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PubMedDate not supplied

Biochemistry of intervertebral disc degeneration and the potential for gene therapy applications.

BACKGROUND CONTEXT: Low back pain continues to be a major cause of morbidity in the United States and the world. Although the exact cause has yet to be defined, the intervertebral disk and its age-related changes have been most frequently implicated. PURPOSE: This article represents a brief summary of intervertebral disk structure and function, both in the "normal" and degenerative states. STUDY DESIGN/SETTING: Review article. A Medline search from 1966 to present was performed to identify pertinent articles related to the topic of the intervertebral disc and degeneration. METHODS: This review article describes the pertinent anatomy, as well as the biochemical and biomechanical changes that occur in the intervertebral disc over time. It presents many of the current theories implicated as causing these changes. RESULTS: Recent studies have shown that gene therapy (the transfer of therapeutic gene[s] into a cell), may have promise as a method of slowing down, or preventing some of the changes seen in the intervertebral disc. CONCLUSION: Intervertebral disc degeneration is a complex phenomenon, likely the result of a combination of biochemical and biomechanical factors that are known to occur in the disk. Ongoing research efforts in the area of gene therapy show promise as a way to prevent, or even reverse, some of these changes.

Adult↗
PubMed2005

Morphologic comparison of cervical, thoracic, lumbar intervertebral discs of cynomolgus monkey (Macaca fascicularis).

The aim was to analyze the morphological differences of the intervertebral disc and endplates at different levels. Forty-five vertebral motion segments were obtained from the spine of nine 3 to 4-year-old cynomolgus monkeys (Macaca fascicularis). From every spine, five discs were sectioned (C5-C6, T3-T4, T9-T10, L2-L3, L4-L5). In all the groups, tissue samples were collected and sections were stained with Masson's trichrome, Safranine-O and van Gieson's connective tissue stain to analyze the intervertebral discs. Immunohistochemistry was performed, using specific antibodies to detect collagens I and II. The intervertebral disc height, the maximum nucleus pulposus height, the superior and inferior endplate heights were histomorphometrically measured and different indexes were calculated to compare the differences between specimens of the same animal and between discs of the same level, and finally the differences between groups of discs of different levels. There were no differences existing in annular fibers anchoring on the endplate between discs of different levels. A positive immune reaction for type I collagen was observed in the longitudinal ligaments and in the annular region adjacent to them. Collagen II immune reactivity was found in the annulus close to the nucleus pulposus, in the endplates and in the nucleus. There were no differences between discs of different levels in the collagen I and II localization. The height of the discs varied along the spine. The smallest value was measured in T3-T4, with a larger increase caudally than cranially. The highest value was measured in L2-L3. A cervical disc was 55% the height of a lumbar one. The endplate height increased along the length of the spine. The inferior EP was always higher than the superior. The study provides a detailed structural characterization of the intervertebral disc and may be useful for further investigations on the disc degeneration process.

Animals↗
PubMed1981

Pseudovacuum of the cervical intervertebral disc: a normal variant.

A lucency in the intervertebral disc space at the superior margin is a normal variant related to Mach band phenomenon. This may easily be confused with a true vacuum sign in intervertebral disc injury. Patients with the pseudovacuum have no associated radiographic findings to suggest injury about the suspected disc space. A review of a group of normal lateral cervical vertebral films showed the phenomenon to occur in 65% of adults and 50% in children.

Adult↗
PubMed1992

RT97- and calcitonin gene-related peptide-like immunoreactivity in lumbar intervertebral discs and adjacent tissue from the rat.

The innervation of rat intervertebral disc and adjacent ligamentous tissue has been investigated using 2 antibodies, RT97 and anti-calcitonin gene-related peptide. Immunoreactivity to the peptide was found in many fibres throughout the long ligaments around the intervertebral discs and in the periosteum, especially associated with vascular channels entering the vertebral bodies. Few of the immunoreactive fibres entered the annular lamellae of the disc tissue. Most of those which terminated did so as fine fibres which lay close to, or in, the interlamellar spaces of the outer annulus fibrosus. Calcitonin gene-related peptide-like immunoreactivity was also found in more complex endings in the longitudinal ligaments and rarely within the annulus fibrosus. RT97-immunoreactivity was also present in the complex endings and associated fibres. Conversely, RT97-immunoreactivity was apparent only in a few fine filamentous fibre endings. This suggested that the majority of fine filamentous, or free, nerve endings were of an unmyelinated sensory origin. Alternatively, those endings of a more complex nature, which were RT97-immunoreactive, were of a myelinated sensory origin. No immunoreactivity to either antibody was seen in the inner annular or nuclear tissue. It was therefore concluded that the sensory innervation of the rat intervertebral disc has both myelinated and unmyelinated components, the latter being more extensive. Both types of innervation appear to be restricted to the outermost rings of the annulus fibrosus.

Animals↗
PubMed2005

Cytokine profiles in conditioned media from cultured human intervertebral disc tissue. Implications of their effect on bone marrow stem cell metabolism.

BACKGROUND: Cytokines released from intervertebral discs cultured in vitro have not been profiled, and the effect of these cytokines on human bone marrow stem cells is yet to be studied. MATERIALS AND METHODS: Intervertebral discs from 14 patients who had undergone spinal fusion surgery were cultured separately in vitro. Conditioned media were collected after 48 and 96 h of culture in serum-free Minimum Essential Medium (MEM). Profiling of the cytokines was conducted using pooled media. Conditioned medium from each patient was also tested in human bone marrow stem cell culture, and incorporation of alkaline phosphatase and 3H-thymidine incorporation was evaluated. RESULTS: Of the 18 cytokines screened, 12 were found to be positive, but only eotaxin, IP-10, Rantes IL-6 and IL-8 seemed to be present at high levels. There was a close correlation between IL-6 and IL-8 levels in the medium (R = 0.90, p < 0.001). When the conditioned media were added to human bone marrow stem cell cultures, cellular proliferation was stimulated (p = 0.02), but alkaline phosphatase activity remained unchanged. Cellular proliferation correlated negatively with IL-6 levels (R = -0.44, p = 0.04). INTERPRETATION: Intervertebral discs secrete certain cytokines into the medium when cultured in vitro, and conditioned media from cultured intervertebral discs stimulate proliferation of bone marrow stem cells.

Adolescent↗
PubMed1993

Sparse substance P-like immunoreactivity in intervertebral discs. Nerve fibers and endings in the rat.

I studied rat lumbar intervertebral discs using a monoclonal antibody to substance P, which revealed immunoreactivity in the periosteum and ligaments adjacent to the intervertebral disc. Fibers containing substance P-like immunoreactivity were also found penetrating and terminating within the annulus fibrosus of both the anterior and posterior intervertebral disc. The maximum depth of penetration was 5 lamellae (annular rings) or approximately one sixth of the depth of the annulus. The terminal structures were not encapsulated (free-nerve endings) and were either branched, looped or both. The majority of fibers were varicose in appearance. Substance P-like immunoreactivity was very minor.

Animals↗
PubMed2003

Human intervertebral disc cell morphology and cytoskeletal composition: a preliminary study of regional variations in health and disease.

Classically, intervertebral disc cells have been described as fibrocytic in the anulus fibrosus and chondrocytic in the nucleus pulposus. Recent animal studies, however, have suggested that disc cell morphology may be more complex than previously considered. Here, by utilizing labelling of components of the cytoskeleton in combination with confocal microscopy, we have examined the detailed morphology of human intervertebral disc cells in pathological and non-pathological tissue. Filamentous-actin- and vimentin-positive cells that appeared either fibrocytic or chondrocytic were observed in all intervertebral discs. However, in localized areas of the disc, stellate cells that extended multiple, branching cytoplasmic processes into their surrounding matrix were also seen. This stellate appearance formed a marked feature of disc cells regionally in certain pathologies, i.e. in cells of the outer anulus fibrosus in scoliotic discs and in inner anulus/nucleus pulposus cells in one spondylolisthetic disc. We conclude that the phenotypic variation of human intervertebral disc cells should be extended to include cells with a stellate appearance, which may be more prevalent in tissue that has been subjected to abnormal load or tension.

Actins↗
PubMed1976

Aging changes in intervertebral discs and spondylosis in Chinese hamsters.

Vertebrae and intervertebral discs of Chinese hamsters, a species of rodents that develop spontaneous diabetes, were investigated for age-linked changes and for the occurrence of spondylosis. Aging changes in the intervertebral discs were similar in diabetic and nondiabetic animals. The incidence of spondylosis was significantly increased and its onset was accelerated in the diabetic animals. The mechanisms operative in the pathogenesis of the lesions and their relation to the human disease are discussed.

Aging↗
PubMedDate not supplied

The computed tomographic appearance of acute thoracolumbar intervertebral disc herniations in dogs.

The appearance of herniated intervertebral disc material in the thoracolumbar vertebral canal was evaluated in 23 dogs using computed tomography (CT). The images were then compared with the myelographic and surgical findings. The normal spinal cord, outlined by epidural fat over intervertebral disc spaces, was of intermediate attenuation on transverse CT images. Herniated disc material was identified in all animals as a heterogeneous hyperattenuating extradural mass. The attenuation of the disc material increased with the degree of mineralization. In seven dogs, the herniated material was only slightly more attenuating than the spinal cord. In these dogs, small fragments of mineralized disc material and significant hemorrhage were found in the epidural space at surgery. In dogs with a long standing history of disc herniations, disc material identified in the vertebral canal had a more hyperattenuating and homogeneous appearance than recently herniated disc material. We conclude that mineralized, herniated disc material and hemorrhage can be identified quickly and safely in dogs using CT.

Animals↗
PubMedDate not supplied

Alterations in biochemical components of extracellular matrix in intervertebral disc herniation: role of MMP-2 and TIMP-2 in type II collagen loss.

Alterations in the composition of intervertebral disc extracellular matrix, mainly collagen and proteoglycans, may cause changes in mechanical properties of the disc, leading to dysfunction, nerve root compression, and herniation with severe clinical manifestations. Matrix metalloproteinases may be involved in degradation by hydrolysing extracellular matrix components. Inhibitors of matrix metalloproteinases, in contrast, function in the maintenance of degradation control. In this study, we investigated: (i) whether the level of matrix degradation correlated with the duration of the symptomatic disease, (ii) roles of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) in intervertebral disc degeneration. Nucleus pulposus of intervertebral discs were obtained from 22 patients and analysed for collagen and proteoglycan contents, and pro-MMP-2, TIMP-2 levels. Collagen content was determined as hydroxyproline and proteoglycan content was measured as glycosaminoglycans. The loss in matrix components did not correlate with the duration of the degenerative disc disease. Pro-MMP-2 levels were higher at early stages of the degenerative disc disease (r = -0.495, P < 0.05). TIMP-2 levels were similar in all samples. Pro-MMP-2 and TIMP-2 levels negatively correlated in herniated discs samples (r = -0.855, P < 0.01). Pro- MMP-2 levels negatively correlated with the collagen content in herniated disc material. Our findings may suggest a silent period of active disease prior to symptomatic outcome during which irreversible matrix loss occurs. Involvement of other proteolytic enzymes at different stages of the disease should also be investigated to help to control the degradation cascade at relatively early stages of disc degeneration before the clinical onset of disease.

Adult↗
PubMed1999

Biomechanical role of the intervertebral disc and costovertebral joint in stability of the thoracic spine. A canine model study.

STUDY DESIGN: Biomechanical evaluation was performed to investigate the stability of the thoracic spine. Unilateral resection of the intervertebral disc, the rib head joint, and the costotransverse joint were sequentially performed, and nondestructive cyclic loading tests were conducted at each injury stage to examine the roles of the intervertebral disc and the costovertebral joint of the thoracic spine. The effects of each resection were three-dimensionally analyzed as the main motion and the associated coupled motions. OBJECTIVE: To examine the role of the intervertebral disc and the costovertebral joint in stability of the thoracic spine. SUMMARY OF BACKGROUND DATA: The effects of unilateral resection of the intervertebral disc and the costovertebral joints in the thoracic spine with the rib cage have not been documented three-dimensionally in a biomechanical study. MATERIALS AND METHODS: Ten canine rib cage-thoracic spine complexes, consisting of the sixth to eighth ribs, the sternum and T5-T8 vertebrae, were used. Six pure moments along three axes, flexion-extension, lateral bending, and axial rotation, were applied to the specimen, and the angular deformation between T6-T7 was recorded by a stereophotogrammetric method. After the intact specimens were tested, staged resections were conducted in the following manner: partial resection of the T6-T7 intervertebral disc, performed as a resection of the anterior longitudinal ligament, the nucleus pulposus, and the annulus fibrosus on the approach side, leaving the posterior longitudinal ligament intact; resection of the right seventh rib head with the joint capsule; and resection of the right seventh costotransverse joint. At each stage, the main motion and associated coupled motions were determined three dimensionally. RESULTS: The ranges of motion (ROM) in flexion-extension, lateral bending, and axial rotation were significantly increased after partial discectomy (P < 0.01). Moreover, along with large increases in the ROM of the main motions in left axial rotation and right lateral bending, coupled motions, expressed by right lateral bending and left axial rotation, showed marked increases after resection of the rib head joint (P < 0.05). The neutral zones also increased in lateral bending, axial rotation, and flexion-extension after partial discectomy (P < 0.01). A further increase in the neutral zone was observed in lateral bending after resection of the right seventh rib head (P < 0.01). CONCLUSIONS: In this canine spine model, the intervertebral disc regulates the stability of the thoracic spine in flexion-extension, lateral bending, and axial rotation. Moreover, the articulation of the rib head with the vertebral bodies provides stability to the thoracic spine in lateral bending and axial rotation. Unilateral resection of the rib head joint after partial discectomy on the same side produces significant coupled motions in lateral bending and axial rotation, resulting in a significant decrease in thoracic spinal stability, and integrity.

Animals↗
PubMed1975

Inadequacies and hazards of chymopapain injections as treatment for intervertebral disc disease.

Chymopapain chemonucleolysis was performed on 100 patients with primary lumbar intervertebral disc disease. The results were compared with those of 174 patients who underwent laminotomy, foraminotomy, and discectomy. Primary lumbar intervertebral disc disease was arbitrarily divided into degenerative, complex, previous surgical, and simple disc syndromes. No difference was seen between chemonucleolysis and surgery in the first three divisions; between 55 percent and 60 per cent of patients responded successfully to treatment. In the simple disc division 89 per cent of the surgical and 60 per cent of the chemonucleolysis patients had successful results.

Adult↗
PubMed2001

Intraspinal cyst communicating with the intervertebral disc in the lumbar spine: discal cyst.

STUDY DESIGN: A retrospective case study of patients with intraspinal cyst having a distinct connection with the corresponding intervertebral disc. OBJECTIVES: To propose a new clinical entity, "discal cyst," by clarifying the clinical, radiographic, and histologic aspects of the disease. SUMMARY OF BACKGROUND DATA: Several types of intraspinal cysts with different pathogenesis, causing symptoms indistinguishable from those of lumbar disc herniation, have been reported, such as perineural cysts, synovial cysts, and ganglion cysts. However, to the authors' knowledge, no detailed analysis has been made of cysts that have a distinct connection with the corresponding intervertebral disc. METHODS: Clinical pictures, radiographic findings, and surgical and histologic findings in eight surgically treated patients with intraspinal cyst having a distinct connection with the intervertebral disc were reviewed. Possible pathogenesis and a proposal for nomenclature were also discussed. RESULTS: This disease can be characterized by (1) clinical symptoms indistinguishable from those of typical disc herniation, manifesting as a unilateral single nerve root lesion; (2) incidence at slightly younger age and at upper intervertebral levels than with typical disc herniation; (3) T1 low signal and T2 high signal intensity, round to oval mass lesion on magnetic resonance imaging, compatible with a liquid-containing cyst; (4) minimal degeneration of the involved disc, either on discography/computed tomographic discography or magnetic resonance imaging; (5) a connection between the cyst and the corresponding intervertebral discs on discograms with severe radiating pain in the affected leg at the time of injection; (6) immediate relief of symptoms after simple removal of the cyst; (7) cyst wall consisting of dense fibrous connective tissue containing bloody to clear serous discharge; and (8) absence of disc materials and a specific lining cell layer on histologic examination. Although the exact cause is unknown, underlying minor disc injury may serve as a basis for cyst formation. CONCLUSION: Eight cases of intraspinal cysts communicating with the intervertebral disc presenting symptoms identical to those of disc herniation are presented. Because all cysts were connected to the corresponding disc and the development of the cyst was assumed to be related to underlying disc injury, it is proposed to name this clinical entity discal cyst.

Adult↗
PubMed1987

Degeneration and the chemical composition of the human lumbar intervertebral disc.

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.

Adult↗
PubMed1998

Sensory nerve fibres from lumbar intervertebral discs pass through rami communicantes. A possible pathway for discogenic low back pain.

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.

Animals↗
PubMed2001

[Dynamic observation on imbalance of dynamic and static forces and degenerated cervical intervertebral disc in rats].

OBJECTIVE: To study the relation between biomechanical imbalance and the degree and course of degeneration of cervical intervertebral disc in rats. METHODS: Sixty SD rats, 8 months old, were randomly divided into 6 groups, the control and model groups of 3, 5, 7 months, 10 in each group. The cervical disc dynamic and static forces imbalance of degeneration model was established to assess the degree of degeneration as well as the content some inflammatory mediators (prostaglandin E2, 6-keto-prostaglandin F1 alpha) and collagenase (MMP-1) activity. RESULTS: (1) In 3 months model group and 5 months control group, fibrous ring of intervertebral disc showed some fissure and slight irregular arrangement, nucleus pulposus shrunken or became smaller, mild herniation of nucleus pulposus was seen in some disc. The nucleus pulposus of intervertebral disc in 5 months model group was fibrosed completely and the disc in 7 months model group herniated or became osteophytosis. (2) Compared with the control group of same time period, MMP-1 was increased significantly in the 5 months and 7 months model groups (P < 0.05), and prostaglandin E2 and 6-keto-prostaglandin F1 alpha elevated in the model groups (P < 0.05, P < 0.01). (3) Comparison between model groups, MMP-1 activity in 5 months and 7 months groups was higher than that in the 3 months group (P < 0.05), and 6-keto-prostaglandin F1 alpha was higher in 7 months group than that in 3 months group (P < 0.05). CONCLUSION: Cervical intervertebral disc undergoes a progressive degenerating process. By breaking the dynamic-static balance of neck in rats could accelerate the progression of degeneration. The fact could be used to elucidate the theory of pathogenesis of cervical spondylopathy, dynamic force imbalance in priority and static force imbalance in predominance.

Animals↗
PubMed2004

Biology of intervertebral disc aging and degeneration: involvement of the extracellular matrix.

STUDY DESIGN: A review of current knowledge and opinions concerning the biologic changes that take place during development, maturation and degeneration of the intervertebral disc. OBJECTIVE: To provide an overview of the changes that occur in structure and composition of the extracellular matrix of the intervertebral disc and to explain the origin of such changes and their functional consequences. SUMMARY OF BACKGROUND DATA: The structure of the intervertebral disc, and, in particular, the composition of its extracellular matrix, changes throughout life, ultimately resulting in tissue degeneration in the adult. METHODS: A review of the published scientific literature. RESULTS: In the young disc, the outer anulus fibrosus and inner nucleus pulposus have clear physical and molecular properties, although these differences become less distinct in the adult. The age changes are due to variations in both the abundance and structure of the macromolecules, particularly aggrecan, and the structural variations may be due to changes in both synthesis and degradation. It is not clear how many of the changes are by design to adapt to the altered environment of the growing spine. However, it is commonly thought that the degradative changes are detrimental to disc function, a property that is exacerbated by the inability of the mature avascular disc to remove and replace accumulated degradation products. The rate at which these detrimental changes occur may vary between individuals because of genetic, biomechanical, and nutritional differences. Such changes are thought to form the basis of tissue loss associated with disc degeneration. CONCLUSION: Changes in intervertebral disc structure throughout life ultimately result in tissue degeneration and the need for medical intervention. Current research is aimed at trying to restore the integrity of the degenerate disc matrix by biologic means, although at present it is not clear what the structure of the most appropriate repair tissue should be or how it can be achieved.

Aging↗