture model with a chondrogenic medium up to 7 days, and were significantly higher than that of fresh NP tissue after 14 days of culture in vitro, whether or not chondrogenic medium was used. In addition, the NP explant responded to treatment with growth factor, and could be infected by virus and transfected by plasmid for further evaluation of growth factor gene therapy. NP explant culture could therefore provide an easy in vitro culture model to characterize NP cells and evaluate potential therapeutic reagents., (Copyright 2008 Orthopaedic Research Society)

We previously demonstrated that VEGF and its receptors were expressed in human herniated discs (HD). TNF-alpha induced VEGF, resulting in neovascularization of disc tissues in a model of HD. The goal of the current research was to investigate the precise role of TNF-alpha-induced VEGF and the mechanism of angiogenesis in disc tissues. We performed ELISAs, Western blots, and immunohistological examinations to assess the role of TNF-alpha-induced VEGF using organ disc cultures with wild type, TNF receptor 1-null (TNF-RI(null)), or TNF receptor 2-null (TNF-RII(null)) mice. VEGF induction was inhibited when we used TNF-RI(null)-derived disc tissues. NF-kappaB pathway inhibitors also strongly suppressed VEGF induction. Thus, TNF-alpha induced VEGF expression in disc cells primarily through the NF-kappaB pathway. In addition, VEGF immunoreactivity was detected predominantly in annulus fibrosus cells and increased after TNF-alpha stimulation. TNF-alpha treatment also resulted in CD31 expression on endothelial cells and formation of an anastomosing network. In contrast, angiogenic activity was strongly inhibited in the presence of NF-kappaB inhibitors or anti-VEGF antibody. Our data show angiogenesis activity in disc tissues is regulated by VEGF and the NF-kappaB pathway, both of which are induced by TNF-alpha. The level of angiogenic activity in disc tissues was closely related to aging. Because neovascularization of HD is indispensable for HD resorption, the prognosis of HD and the rate of the resorption process in patients may vary as a function of the patient's age.

The objective of the study was to improve the biological understanding of degenerative disc disease using a rabbit model in which different stages of disc degeneration are induced by variation of the duration of loading with an external compression-device applying 2.4 MPa. Gene expression and protein distribution were analyzed in controls and after 1, 28, and 56 days of hyperphysiologic loading. To evaluate extracellular matrix genes, quantitative real-time reverse-transcriptase polymerase chain reaction was applied for collagen I, collagen II, biglycan, decorin, fibromodulin, fibronectin, aggrecan, and osteonectin. As representatives of catabolic, anticatabolic, and anabolic factors, matrix metalloproteinase-13 (MMP-13), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), and bone morphogenetic protein-2 (BMP-2) were chosen. To evaluate protein distribution, immunohistochemistry was performed for collagen I, collagen II, and BMP-2/4. Matrix gene expression was characterized by two major developments: collagen I and II, biglycan, and decorin showed early elevation followed by later downregulation to control levels, whereas fibromodulin, fibronectin, aggrecan, and osteonectin showed continuous upregulation or remained at similar levels. Induction of MMP-13 gene expression was found in degenerated discs. TIMP-1 and BMP-2 were elevated immediately after hyperphysiologic loading and presented highest levels in the 56-day group. Immunohistochemistry showed less collagen II and BMP-2/4 positive cells after compression. In conclusion, elevated matrix gene expression represents an early cellular response to hyperphysiologic loading. As degeneration progresses, some matrix genes increase upregulation, whereas others start downregulation. Continuous upregulation of catabolic, anticatabolic, and anabolic factors indicates their important role in the degeneration process., (Copyright 2005 Orthopaedic Research Society.)

GDF-8, also known as myostatin, is a member of the transforming growth factor-beta superfamily of secreted growth and differentiation factors that is expressed in vertebrate skeletal muscle. Myostatin functions as a negative regulator of skeletal muscle growth and myostatin null mice show a doubling of muscle mass compared to normal mice. We describe here morphology of the lumbar spine in myostatin knockout (Mstn(-/-)) mice using histological and densitometric techniques. The Mstn(-/-) mice examined in this study weigh approximately 10% more than controls (p<0.001) but the iliopsoas muscle is over 50% larger in the knockout mice than in wild-type mice (p<0.001). Peripheral quantitative computed tomography (pQCT) data from the fifth lumbar vertebra show that mice lacking myostatin have approximately 50% greater trabecular bone mineral density (p=0.001) and significantly greater cortical bone mineral content than normal mice. Toluidine blue staining of the intervertebral disc between L4-L5 reveals loss of proteoglycan staining in the hyaline end plates and inner annulus fibrosus of the knockout mice. Loss of cartilage staining in the caudal end plate of L4 is due to ossification of the end plate in the myostatin-deficient animals. Results from this study suggest that increased muscle mass in mice lacking myostatin is associated with increased bone mass as well as degenerative changes in the intervertebral disc.

We studied whether applying nucleus pulposus tissue, obtained from tail intervertebral discs that had been subjected to chronic mechanical compression, to the lumbar nerve roots produces hyperalgesia, which is thought to be a pain-related behavior in the rat. An Ilizarov-type apparatus was used for immobilization and chronically applied compression of the rat tail for eight weeks. Three weeks after application of extracted nucleus pulposus tissue on the lumbar nerve roots, motor function, sensitivity to noxious mechanical stimuli was measured. Eight weeks after application of the apparatus, the instrumented vertebrae were resected and sections were stained with hematoxylin and eosin to evaluate degeneration of the intervertebral disc. Mechanical hyperalgesia observed in rats treated with the compressed nucleus pulposus tissue was greater and of longer duration than in the rats treated with normal and non-compressed discs. The nucleus pulposus in the instrumented vertebrae showed some histological degeneration. In conclusion, chronic mechanical compression of nucleus pulposus, which resulted in degeneration to some extent, enhanced mechanical hyperalgesia, which was induced by application of nucleus pulposus on the nerve root in the rat. Degenerative intervertebral discs might induce more significant pain than normal intervertebral discs.

Although the precise etiology of low back pain is disputed, degeneration of the intervertebral disc is believed to play an important role. Many animal models have been described which reproduce the changes found in degenerative disc disease, but none allow for efficient, large-scale testing of purported therapeutic agents. The purpose of this study was to develop a simple animal model resembling degenerative disc disease using the intervertebral discs found in the tails of rats. The proximal two intervertebral discs in the tails of 20 rats were injected with either chondroitinase ABC or control (phosphate buffered saline, PBS). The tails were harvested at 2 weeks, and measurements were made of intervertebral disc height (measured radiographically and histologically), biomechanics (stiffness, hysteresis, and residual deformation), and histologic appearance. Treatment with chondroitinase ABC resulted in a significant loss in intervertebral disc height (radiographic intervertebral disc height, p=0.001; histologic intervertebral disc height, p<0.001) and significant increases in all biomechanical parameters (stiffness, p<0.001; hysteresis, p=0.006; residual deformation, p=0.004) compared to PBS controls. Intervertebral discs treated with chondroitinase ABC had significantly lower histologic grades for each grading category (nucleus pulposus (NP), annulus fibrosus, and proteoglycan staining) compared to controls. The results of injury with chondroitinase ABC were similar to the findings in degenerative disc disease: reduced intervertebral disc height, diminished proteoglycan content, loss of NP cells, and increased stiffness of the disc. Thus, the model appears to be a reasonable tool for the preliminary in vivo evaluation of proposed treatments for degenerative disc disease.

In this study, we hypothesized that vertebral bone density and disc degeneration would affect the structural property distributions of the lower lumbar vertebral endplates (L3-L5). The results may have implications for improving interbody implant designs to better resist subsidence. A 3 mm diameter hemispherical indenter was used to perform indentation tests at 0.2 mm/s to a depth of 3 mm at 27 standardized locations in 55 bony endplates of intact human lumbar vertebrae (L3-L5). The resulting load-displacement curves were used to extract the failure load and stiffness of each test site. Bone density was measured using lateral DEXA scans. Disc condition was determined using a four-point grading scale. Three-way analyses of variance were used to analyze the relationships between the data. The overall failure load decreased with bone mineral density (BMD) in the superior (p < 0.0001) and inferior (p = 0.011) lumbar endplates. In both endplates, the posterolateral regions were significantly stronger than more central regions. With increasing BMD, this difference became more pronounced in the superior endplates only (p = 0.005). Increased disc degeneration was associated with an overall failure load decrease in the inferior lumbar endplates (p = 0.002). The strength in the central regions of the superior endplates was reduced with increasing degeneration, but this was not observed peripherally (p = 0.001). Stiffness magnitude or distribution was not significantly affected by BMD or disc degeneration. The locations of the strongest regions of the endplate did not change with either bone density or disc degeneration. This implies that implant shapes designed using the basic structural property maps for the L3-L5 endplates are appropriate for use in patients with a wide range of pathologies, even though overall failure loads are generally lower in patients with reduced bone density and greater degrees of disc degeneration.

Biologically active substances, such as prostaglandins, thromboxanes, and leukotrienes, which are metabolites involved in the arachidonic acid cascade, are detected in herniated disc samples obtained from patients with lumbar disc herniation. However, little is known concerning the relationships between these substances and clinical symptoms such as radicular pain. Thromboxane A2 (TXA2) induces not only potent platelet aggregation, but also blood vessel contraction. Leukotriene B4 (LTB4), a potent chemotactic agent, plays a role in inflammatory reactions by recruiting neutrophils and lymphocytes. The purpose of this study was to examine the roles of TXA2 and LTB4 in the hyperalgesia induced by application of nucleus pulposus to the lumbar nerve root in the rat. TXA2 synthetase inhibitor and LTB4 receptor antagonist, which were injected into the epidural space, decreased mechanical hyperalgesia at both three and seven days after epidural injection. There were no significant differences in sensitivity to noxious thermal stimuli following application of the nucleus pulposus or an epidural injection. Epidural injection of LTB4 receptor antagonist and/or TXA2 synthetase inhibitor may attenuate the painful radiculopathy due to lumbar disc herniation. In conclusion, our findings suggest that TXA2 and LTB4 may play significant roles in mechanical hyperalgesia induced by autologous nucleus pulposus.

Autologous nucleus pulposus is known to have injurious effects on spinal nerve roots when applied epidurally. Both inflammatory and immunological mechanisms have been implicated in this regard. Various proinflammatory substances might be released or activated by nucleus pulposus and might affect the endoneural nerve root vessels. The present study assessed nucleus pulposus-induced early vascular reactions and the possibility of blocking these reactions with intravenous, high-dose, methylprednisolone pretreatment. In 25 pigs, the S2 and S3 nerve roots were exposed. In five pigs (control group), retroperitoneal fat was applied epidurally on the nerve roots, and the other 20 pigs had nucleus pulposus applied. This group was sub-divided into the treatment group (n = 8), in which the pigs were pretreated with intravenous high-dose methylprednisolone (30 mg/kg body weight), and the nontreatment group (n = 12), in which the pigs received a corresponding volume of saline solution. After 2 hours, Evans blue labeled albumin was injected intravenously 5 minutes before death. Endoneural extravasation of Evans blue labeled albumin was evaluated with fluorescence microscopy. A marked albumin leakage was found in 67% of the nontreated animals, in 25% of those in the treatment group, and in none of the control animals. These results demonstrate that nucleus pulposus can induce a rapid increase in endoneural vascular permeability in spinal nerve roots after epidural application. This increase can be partially prevented by pretreatment with high-dose methylprednisolone.

Reinsertion of autogenous nucleus pulposus, an innovative method to delay further disc degeneration, has been proved with an experimental animal model. This study examined whether coculture of nucleus pulposus cells with annulus fibrosus cells (a) activates annulus fibrosus cells and (b) retards disc degeneration when reinserted into the disc in a rabbit model of disc degeneration. Coculture of the two cell types stimulated proliferation of each, as indicated by increased DNA synthesis measured by increases in DNA polymerase alpha expression and uptake of 5-bromo-2'deoxy-uridine assessed by an enzyme-linked immunosorbent assay. In a model of disc degeneration in rabbits, reinsertion of activated nucleus pulposus cells delayed the formation of clusters of chondrocyte-like cells, the destruction of disc architecture, and the elaboration of type-II collagen as measured immunohistochemically compared with no treatment. The direct reinsertion of activated nucleus pulposus cells into the disc offers a promising line of investigation for delaying intervertebral disc degeneration, although these results obtained with notochordal cells may not necessarily apply when mature central nucleus pulposus cells are used.

We previously demonstrated that the granulation tissues of herniated nucleus pulposus are composed of a marked infiltration of macrophages that strongly express monocyte chemotactic protein-1. Monocyte chemotactic protein-1 is a chemotactic cytokine that contributes to the activation and recruitment of macrophages. Relatively little is known about its role in the resorption process of herniated nucleus pulposus. To clarify the sequential dynamics of expression of monocyte chemotactic protein-1 in the granulation tissues of herniated nucleus pulposus, we introduced a rat autologous transplantation model of nuclear materials onto its lumbar dura mater and performed immunohistological analysis and competitive polymerase chain reaction assay using the grafted samples. Immunohistological analysis demonstrated that the majority of infiltrating mononuclear cells expressed monocyte chemotactic protein-1. Monocyte chemotactic protein-1 mRNA was expressed in the first 3 weeks after the procedure and was significantly and maximally upregulated at 1 week. To determine whether human recombinant monocyte chemotactic protein-1 facilitates the resorption process of herniated nucleus pulposus, we introduced another model of autologous transplantation, wherein the nuclear materials were grafted to the abdominal subcutaneous tissues and recombinant monocyte chemotactic protein-1 was subsequently applied to these materials. When monocyte chemotactic protein-1 was injected into the murine nucleus pulposus tissues, they reduced in size more rapidly than in the control group. These findings suggest that monocyte chemotactic protein-1 plays an important role in the recruitment of macrophages in the early phase of the resorption process of herniated nucleus pulposus and that its application may physiologically facilitate the resorption process of the nucleus pulposus.

The purpose of this investigation was to determine differences in tissue composition of symptomatic and asymptomatic disc herniations as reflected in T1 and T2 relaxation times (quantitative magnetic resonance imaging). Thirty patients with sciatica severe enough to require a discectomy and 46 asymptomatic volunteers (controls) were included in this study. Both groups had a clinical examination as well as a magnetic resonance investigation of the lumbar spine. The longitudinal and transverse magnetic relaxation times (T1 and T2, respectively) were calculated from a set of 20 images obtained with five single-slice/multi-echo sequences at different repetition time values on a commercial whole-body system (1.5 T). Twenty-two symptomatic and asymptomatic disc herniations could be matched according to age, gender, disc level, and the extent of herniation (protrusion or extrusion) and were compared with regard to T1 and T2 relaxation times. Symptomatic disc herniations exhibited significantly (pT1 < 0.04 and pT2 < 0.003) shorter T1 (delta T1: -182.1 milliseconds, -15%) and T2 (delta T2: -11.0 milliseconds, -21%) relaxation times than matched asymptomatic herniations. Symptomatic disc herniations also exhibited more advanced disc degeneration as graded by Pearce's criteria (p < 0.01). These results suggest that symptomatic and morphologically matched asymptomatic disc herniations differ with regard to disc matrix composition.

Swelling of the intervertebral disc nucleus pulposus may be a contributing factor in lower back pain syndromes. We have designed and tested a new osmometer for in vitro determination of nucleus pulposus swelling pressure. The functional principle of the osmometer involves compressing a sample of nucleus pulposus with nitrogen gas until saline pressure gradients across a 0.45-micron Millipore filter are eliminated. Swelling pressures of both pooled dog and pooled pig lumbar disc nucleus pulposus were measured on the new osmometer and were compared with swelling pressure determined using the equilibrium dialysis technique. The osmometer measured swelling pressures comparable to those obtained by the dialysis technique. This osmometer provides a rapid, direct, and accurate measurement of swelling pressure of the nucleus pulposus.

Breeding experiments confirmed that a hereditary form of kyphoscoliosis in the BDL strain mouse was due to an autosomal recessive gene (ky). Sagittal sections of whole vertebral columns from adult homozygous recessive mice (ky/ky) were examined histologically. All mice showed varying degrees of degenerative change in one or more intervertebral discs between the fifth cervical and the second thoracic vertebrae. The changes comprised loss of cells, loss of distinction between nucleus pulposus and annulus fibrosus, loss of characteristic ring-like structure in the annulus, and development of wedge-shaped discs. In most animals, degenerative disc substance protruded from the disc space, usually posteriorly, sometimes anteriorly, and occasionally through the vertebral end plate cartilage. Posterior protrusions impinged on the spinal cord.

Fifteen lumbar spines were collected postmortem. The intervertebral discs were assigned morphological grades and were analyzed for water, collagen, and proteoglycan. In order of increasing degeneration, five grade 0, four grade 1, 45 grade 2, 12 grade 3A, and nine grade 3B discs were identified. The proteoglycan concentration fell progressively with increasing grade, although the concentrations of each component overlapped extensively among the grades. Grade 2 discs showed no consistent differences from adjacent grade 3A or 3B discs in the same spine. All discs in seven of the eight spines with grade 3A or 3B discs and all discs in three spines with no grade 3A or 3B discs had proteoglycan concentrations below 52 mg/g fresh weight. Four of five spines with at least one disc of proteoglycan concentration above this value contained no grade 3A or 3B discs. These observations support the hypothesis that low proteoglycan concentrations in all the discs of a spine precede degeneration.