Aims. CRP is an acute-phase protein that is used as a biomarker to follow severity and progression in infectious and inflammatory diseases. Its pathophysiological mechanisms of action are still poorly defined. CRP in its pentameric form exhibits weak anti-inflammatory activity. The monomeric isoform (mCRP) exerts potent proinflammatory properties in chondrocytes, endothelial cells, and leucocytes. No data exist regarding mCRP effects in human intervertebral disc (IVD) cells. This work aimed to verify the pathophysiological relevance of mCRP in the aetiology and/or progression of IVD degeneration. Methods. We investigated the effects of mCRP and the signalling pathways that are involved in cultured human primary annulus fibrosus (AF) cells and in the human nucleus pulposus (NP) immortalized cell line HNPSV-1. We determined messenger RNA (mRNA) and protein levels of relevant factors involved in inflammatory responses, by quantitative real-time polymerase chain reaction (RT-qPCR) and western blot. We also studied the presence of mCRP in human AF and NP tissues by immunohistochemistry. Results. We demonstrated that mCRP increases nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and Lipocalin 2 (LCN2) expression in human AF and NP cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signalling of mCRP. Finally, we demonstrated the presence of mCRP in human AF and NP tissues. Conclusion. Our results indicate, for the first time, that mCRP can be localized in IVD tissues, where it triggers a proinflammatory and catabolic state in degenerative and healthy IVD cells, and that NF-κβ signalling may be implicated in the mediation of this mCRP-induced state. Cite this article: Bone Joint Res 2023;12(3):189–198

This article reviews the current knowledge of the intervertebral disc (IVD) and its association with low back pain (LBP). The normal IVD is a largely avascular and aneural structure with a high water content, its nutrients mainly diffusing through the end plates. IVD degeneration occurs when its cells die or become dysfunctional, notably in an acidic environment. In the process of degeneration, the IVD becomes dehydrated and vascularised, and there is an ingrowth of nerves. Although not universally the case, the altered physiology of the IVD is believed to precede or be associated with many clinical symptoms or conditions including low back and/or lower limb pain, paraesthesia, spinal stenosis and disc herniation. New treatment options have been developed in recent years. These include biological therapies and novel surgical techniques (such as total disc replacement), although many of these are still in their experimental phase. Central to developing further methods of treatment is the need for effective ways in which to assess patients and measure their outcomes. However, significant difficulties remain and it is therefore an appropriate time to be further investigating the scientific basis of and treatment of LBP

The belief that an intervertebral disc must degenerate before it can herniate has clinical and medicolegal significance, but lacks scientific validity. We hypothesised that tissue changes in herniated discs differ from those in discs that degenerate without herniation. Tissues were obtained at surgery from 21 herniated discs and 11 non-herniated discs of similar degeneration as assessed by the Pfirrmann grade. Thin sections were graded histologically, and certain features were quantified using immunofluorescence combined with confocal microscopy and image analysis. Herniated and degenerated tissues were compared separately for each tissue type: nucleus, inner annulus and outer annulus. Herniated tissues showed significantly greater proteoglycan loss (outer annulus), neovascularisation (annulus), innervation (annulus), cellularity/inflammation (annulus) and expression of matrix-degrading enzymes (inner annulus) than degenerated discs. No significant differences were seen in the nucleus tissue from herniated and degenerated discs. Degenerative changes start in the nucleus, so it seems unlikely that advanced degeneration caused herniation in 21 of these 32 discs. On the contrary, specific changes in the annulus can be interpreted as the consequences of herniation, when disruption allows local swelling, proteoglycan loss, and the ingrowth of blood vessels, nerves and inflammatory cells. In conclusion, it should not be assumed that degenerative changes always precede disc herniation. Cite this article: Bone Joint J 2013;95-B:1127–33

Aims. This study aimed, through bioinformatics analysis and in vitro experiment validation, to identify the key extracellular proteins of intervertebral disc degeneration (IDD). Methods. The gene expression profile of GSE23130 was downloaded from the Gene Expression Omnibus (GEO) database. Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases, and we used Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) to analyze the functions and pathways of EP-DEGs. STRING and Cytoscape were used to construct protein-protein interaction (PPI) networks and identify hub EP-DEGs. NetworkAnalyst was used to analyze transcription factors (TFs) and microRNAs (miRNAs) that regulate hub EP-DEGs. A search of the Drug Signatures Database (DSigDB) for hub EP-DEGs revealed multiple drug molecules and drug-target interactions. Results. A total of 56 EP-DEGs were identified in the differential expression analysis. EP-DEGs were enriched in the extracellular structure organization, ageing, collagen-activated signalling pathway, PI3K-Akt signalling pathway, and AGE-RAGE signalling pathway. PPI network analysis showed that the top ten hub EP-DEGs are closely related to IDD. Correlation analysis also demonstrated a significant correlation between the ten hub EP-DEGs (p＜0.05), which were selected to construct TF–gene interaction and TF–miRNA coregulatory networks. In addition, ten candidate drugs were screened for the treatment of IDD. Conclusion. The findings clarify the roles of extracellular proteins in IDD and highlight their potential as promising novel therapeutic targets. Cite this article: Bone Joint Res 2023;12(9):522–535

Objectives. Interleukin 18 (IL-18) is a regulatory cytokine that degrades the disc matrix. Bone morphogenetic protein-2 (BMP-2) stimulates synthesis of the disc extracellular matrix. However, the combined effects of BMP-2 and IL-18 on human intervertebral disc degeneration have not previously been reported. The aim of this study was to investigate the effects of the anabolic cytokine BMP-2 and the catabolic cytokine IL-18 on human nucleus pulposus (NP) and annulus fibrosus (AF) cells and, therefore, to identify potential therapeutic and clinical benefits of recombinant human (rh)BMP-2 in intervertebral disc degeneration. Methods. Levels of IL-18 were measured in the blood of patients with intervertebral disc degenerative disease and in control patients. Human NP and AF cells were cultured in a NP cell medium and treated with IL-18 or IL-18 plus BMP-2. mRNA levels of target genes were measured by real-time polymerase chain reaction, and protein levels of aggrecan, type II collagen, SOX6, and matrix metalloproteinase 13 (MMP13) were assessed by western blot analysis. Results. The serum level of patients (IL-18) increased significantly with the grade of IVD degeneration. There was a dramatic alteration in IL-18 level between the advanced degeneration (Grade III to V) group and the normal group (p = 0.008) Furthermore, IL-18 induced upregulation of the catabolic regulator MMP13 and downregulation of the anabolic regulators aggrecan, type II collagen, and SOX6 at 24 hours, contributing to degradation of disc matrix enzymes. However, BMP-2 antagonised the IL-18 induced upregulation of aggrecan, type II collagen, and SOX6, resulting in reversal of IL-18 mediated disc degeneration. Conclusions. BMP-2 is anti-catabolic in human NP and AF cells, and its effects are partially mediated through provocation of the catabolic effect of IL-18. These findings indicate that BMP-2 may be a unique therapeutic option for prevention and reversal of disc degeneration. Cite this article: S. Ye, B. Ju, H. Wang, K-B. Lee. Bone morphogenetic protein-2 provokes interleukin-18-induced human intervertebral disc degeneration. Bone Joint Res 2016;5:412–418. DOI: 10.1302/2046-3758.59.BJR-2016-0032.R1

Mesenchymal stem-cell based therapies have been proposed as novel treatments for intervertebral disc degeneration, a prevalent and disabling condition associated with back pain. The development of these treatment strategies, however, has been hindered by the incomplete understanding of the human nucleus pulposus phenotype and by an inaccurate interpretation and translation of animal to human research. This review summarises recent work characterising the nucleus pulposus phenotype in different animal models and in humans and integrates their findings with the anatomical and physiological differences between these species. Understanding this phenotype is paramount to guarantee that implanted cells restore the native functions of the intervertebral disc. Cite this article: Bone Joint Res 2013;2:169–78

Aims. Interleukin (IL)-1β is one of the major pathogenic regulators during the pathological development of intervertebral disc degeneration (IDD). However, effective treatment options for IDD are limited. Suramin is used to treat African sleeping sickness. This study aimed to investigate the pharmacological effects of suramin on mitigating IDD and to characterize the underlying mechanism. Methods. Porcine nucleus pulposus (NP) cells were treated with vehicle, 10 ng/ml IL-1β, 10 μM suramin, or 10 μM suramin plus IL-1β. The expression levels of catabolic and anabolic proteins, proinflammatory cytokines, mitogen-activated protein kinase (MAPK), and nuclear factor (NF)-κB-related signalling molecules were assessed by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence analysis. Flow cytometry was applied to detect apoptotic cells. The ex vivo effects of suramin were examined using IDD organ culture and differentiation was analyzed by Safranin O-Fast green and Alcian blue staining. Results. Suramin inhibited IL-1β-induced apoptosis, downregulated matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5, and upregulated collagen 2A (Col2a1) and aggrecan in IL-1β-treated NP cells. IL-1β-induced inflammation, assessed by IL-1β, IL-8, and tumour necrosis factor α (TNF-α) upregulation, was alleviated by suramin treatment. Suramin suppressed IL-1β-mediated proteoglycan depletion and the induction of MMP-3, ADAMTS-4, and pro-inflammatory gene expression in ex vivo experiments. Conclusion. Suramin administration represents a novel and effectively therapeutic approach, which could potentially alleviate IDD by reducing extracellular matrix (ECM) deposition and inhibiting apoptosis and inflammatory responses in the NP cells. Cite this article: Bone Joint Res 2021;10(8):498–513

Aims. In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD. Methods. An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel’s mechanism in IVDD. Results. A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats. Conclusion. DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD. Cite this article: Bone Joint Res 2024;13(5):247–260

It has been proposed that intervertebral disc degeneration might be caused by low-grade infection. The purpose of the present study was to assess the incidence of herpes viruses in intervertebral disc specimens from patients with lumbar disc herniation. A polymerase chain reaction based assay was applied to screen for the DNA of eight different herpes viruses in 16 patients and two controls. DNA of at least one herpes virus was detected in 13 specimens (81.25%). Herpes Simplex Virus type-1 (HSV-1) was the most frequently detected virus (56.25%), followed by Cytomegalovirus (CMV) (37.5%). In two patients, co-infection by both HSV-1 and CMV was detected. All samples, including the control specimens, were negative for Herpes Simplex Virus type-2, Varicella Zoster Virus, Epstein Barr Virus, Human Herpes Viruses 6, 7 and 8. The absence of an acute infection was confirmed both at the serological and mRNA level. To our knowledge this is the first unequivocal evidence of the presence of herpes virus DNA in intervertebral disc specimens of patients with lumbar disc herniation suggesting the potential role of herpes viruses as a contributing factor to the pathogenesis of degenerative disc disease

Antibiotics are often administrated prophylactically in spinal procedures to reduce the risk of infection of the disc space. It is still not known which antibiotics are able to penetrate the intervertebral disc effectively. In a prospective, randomised, double-blind clinical study, we examined the penetration of the intervertebral discs of two commonly used antibiotics, cefuroxime and gentamicin. The patients, randomised into two groups, received either 1.5 g of cefuroxime or 5 mg/kg of gentamicin prophylactically two hours before their intervertebral discs were removed. A specimen of blood, from which serum antibiotic levels were determined, was obtained at the time of discectomy. Therapeutic levels of antibiotic were detectable in the intervertebral discs of the ten patients who received gentamicin. Only two of the ten patients (20%) who received cefuroxime had a quantifiable level of antibiotic in their discs although therapeutic serum levels of cefuroxime were found in all ten patients. Our results show that cefuroxime does not diffuse into human intervertebral discs as readily as gentamicin. It is possible that the charge due to ionisable groups on the antibiotics can influence the penetration of the antibiotics. We therefore recommend the use of gentamicin in a single prophylactic dose for all spinal procedures in order to reduce the risk of discitis

Objectives. The aim of this study was to examine whether asymmetric loading influences macrophage elastase (MMP12) expression in different parts of a rat tail intervertebral disc and growth plate and if MMP12 expression is correlated with the severity of the deformity. Methods. A wedge deformity between the ninth and tenth tail vertebrae was produced with an Ilizarov-type mini external fixator in 45 female Wistar rats, matched for their age and weight. Three groups were created according to the degree of deformity (10°, 30° and 50°). A total of 30 discs and vertebrae were evaluated immunohistochemically for immunolocalisation of MMP12 expression, and 15 discs were analysed by western blot and zymography in order to detect pro- and active MMP12. Results. No MMP12 expression was detected in the nucleus pulposus. Expression of MMP12 in the annulus progressively increased from group I to groups II and III, mainly at the concave side. Many growth plate chondrocytes expressed MMP12 in the control group, less in group I and rare in groups II and III. Changes in cell phenotype and reduction of cell number were observed, together with disorganisation of matrix microstructure similar to disc degeneration. ProMMP12 was detected at the area of 54 kDa and active MMP12 at 22 kDa. Conclusions. Expression of MMP12 after application of asymmetric loading in a rat tail increased in the intervertebral disc but decreased in the growth plate and correlated with the degree of the deformity and the side of the wedged disc. Cite this article: Bone Joint Res 2014;3:273–9

1. The intervertebral disc is an organic viscous elastic structure capable of maintaining very great loads without disintegration. 2. Recovery of the disc after deformation depends upon: a) the imbibition of tissue fluid by the disc, b) the removal of the deforming force. Complete recovery is modified by the duration of the force. 3. Factors that interfere with the elasticity of the disc are: extreme youth (immaturity of the disc), chronic wasting diseases (general nutritional disturbance), and local pathological changes in the bodies of the vertebrae which interrupt or damage its blood supply. The intervertebral disc reaches its greatest state of efficiency in adult life—that is, when the nucleus pulposus has disappeared as an entity. The function of the disc appears not to depend upon the presence of the nucleus : rather does the presence of the nucleus indicate immaturity of the disc. 4. The highly resilient elastic nature of the vertebral column is provided by the intervertebral discs, which constitute one-third of the whole length of the column. 5. The imbibition of fluid requires further investigation. It appears that from lacunae in the adjacent bodies finger-like pockets dip into the discs and that fluid passes through the lining membrane of these pockets

1. An account of experiences in seventy-five cases with a new method of treatment of low back pain and sciatica caused by intervertebral disc lesions has been presented. The method is based on the fact that chymopapain, a proteolytic enzyme, can break down displaced intervertebral disc material without deleterious effects upon adjacent tissues. 2. Chymopapain was injected into intervertebral discs by the postero-lateral or preferably the lateral approach. Two milligrams per disc constitute an effective dose. The enzyme was administered to seventy-five patients who were potential candidates for laminectomy. These patients were followed for four to thirty months and results were graded as "good" (76 per cent), "fair" (15 per cent) and "poor" (9 per cent). 3. Although untoward reactions have been encountered, none of these has been attributable to chymopapain. 4. Our investigations have convinced us that enzymatic dissolution of a lumbar intervertebral disc lesion is a safe, effective method of relieving sciatica and low back pain in selected cases

1. The normal anatomy of the intervertebral disc of immature rabbits is described. 2. An account is given of the changes that occur after an operative incision in the ventral part of the intervertebral discs of rabbits which allowed the escape of the nucleus pulposus. The account is based on observations made on fifty-five young animals killed at intervals during the twenty-five months after operation. 3. The superficial part of the wound in the annulus heals rapidly by active fibrosis. Thereafter there is a chondrification of the ventral region of the disc, followed by ossification. A prominent bony ridge ultimately ankyloses the vertebrae adjoining the disc. 4. The site of the nucleus pulposus is eventually occupied by a dense pad of fibrocartilage. A tongue of this tissue projects into the deep median part of the wound which remains unhealed. 5. A hypothesis is submitted regarding the mechanism of rupture of the annulus fibrosus and prolapse of the nucleus pulposus in man; this hypothesis is based in part on the observations of lesions in discs not subjected to operation

Specific antisera to collagen Types I, II and III and proteoglycan were used to investigate the distributions of these molecules in normal human intervertebral discs. Immunofluorescent staining indicated the presence of small amounts of Type III collagen located pericellularly in normal adult intervertebral discs. This finding had not been demonstrated previously by other methods. Similar specimens of intervertebral discs from 17 patients with scoliosis of varying aetiologies were examined, but no evidence was obtained for primary connective tissue defects. Secondary changes, especially marked vascularisation of the inner annulus, were apparent in a number of scoliotic discs, and some of these showed enhanced staining for collagen Type I and proteoglycan, and intercellular matrix staining for Type III collagen

It has been thought that lumbar intervertebral discs were innervated segmentally. We have previously shown that the L5-L6 intervertebral disc in the rat is innervated bilaterally from the L1 and L2 dorsal root ganglia through the paravertebral sympathetic trunks, but the pathways between the disc and the paravertebral sympathetic trunks were unknown. We have now studied the spines of 17 rats to elucidate the exact pathways. We examined serial sections of the lumbar spine using immunohistochemistry for calcitonin gene-related peptide, a sensory nerve marker. We showed that these nerve fibres from the intervertebral disc ran through the sinuvertebral nerve into the rami communicantes, not into the corresponding segmental spinal nerve. In the rat, sensory information from the lumbar intervertebral discs is conducted through rami communicantes. If this innervation pattern applies to man, simple decompression of the corresponding nerve root will not relieve discogenic pain. Anterior interbody fusion, with the denervation of rami communicantes, may be effective for such low back pain

Posterior fixation of intervertebral discs is used to treat, and occasionally diagnose, discogenic pain since it is thought that it will reduce the internal loading of the discs in vitro. We measured the internal loading of ten intervertebral discs using stress profilometry under simulated physiological loads and then after posterior fixation. Partial discectomies were performed to simulate advanced disc degeneration and the sequence repeated. Posterior fixation had very little effect on the magnitude of the loads acting on the disc and none when disc degeneration was simulated. It did, however, reduce bulging of the anterior annulus under combined bending and compression (p < 0.03). Recent experiments in vivo have shown that discogenic pain is associated with abnormal bulging of the annulus which suggests that the clinical benefit of fixation may be due to this

Magnetic resonance imaging (MRI) of the spine produces images which reflect the chemical composition of the intervertebral disc. We have conducted a prospective study of the serial changes in the MRI appearance of the intervertebral disc after chemonucleolysis with the enzyme chymopapain. Fourteen patients were studied after single-level chemonucleolysis and the results compared with a control group of 17 discs in six patients who had diagnostic discography without enzyme insertion. A consistent pattern of gradual loss of signal from the nucleus pulposus culminating in complete loss of nuclear signal was seen in all cases after chemonucleolysis. Chymopapain therefore produced MRI changes analogous with premature gross disc degeneration. The rate at which this occurred varied; complete loss of signal took at least six weeks. Transitory minor end-plate changes were present in five patients, probably representing a mild chemical discitis. No similar changes were seen in the discography group

We attempted to correlate the findings of MRI and discography in patients with low back pain, examining 108 lumbar intervertebral discs in 33 consecutive patients. MRI results were assessed from the intensity and shape of the signal obtained from the central part of the disc. Discography was classified according to the pattern of contrast material, the pressure accepted and the pain reproduced. All discs which were abnormal on MRI had altered patterns on discography, but 18 of the 60 discs with normal MRI had abnormal discograms. Of 39 asymptomatic discs, 33 had normal MRI signals and 24 had normal discograms. None of the 15 discs showing severe degeneration on MRI sustained high levels of intradiscal pressure, but only six of the 60 discs giving normal MRI had low pressure. With current techniques, discography is more accurate than MRI for the detection of annular pathology: a normal MRI does not exclude significant changes in the peripheral structure of the intervertebral disc which can produce low back pain

1. As a result of degenerative changes in the intervertebral disc, nuclear tissue often herniates through its confining structures. These lesions are common, even in children, and often lead to difficulty in diagnosis. 2. The radiological manifestations of nuclear herniations into the spongiosa of the vertebral body, through the anterior part of the annulus fibrosus, beneath the epiphysial ring, and through the posterior part of the annulus are described and illustrated. The clinical significance of these radiological appearances and their pathological basis is indicated. 3. An understanding of the significance of the radiological findings in herniation of the nucleus pulposus and a careful correlation with the clinical features of the case are necessary for accurate diagnosis

One hundred and twenty-seven cases of intervertebral disc calcification in children, including 11 previously unreported cases, have been analysed. A distinction is made between symptomatic and asymptomatic patients, whose age, sex and spinal distributions of the calcifications have been shown to differ. Radiologically detectable protrusions and later resorption of the calcifications are common events in symptomatic children, but are unrecorded in asymptomatic children. The spinal distribution of paediatric calcifications is quite different to that of adult and canine calcifications of the nucleus pulposus

The role of antibiotics in the treatment of disc-space infection is controversial. This study assessed the tissue penetration of flucloxacillin and cephradine into the normal intervertebral disc after intravenous administration of a bolus dose of antibiotic. Twenty-five discs were removed from 12 adolescent patients having anterior spinal surgery to correct scoliosis; antibiotic had been administered between 30 minutes and four hours before operation. Despite high blood levels, no antibiotic could be detected by bioassay or by high-pressure liquid chromatography (h.p.l.c.) in any of the specimens from the nucleus pulposus or the annulus fibrosus

Computerised tomography of the lumbar spine was performed on 22 patients with clinical evidence of prolapse of an intervertebral disc and normal or equivocal radiculograms. Of 11 patients with positive scans who had an operation the presence of pathology was confirmed in 10. Although CT scanning is always helpful in diagnosing disc disorders, where facilities are scarce (as in Great Britain) it is best employed in patients with negative or non-contributory radiculography

Two groups of intervertebral discs, one normal, as obtained from the post-mortem room, the other prolapsed, as removed at operation, have been compared by chemical analysis of their principal constituents. There is a progression of chemical changes associated with the ageing of the normal disc. This shows not only the expected slight increase in collagen as age advances, but also, surprisingly, that the polysaccharide content rises to a maximum in the fourth decade, in the same way as does polysaccharide in costal cartilage. In prolapsed discs the ageing process is superseded by a different and distinctive progression, which advances, not according to age, but according to the duration of the prolapse. There is a critical level to which the polysaccharide content must apparently fall, irrespective of the normal level for the patient's age, before a prolapse occurs. Normal ageing probably consists in the breakdown of a particular polysaccharide/protein linkage, with coincident "maturation" of collagen. In the prolapsing disc multiple, and possibly different, linkages are rapidly broken down. This depolymerisation of a gel structure must be presumed to be the basis of the decreased imbibition capacity of the nucleus pulposus, and to be the source of the hydrostatic abnormalities which result in disc prolapse. In both normal and prolapsing discs the products of mucopolysaccharide breakdown appear to participate in the metabolism of collagen

By polarising microscope and x-ray crystallographic techniques the annulus fibrosus has been shown to consist of regularly oriented sheets of collagen fibres. These results have been interpreted in terms of an elastic mechanism whereby thrust from the nucleus causes increased girth in the annulus. It is suggested that this is accomplished by a change in the angle between the axis of the fibres in adjacent uniaxial layers of the annulus. Furthermore, the loss of elasticity of the intervertebral disc associated with age would seem to be mainly due to changes occurring in the nucleus pulposus

Our study establishes a rabbit model of disc degeneration which requires neither a chemical nor physical injury to the disc. Disc degeneration similar to that seen in man was created at levels proximal (L4-L5) and caudal (L7-S1) to a simulated lumbar fusion and was studied for up to nine months after arthrodesis. Loss of the normal parallel arrangement of collagen bundles within the annular lamellae was observed in intervertebral discs adjacent to the fusion at three months. By six months there was further disorganisation as well as loss of distinction between the lamellae themselves. By nine months the structure of the disc had been replaced by disorganised fibrous tissue, and annular tears were seen. There was an initial cellular proliferative response followed by loss of chondrocytes and notochordal cells in the nucleus pulposus. Degeneration was accompanied by a decrease in the monomer size of proteoglycans. Narrowing of the disc space, endplate sclerosis and the formation of osteophytes at adjacent disc spaces were observed radiologically

We studied degenerative changes in the cervical intervertebral discs of 497 asymptomatic subjects by MRI and evaluated disc degeneration by loss of signal intensity, posterior and anterior disc protrusion, narrowing of the disc space and foraminal stenosis. In each subject, five disc levels from C2–C3 to C6–C7 were evaluated. The frequency of all degenerative findings increased linearly with age. Disc degeneration was the most common observation, being present in 17% of discs of men and 12% of those of women in their twenties, and 86% and 89% of discs of both men and women over 60 years of age. We found significant differences in frequency between genders for posterior disc protrusion and foraminal stenosis. The former, with demonstrable compression of the spinal cord, was observed in 7.6% of subjects, mostly over 50 years of age. Our results should be taken into account when interpreting the MRI findings in patients with symptomatic disorders of the cervical spine

A new technique for the transthoracic removal of a prolapsed intervertebral disc in the mid or lower thoracic spine is described. Investigations before operation include thoracic myelography, selective spinal angiography and CT scanning. Image intensification is used at operation to check the level of the prolapse. A tunnel in the coronal plane (vertebrotomy) is made through the posterolateral part of the disc and the adjacent vertebral bodies, to reach the spinal canal at the site of the prolapse. This gives good exposure and enables gentle removal of the disc prolapse and any associated osteophytes, under direct vision without need for retraction or pressure on the dura or spinal cord. Spinal stability is not compromised, and the blood supply of the cord is not disturbed. Five consecutive patients are reported, including one in whom the disc prolapse was calcified and had herniated into the spinal cord. All were treated successfully

We studied the presence of anabolic growth factors in human herniated intervertebral discs (IVD) using a reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Messenger RNA (mRNA) was isolated from the nucleus pulposus using oligo (dT). 25. superparamagnetic beads and probing with gene-specific primers in RT-PCR. mRNA coding for TGF-α (3/10), EGF (0/10), TGF-β1 (0/10) and TGF-β3 (2/10) or the EGF receptor (EGF-R; 0/10) and TGF-β type-II receptor (0/10) was found only occasionally. Beta-actin was always present and positive sample controls confirmed the validity of the RT-PCR assay. These RT-PCR findings were confirmed using immunohistochemical staining of EGF and TFG-β, whereas TGF-α protein was always found associated with discocytes. We conclude that the nucleus pulposus of the herniated IVD is vulnerable to proteolytic degradation and depletion of proteoglycans due to the lack and/or low production of anabolic growth factors/receptors which could increase the local synthesis of the extracellular matrix

Doubt remains as to the safest surgical approach to the prolapsed thoracic intervertebral disc. Laminectomy, lateral rhachotomy and the transthoracic approach all have their protagonists. Twenty-two patients from the National Hospital for Nervous Diseases, Queen Square, and Atkinson Morley's Hospital have been reviewed. Their clinical presentation is discussed and the ancillary aids to diagnosis assessed. The diagnostic value of disc space calcification is stressed, and the use of air myelography as an adjunct to positive contrast myelography is noted. Fifteen patients were subjected to laminectomy, and seven to lateral rhachotomy. Each group contained patients with a wide range of neurological deficit. Six of the patients who underwent laminectomy were improved, two were unchanged, six deteriorated and one died. Of the patients who had lateral rhachotomy, six were improved, one was unchanged and none deteriorated. The conclusion is drawn that lateral rhachotomy is a safer procedure

1. The uptake of S. 35. labelled sodium sulphate has been studied autoradiographically in the intervertebral disc of the young rabbit. 2. The sojourn of the isotope in the tissues includes an intracellular phase of approximately twenty-four hours, followed by an extracellular phase. 3. The cells exhibiting by far the greatest affinity for the sulphate ion are the peripheral groups of cells of the nucleus pulposus, while the chondrocyte-like cells of the cartilaginous segment of the annulus fibrosus are also fairly active. The central cells of the nucleus and the fibroblasts of the outer one-third of the annulus have a much lower uptake. 4. By analogy with similar studies on hyaline cartilage, and on the basis of correlation between the alcinophilia of the tissues and the concentration of the label, both before and after hyalase digestion of the tissue, it is considered that in the young rabbit disc, as in articular cartilage, the sulphate is incorporated primarily into chondroitin sulphate. 5. The elimination of the isotope from the nucleus at twenty-four days and the persistence of the label in the annulus fibrosus at thirty-two days tends to suggest that the metabolic turnover of acid mucopolysaccharide is considerably slower in the annulus than in the nucleus

We have studied the ability of a range of antibiotics to penetrate intervertebral disc tissue in vitro, using a mouse disc model. Equilibrium concentrations of antibiotics incorporated into the entire disc were determined by bioassay using a microbial growth-inhibition method. Uptake was significantly higher with positively-charged aminoglycosides compared with negatively-charged penicillins and cephalosporins. Uncharged ciprofloxacin showed an intermediate degree of uptake. Our results support the hypothesis that electrostatic interaction between charged antibiotics and negatively-charged glycosaminoglycans in the disc is an important factor in antibiotic penetration, and may explain their differential uptake

We report the cases of teenage twin girls presenting within months of each other with severe symptoms from lumbosacral disc prolapses, requiring laminectomy in one and chemonucleolysis in the other. CT scans showed similarities in spinal configuration, including the presence of disc bulges at the L4-5 level. This suggests a strong hereditary factor in prolapse of intervertebral discs, but a review of the literature showed little information on that aspect

Herniated intervertebral disc tissue has been shown to produce a number of proinflammatory mediators and cytokines, but there have been no similar studies using discs from patients with discogenic low back pain. We have compared the levels of production of interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E. 2. (PGE. 2. ) in disc tissue from patients undergoing discectomy for sciatica (63) with that from patients undergoing fusion for discogenic low back pain (20) using an enzyme-linked immunoabsorbent assay. There was a statistically significant difference between levels of production of IL-6 and IL-8 in the sciatica and low back pain groups (p < 0.006 and p < 0.003, respectively). The high levels of proinflammatory mediator found in disc tissue from patients undergoing fusion suggest that production of proinflammatory mediators within the nucleus pulposus may be a major factor in the genesis of a painful lumbar disc

It has been suggested that matrix metalloproteinase-3 (MMP-3, stromelysin-1) has an important role in the degeneration of intervertebral discs (IVDs). A human MMP-3 promoter 5A/6A polymorphism was reported to be involved in the regulation of MMP-3 gene expression. We suggest that IVD degeneration is associated with 5A/6A polymorphism. We studied 54 young and 49 elderly Japanese subjects. Degeneration of the lumbar discs was graded using MRI in the younger group and by radiography in the elderly. 5A/6A polymorphism was determined by polymerase-chain reaction-based assays. We found that the 5A5A and 5A6A genotype in the elderly was associated with a significantly larger number of degenerative IVDs than the 6A6A (p < 0.05), but there was no significant difference in the young. In the elderly, the IVD degenerative scores were also distributed more highly in the 5A5A and 5A6A genotypes (p = 0.0029). Our findings indicate that the 5A allele is a possible risk factor for the acceleration of degenerative changes in the lumbar disc in the elderly

To clarify the pathomechanisms of discogenic low back pain, the sympathetic afferent discharge originating from the L5-L6 disc via the L2 root were investigated neurophysiologically in 31 Lewis rats. Sympathetic afferent units were recorded from the L2 root connected to the lumbar sympathetic trunk by rami communicantes. The L5-L6 discs were mechanically probed, stimulated electrically to evoke action potentials and, finally, treated with chemicals to produce an inflammatory reaction. We could not obtain a response from any units in the L5-L6 discs using mechanical stimulation, but with electrical stimulation we identified 42 units consisting mostly of A-delta fibres. In some experiments a response to mechanical probing of the L5-L6 disc was recognised after producing an inflammatory reaction. This study suggests that mechanical stimulation of the lumbar discs may not always produce pain, whereas inflammatory changes may cause the disc to become sensitive to mechanical stimuli, resulting in nociceptive information being transmitted as discogenic low back pain to the spinal cord through the lumbar sympathetic trunk. This may partly explain the variation in human symptoms of degenerate discs.

Previous studies on the anatomy of the lumbar spine have not clarified the precise relationship of the origin of the lumbar roots to their corresponding discs or their angulation to the dural sac. We studied 33 cadavers (25 formalin-preserved and eight fresh-frozen) and their radiographs to determine these details.

All cadavers showed a gradual decrease in the angle of the nerve root from L1 to S1. The origin of the root was found to be below the corresponding disc for the L1 to L4 roots. In the formalin-preserved cadavers 8% of the L5 roots originated above, 64% below and 28% at the L4/L5 disc. In the fresh cadavers the values were 12.5%, 62.5% and 25%, respectively. For the S1 root 76% originated above and 24% at the L5-S1 disc in the formalin-preserved cadavers and 75% and 25%, respectively, in the fresh cadavers.

A herniated disc usually compresses the root before division of the root sleeve. Thus, compression of the thecal sac before the origin of the root sleeve is common for L1 to L5 whereas compression at the root sleeve is common for S1.

Our findings are of value in understanding the pathophysiology of prolapse of the disc and in preventing complications during surgery.

We studied 52 patients, each with a lumbosacral transitional vertebra. Using MRI we found that the lumbar discs immediately above the transitional vertebra were significantly more degenerative and those between the transitional vertebrae and the sacrum were significantly less degenerative compared with discs at other levels. We also performed an anatomical study using 70 cadavers. We found that the iliolumbar ligament at the level immediately above the transitional vertebra was thinner and weaker than it was in cadavers without a lumbosacral transitional vertebra.

Instability of the vertebral segment above the transitional vertebra because of a weak iliolumbar ligament could lead to subsequent disc degeneration which may occur earlier than at other disc levels. Some stability between the transitional vertebra and the sacrum could be preserved by the formation of either an articulation or by bony union between the vertebra and the sacrum through its transverse process. This may protect the disc from further degeneration in the long term.

The anatomical studies, basic to our understanding of lumbar spine innervation through the sinu-vertebral nerves, are reviewed. Research in the 1980s suggested that pain sensation was conducted in part via the sympathetic system. These sensory pathways have now been clarified using sophisticated experimental and histochemical techniques confirming a dual pattern. One route enters the adjacent dorsal root segmentally, whereas the other supply is non-segmental ascending through the paravertebral sympathetic chain with re-entry through the thoracolumbar white rami communicantes.

Sensory nerve endings in the degenerative lumbar disc penetrate deep into the disrupted nucleus pulposus, insensitive in the normal lumbar spine. Complex as well as free nerve endings would appear to contribute to pain transmission.

The nature and mechanism of discogenic pain is still speculative but there is growing evidence to support a ‘visceral pain’ hypothesis, unique in the muscloskeletal system. This mechanism is open to ‘peripheral sensitisation’ and possibly ‘central sensitisation’ as a potential cause of chronic back pain.

Although success has been achieved with implantation of bone marrow mesenchymal stem cells (bMSCs) in degenerative discs, its full potential may not be achieved if the harsh environment of the degenerative disc remains. Axial distraction has been shown to increase hydration and nutrition. Combining both therapies may have a synergistic effect in reversing degenerative disc disease. In order to evaluate the effect of bMSC implantation, axial distraction and combination therapy in stimulating regeneration and retarding degeneration in degenerative discs, we first induced disc degeneration by axial loading in a rabbit model.

The rabbits in the intervention groups performed better with respect to disc height, morphological grading, histological scoring and average dead cell count. The groups with distraction performed better than those without on all criteria except the average dead cell count.

Our findings suggest that bMSC implantation and distraction stimulate regenerative changes in degenerative discs in a rabbit model.

Cadaveric lumbar discs were injected with chymopapain and subjected to a series of mechanical tests over a period of up to 19 hours. Discs from the same spine injected with saline were used as controls. The results showed that chymopapain had no measurable effect on the mechanical properties of the disc apart from the increased height and stiffening caused by fluid injection. Another series of tests on isolated pieces of disc material showed that chymopapain could reduce the size of prolapsed nuclear material by 24% in one hour and by 80% in 48 hours. It is concluded that, in the short-term, chymopapain has a negligible effect on the mechanics of a disc but it can reduce the size of any prolapsed nuclear material with which it comes in contact.

Forty-one cadaveric lumbar intervertebral joints from 18 spines were flexed and fatigue loaded to simulate a vigorous day's activity. The joints were then bisected and the discs examined. Twenty-three out of 41 of the discs showed distortions in the lamellae of the annulus fibrosus and, in a few of these, complete radial fissures were found in the posterior annulus.

Infection of the intervertebral space is a rare complication of operation on the disc (Ford and Key 1955). It occurred in five cases in a series of 650 operations for lumbar disc protrusion done by two of the authors of this paper--an incidence of 0-8%. Symptoms began between seven and twelve days after operation. After initial relief of the original sciatic pain, the patients developed severe back pain and muscle cramps in the legs. Straight-leg raising became much more limited than before operation. The erythrocyte sedimentation rate was raised in all cases. The diagnosis was confirmed by rescreening the Myodil, when an indentation was seen opposite the intervertebral space from which the disc had been excised. Early removal of infected material from the disc space resulted in complete relief of pain and cure of the infection.

We investigated the relationship between spinopelvic parameters and disc degeneration in young adult patients with spondylolytic spondylolisthesis. A total of 229 men with a mean age of 21 years (18 to 26) with spondylolytic spondylolisthesis were identified. All radiological measurements, including pelvic incidence, sacral slope, pelvic tilt, lumbar lordosis, sacral inclination, lumbosacral angle (LSA), and sacrofemoral distance, were calculated from standing lateral lumbosacral radiographs. The degree of intervertebral disc degeneration was classified using a modified Pfirrmann scale. We analysed the spinopelvic parameters according to disc level, degree of slip and disc degeneration.

There were significant positive correlations between the degree of slip and pelvic incidence (p = 0.009), sacral slope (p = 0.003) and lumbar lordosis (p = 0.010). The degree of slip and the LSA were correlated with disc degeneration (p < 0.001 and p = 0.003, respectively). There was also a significant difference between the degree of slip (p < 0.001) and LSA (p = 0.006) according to the segmental level of disc degeneration.

Cite this article: Bone Joint J 2013;95-B:1239–43.