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PubMed2006

Localization and distribution of cartilage oligomeric matrix protein in the rat intervertebral disc.

STUDY DESIGN: Whole rat intervertebral disc (IVD), as well as the anulus fibrosus (AF) and the nucleus pulposus (NP) were studied using immunoblot, immunohistochemistry, and reverse-transcription followed by polymerase chain reaction (RT-PCR) methods to investigate the expression and distribution of cartilage oligomeric matrix protein (COMP). OBJECTIVES: To investigate the expression and distribution patterns of COMP in normal IVD. SUMMARY OF BACKGROUND DATA: COMP is an extracellular matrix protein abundantly expressed in articular and growth plate cartilage, as well as bone, ligament, tendon, and synovium. The potential importance of COMP to the spine has been underscored by its mutations that lead to skeletal dysplasia with characteristic platyspondyly. However, the expression and distribution of COMP in spine and IVD has not been illustrated before. METHODS: The presence of COMP protein was investigated by immunoblotting using a COMP antibody F8 on protein extractions from whole IVD and AF or NP. To compare the expression levels of COMP between lumbar and tail IVDs, and between AF and NP of the IVD, wet weight of the tissues were used for normalization. To show that COMP can be made by IVD cells in situ, RT-PCR was used to investigate the COMP mRNA message. The distribution patterns of COMP in IVD were investigated using immunohistochemistry studies with COMP antibody F8. RESULTS: COMP is expressed at both the protein and mRNA levels in both the AF and NP of both the lumbar spine and tail IVD. Immunohistochemistry studies show that COMP is found in the extracellular matrix of the IVD, exhibiting lamellar distribution pattern in the AF region. When normalized to wet weight, COMP is found to be expressed at higher levels in the lumbar than the tail IVD, and within the IVD, greater in the AF than the NP region. CONCLUSIONS: Our results demonstrate the expression of COMP in both the AF and NP of the IVD. COMP is a component of the extracellular matrix of AF and NP, with a lamellar distribution pattern in the AF. Our data suggest that COMP may play a role in the normal structure of IVD.

Animals↗
PubMed1998

Adenovirus-mediated gene transfer to nucleus pulposus cells. Implications for the treatment of intervertebral disc degeneration.

STUDY DESIGN: In vitro and in vivo studies using a rabbit model were performed to determine the feasibility of adenovirus-mediated gene transfer to the intervertebral disc. OBJECTIVES: This study was conducted to determine whether it is possible to transfer genes to cells within the intervertebral disc by direct injection of an adenovirus and to determine the duration of gene expression obtained by this method. SUMMARY OF BACKGROUND DATA: Although growth factors have the potential to stimulate the regeneration of nucleus pulposus, sustained delivery of growth factors to a degenerated disc is clinically unfeasible with present technology. Novel approaches such as gene transfer should be investigated as possible solutions to this problem. METHODS: The lacZ marker gene was used to evaluate gene delivery to cells within intervertebral discs. For the in vitro study, cell cultures were established from the nucleus pulposus tissue of New Zealand white rabbits and infected with an adenovirus encoding the lacZ gene (Ad-lacZ). For the in vivo study, the anterior aspects of lumbar intervertebral discs were surgically exposed, and Ad-lacZ in saline solution was directly injected into the nucleus pulposus. An equal volume of saline only was injected into control discs. Expression of the transferred gene was detected by staining with 5-bromo-4-chloro-3-indolyl-beta-galactosidase (X-Gal). RESULTS: The in vitro experiments confirmed that nucleus pulposus cells were efficiently transduced by an adenoviral vector carrying the lacZ gene. In vivo injection of Ad-lacZ into the nucleus pulposus resulted in the transduction of a considerable number of cells. Marker gene expression in vivo persisted at an apparently undiminished level for at least 12 weeks. No staining was noted in control discs. CONCLUSIONS: The results show the feasibility of adenovirus-mediated gene transfer to the intervertebral disc. Expression of the marker gene persisted at least 12 weeks in vivo. This successful demonstration of exogenous gene transfer to the disc and sustained, long-term expression suggests that the adenoviral vector may be suitable for delivery of appropriate genes to the disc for the treatment of spinal disorders.

Adenoviridae↗
PubMed2004

Medical imaging of intervertebral disc degeneration: current status of imaging.

STUDY DESIGN: The author reviewed literature and reports on spine imaging, selected key articles in which novel imaging strategies were described, and prepared a review of currently developing imaging strategies in intervertebral disc degeneration. OBJECTIVES: To provide a review of imaging in intervertebral disc degeneration that covers the current methodology briefly and describes developing techniques in detail. SUMMARY OF BACKGROUND DATA: Computed tomography and magnetic resonance imaging provide excellent anatomic images of the spine. However, anatomic imaging of the spine does not reliably identify the source of pain in patients with intervertebral disc degeneration. Many functional imaging techniques are suited to the study of the spine. Some of these techniques will improve our understanding of intervertebral disc degeneration and clinical symptomatology. METHODS: The author selected reports in the current literature for further review and attempted to describe succinctly the material in the reports that are most relevant to spine imaging. RESULTS: New and potentially useful imaging strategies for spine imaging include dynamic computed tomography, dynamic magnetic resonance imaging, functional magnetic resonance imaging, diffusion imaging, and magnetic resonance spectroscopy. CONCLUSIONS: Technological advances in magnetic resonance imaging and computed tomography imaging continue to offer more opportunities to investigate and diagnose back pain and intervertebral disc degeneration.

Back Pain↗
PubMed2001

Effects of nicotine on the intervertebral disc: an experimental study in rabbits.

Clinically, we have observed that a large proportion of patients presenting with low back pain as the chief complaint are smokers. It was therefore postulated that smoking might affect the intervertebral disc. We investigated the histological and functional effects of nicotine on intervertebral discs in rabbits. Rabbits were implanted subcutaneously with minipumps for the delivery of 200 microg/ml nicotine for 4 or 8 weeks. The selected dose produced blood nicotine levels equivalent to those found in heavy smokers (30 cigarettes/day). Nicotine injection caused necrosis and fibrous tissue and vitreous formation in the nucleus pulposus of the intervertebral disc, as well as hypertrophy of the fibrous ring, with partial cracks and detachment. Measurement of collagen and proteoglycan production in intervertebral discs showed reduced synthesis of these proteins in nicotine-treated rabbits compared with the control findings. Our results indicated that the harmful effects of nicotine on the integrity of the intervertebral disc might be mediated by the direct effect of nicotine, or indirectly, by causing vasoconstriction of the vascular network surrounding the intervertebral discs.

Animals↗
PubMed2004

Intervertebral disc replacement maintains cervical spine kinetics.

STUDY DESIGN: An in vitro biomechanical study of C4-C5 intervertebral disc replacement using a cadaveric model. OBJECTIVES: To investigate the degree of motion afforded by a ball-and-socket cervical intervertebral disc prosthesis design. SUMMARY OF BACKGROUND DATA: Intervertebral disc prostheses designs attempt to restore or maintain cervical disc motion after anterior cervical discectomy and reduce the likelihood of accelerated degeneration in adjacent discs by maintaining normal motion at the affected disc level. Surprisingly, the actual kinetic and biomechanical effects that cervical disc arthroplasty imparts on the spine have not been widely reported. Accordingly, we investigated what effect implanting a cervical disc prosthesis has on the range of motion at the affected level as well as how it changes the coupled motion patterns at the level of implantation. METHODS: Six fresh-frozen human cadaveric cervical spines (C2-C7) were used in this study. We evaluated two different spinal conditions: intact and after disc replacement at C4-C5. Compression (using the follower load concept) and pure moment loading were applied to the specimen. Range of motion was measured using an optical tracking system. Statistical differences between the intact and replaced condition range of motion was determined using analysis of variance with post hoc comparisons (alpha = 0.05). RESULTS: The data indicate that the intervertebral disc prosthesis approximated the intact motion in all three rotation planes at the affected level. Finally, changes in cervical coupled rotations, specifically lateral bending during axial rotation loading and axial rotation during lateral bending loading, were not statistically significant between the two tested conditions. CONCLUSIONS: Our data demonstrate that a ball-and-socket design can replicate physiologic motion at the affected and adjacent levels. More importantly, the data indicate that motion coupling, which is most dramatic in the cervical spine and plays an important biomechanical role, is maintained.

Arthroplasty, Replacement↗
PubMed2003

Gene therapy applications for intervertebral disc degeneration.

STUDY DESIGN: Review of current approaches to gene therapy as a potential treatment modality for regeneration of the degenerating intervertebral disc. OBJECTIVES: Describe recent advances in the field of gene therapy pertaining to treatment of the degenerating intervertebral disc. SUMMARY OF BACKGROUND DATA: The potential application of gene therapy to the treatment of degenerative disc disease has been an area of exciting and active research. Several in vitro studies have documented the capacity of gene therapy to favorably modify the biologic functions of the intervertebral disc cells with the delivery of the cDNA for various growth factors, whereas in vivo studies have reinforced this potential in animal models. Currently, investigators are exploring the therapeutic potential of gene delivery of the cDNA for several promising factors. METHODS: Literature review. RESULTS/CONCLUSIONS: The application of gene therapy to the treatment of the degenerating intervertebral disc holds much clinical promise and continues to expand as an area of active research. The therapeutic potential of multiple agents, as well as possible vectors, are currently being investigated with encouraging results.

Animals↗
PubMed2005

Growth factor expression in degenerated intervertebral disc tissue. An immunohistochemical analysis of transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor.

Degenerated intervertebral disc has lost its normal architecture, and there are changes both in the nuclear and annular parts of the disc. Changes in cell shape, especially in the annulus fibrosus, have been reported. During degeneration the cells become more rounded, chondrocyte-like, whereas in the normal condition annular cells are more spindle shaped. These chondrocyte-like cells, often forming clusters, affect extracellular matrix turnover. In previous studies transforming growth factor beta (TGFbeta) -1 and -2, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) have been highlighted in herniated intervertebral disc tissue. In the present study the same growth factors are analysed immunohistochemically in degenerated intervertebral disc tissue. Disc material was obtained from 16 discs operated for painful degenerative disc disease. Discs were classified according to the Dallas Discogram Description. Different disc regions were analysed in parallel. As normal control disc tissue material from eight organ donors was used. Polyclonal antibodies against different growth factors and TGFbeta receptor type II were used, and the immunoreaction was detected by the avidin biotin complex method. All studied degenerated discs showed immunoreactivity for TGFbeta receptor type II and bFGF. Fifteen of 16 discs were immunopositive for TGFbeta-1 and -2, respectively, and none showed immunoreaction for PDGF. Immunopositivity was located in blood vessels and in disc cells. In the nucleus pulposus the immunoreaction was located almost exclusively in chondrocyte-like disc cells, whereas in the annular region this reaction was either in chondrocyte-like disc cells, often forming clusters, or in fibroblast-like disc cells. Chondrocyte-like disc cells were especially prevalent in the posterior disrupted area. In the anterior area of the annulus fibrosus the distribution was more even between these two cell types. bFGF was expressed in the anterior annulus fibrosus more often in chondrocyte-like disc cells than in fibroblast-like disc cells. Control discs showed cellular immunopositivity for only TGFbeta-1 and -2 and TGFbeta receptor type II . We suggest that growth factors create a cascade in intervertebral disc tissue, where they act and participate in cellular remodelling from the normal resting stage via disc degeneration to disc herniation.

Adult↗
PubMed1996

Prolapsed cervical intervertebral disc in male professional drivers in Denmark, 1981-1990. A longitudinal study of hospitalizations.

STUDY DESIGN: This study of professional drivers is a part of a longitudinal record linkage study of all economically active men in Denmark, identified on January 1, 1981. Information about the main occupation was identified in 1980. The cohort was followed for first hospitalization with prolapsed cervical intervertebral disc until December 31, 1990. OBJECTIVES: To examine the risk of prolapsed cervical intervertebral disc in all Danish professional drivers, and to analyze exposures of the male drivers in a sample of all Danish male drivers. SUMMARY OF BACKGROUND DATA: Only a few studies on occupation and prolapsed cervical intervertebral disc have been published. These studies suggest that professional driving may be a risk factor for development of prolapsed cervical intervertebral disc. Drivers are exposed to whole-body vibrations, heavy lifting, and a sedentary position. Other potential exposures are accelerations and decelerations and whiplash accidents. Such exposure may be involved in the causation of prolapsed cervical intervertebral disc. METHODS: A standardized hospitalization ratio was calculated for each subgroup of drivers using all economically active people as the standard. Additional exposure information was extracted from a national survey on work environment. RESULTS: Almost all men in occupations involving professional driving had a statistically significant elevated risk of being hospitalized with prolapsed cervical intervertebral disc. CONCLUSIONS: Professional driving is a risk factor for prolapsed cervical intervertebral disc.

Accidents, Occupational↗
PubMed2003

The effect of bone morphogenetic protein-2 on rat intervertebral disc cells in vitro.

STUDY DESIGN: An in vitro experiment to determine the molecular and cellular effect of recombinant human bone morphogenetic protein-2 on cultured rat intervertebral disc cells was performed. OBJECTIVES: To determine the effect of recombinant human bone morphogenetic protein-2 on cell proliferation, production of sulfated-glycosaminoglycan, and the expression of genes specific for chondrocytes (Type II collagen, aggrecan, and Sox9) in cultured rat intervertebral disc cells. SUMMARY OF BACKGROUND DATA: Intervertebral disc degeneration is associated with cellular and biochemical changes, which include decreased synthesis of cartilage specific gene products such as Type II collagen and aggrecan. Although bone morphogenetic protein-2 is known to induce chondrogenesis during new bone formation, the effects on intervertebral disc cells have not been characterized. METHOD: Cells were isolated from the anulus fibrosus and transition zones of lumbar discs from Sprague-Dawley rats. The cells were grown in monolayer and treated with recombinant human bone morphogenetic protein-2 (0, 10, 100, 1000 ng/mL) in Dulbecco's Modified Eagle Medium/F-12 with 1% fetal bovine serum (day 0). On days 2, 4, and 7 after recombinant human bone morphogenetic protein-2 treatment, sulfated-glycosaminoglycan content in the media was quantified using 1,9-dimethylmethylene blue staining. The results were normalized according to culture duration and cell number. On day 7, mRNA was extracted for reverse transcriptase-polymerase chain reaction and real-time polymerase chain reaction to quantitate mRNAs of Type I collagen, Type II collagen, aggrecan, Sox9, osteocalcin, and glyceraldehyde phosphate dehydrogenase. Cell number was determined with a hemocytometer. RESULTS: Recombinant human bone morphogenetic protein-2 at 100 and 1000 ng/mL yielded a 17% and 42% increase in cell number on day 4, and a 59% and 79% on day 7, respectively. Recombinant human bone morphogenetic protein-2 at 10 ng/mL had no effect on cell number. Sulfated-glycosaminoglycan increase was greatest at day 7, increasing by 1.3-, 2.1-, and 3.6-fold with recombinant human bone morphogenetic protein-2 treatments of 10, 100, and 1000 ng/mL, respectively. Increases in mRNA levels of Type II collagen, aggrecan, Sox9, and osteocalcin were observed with recombinant human bone morphogenetic protein-2 concentrations of 100 and 1000 ng/mL on day 7 as determined by reverse transcriptase-polymerase chain reaction. No detectable increase in mRNA level of Type I collagen was observed with any levels of recombinant human bone morphogenetic protein-2. Real-time polymerase chain reaction showed the greatest effect at 1000 ng/mL recombinant human bone morphogenetic protein-2, leading to an 11.5-fold increase in aggrecan, a 4.6-fold increase in Type II collagen, a 5.3-fold increase in Sox9, and a 1.9-fold increase in osteocalcin mRNA above untreated controls at day 7. CONCLUSION: The results of this study show that recombinant human bone morphogenetic protein-2 enhances disc matrix production and chondrocytic phenotype of intervertebral disc cells. Recombinant human bone morphogenetic protein-2 increases cell proliferation and sulfated-glycosaminoglycan (proteoglycan) synthesis. It increases mRNA of Type II collagen, aggrecan, and Sox9 genes (chondrocyte specific genes), and osteocalcin, but not Type I collagen or glyceraldehyde phosphate dehydrogenase.

Aggrecans↗
PubMed2001

Elevated synthetic activity in the convex side of scoliotic intervertebral discs and endplates compared with normal tissues.

STUDY DESIGN: We measured concentrations of specific molecules reflecting matrix synthesis and degradation in normal and scoliotic intervertebral discs and endplates. OBJECTIVES: The aim of this work was to quantitate markers of matrix turnover in normal versus adolescent idiopathic scoliotic intervertebral discs and cartilaginous endplates. SUMMARY OF BACKGROUND DATA: Changes in the intervertebral disc and endplate composition have been implicated as possible etiologic factors in the pathogenesis of adolescent idiopathic scoliosis. To better understand this process, it is important to compare the turnover of matrix components in scoliotic and normal intervertebral disc and endplate tissues. This comparison may help to improve our understanding of the role that disc and endplate tissues may play in the induction and/or progression of idiopathic scoliosis. METHODS: Fifteen scoliotic and 17 normal intervertebral discs and endplates were analyzed for their water, collagen, proteoglycan, and protein content. In addition, newly synthesized aggrecan and collagen Types I and II were measured. Percent total denatured collagen was also determined. RESULTS: The total collagen content was significantly lower in the scoliotic anulus and endplate regions, whereas glycosaminoglycan (GAG) content was significantly lower in the scoliotic endplates and nucleus regions. Conversely, total protein content was significantly higher in scoliotic endplates and elevated in scoliotic nucleus regions. Water content was significantly lower in the scoliotic anulus and endplate regions. When comparing the concave and convex regions of scoliotic endplates, there was no significant difference in concentration of any matrix component. The major difference in the synthetic marker levels relates to the synthesis of Type II collagen, which was higher in the nucleus, anulus, and endplate regions of scoliotic discs than in the corresponding regions of normal tissues. By contrast, the percent total denatured collagen was significantly elevated in the nucleus of normal tissues compared with the scoliotic ones. CONCLUSIONS: The higher collagen Type II synthetic levels and increased total protein content with no matrix turnover suggest that scoliotic changes are due to an altered and ineffective synthetic response to a pathologic mechanical environment.

Adolescent↗
PubMed1997

Toward a biochemical understanding of human intervertebral disc degeneration and herniation. Contributions of nitric oxide, interleukins, prostaglandin E2, and matrix metalloproteinases.

STUDY DESIGN: Normal and herniated human intervertebral disc specimens were cultured to study the effects of interleukin-1 beta on the production of nitric oxide, interleukin-6, prostaglandin E2, and matrix metalloproteinases. The effects of endogenously produced nitric oxide on the synthesis of other mediators also were studied. OBJECTIVES: To test the hypothesis that the cells of the intervertebral disc are metabolically active and are capable of responding to biochemical stimuli such as interleukin-1 beta in a manner that could engender degenerative changes. As part of this study, the authors also investigated some of the possible autocrine regulatory mechanisms that may operate during the biochemical responses of disc cells. SUMMARY OF BACKGROUND DATA: The authors previously showed, for the first time, that herniated cervical and lumbar disc specimens spontaneously produce increased amounts of nitric oxide, interleukin-6, prostaglandin E2, and certain matrix metalloproteinases. These results suggest that these biochemical agents are in some manner involved with degenerative processes in the intervertebral disc. This novel hypothesis merits further evaluation; the current communication reports the results of experiments designed to do so. METHODS: Fourteen normal, nondegenerated discs (control group) were obtained from seven patients undergoing anterior spinal surgery for trauma or lumbar scoliosis. Thirty-six herniated discs (18 lumbar and 18 cervical) were obtained from 30 patients undergoing surgery for persistent radiculopathy. The specimens were placed into tissue culture and incubated for 72 hours in the presence or absence of interleukin-1 beta and NG-monomethyl-L-arginine, and inhibitor of nitric oxide synthases, and the media were subsequently collected for biochemical analysis. Biochemical assays for matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 were performed. RESULTS: Normal, control disc specimens significantly increased their production of matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 in response to interleukin-1 beta. Herniated lumbar and cervical discs, which were spontaneously releasing increased levels of these biochemical agents, further increased their production of nitric oxide, interleukin-6, and prostaglandin E2 in response to interleukin-1 beta. Blocking the biosynthesis of nitric oxide in interleukin-1 beta-stimulated disc cells provoked a large increase in the production of interleukin-6. CONCLUSIONS: Cells of the intervertebral discs are biologically responsive and increase their production of matrix metalloproteinases, nitric oxide, interleukin-6, and prostaglandin E2 when stimulated by interleukin-1 beta. The effect is more dramatic in normal, nondegenerated discs where spontaneous synthesis of these mediators is low. Nevertheless, cells of the herniated degenerated discs where spontaneous production was high were still capable of further increasing their synthesis of several of these biochemical agents in response to interleukin-1 beta. Endogenously produced nitric oxide appears to have a strong inhibitory effect on the production of interleukin-6, which suggests that autocrine mechanisms play an important role in the regulation of disc cell metabolism.

Adult↗
PubMed2006

Case-control study of risk factors for lumbar intervertebral disc herniation in Croatian island populations.

AIM: To investigate the risk factors for lumbar intervertebral disc herniation (L4/L5 or L5/S1) severe enough to require surgery of the lower spine among 9 isolated populations of Croatian islands and to evaluate predictive value, sensitivity, and specificity of a simple screening test based on the understanding of the risk factors in this population. METHODS: In a sample of 1001 examinees from Croatian island populations, we identified all subjects who underwent surgery of the lower spine due to lumbar intervertebral disc herniation L4/L5 or L5/S1 and selected 4 controls matched by age, gender, and village of residence for each of them. Odds ratio was computed for the following variables: body mass index, occupation, intensity of physical labor at work, intensity of physical labor at home, smoking index, claudication index, self-assessed limitation in physical activity, level of education, socio-economic status, and family history of lumbar intervertebral disc herniation requiring surgery. RESULTS: Comparison of 67 identified cases with 268 controls revealed the highest odds ratios (OR) for positive family history (OR 4.00; 95% confidence intervals [CI], 1.89-6.11, P<0.001), intensity of physical labor at work defined as (hard) (OR 2.94; 95% CI, 1.07-4.81, P<0.001), and body mass index of 25.7 or more (OR 2.77, 95% CI, 1.05-4.49, P=0.002). A simple screening test based on the presence of any two of these three criteria has 74% sensitivity and 82% specificity to detect persons who underwent lower spine surgery due to lumbar intervertebral disc herniation in the population aged 40 years or more. CONCLUSION: Occurrence of lumbar disk herniation severe enough to require surgery of the lower spine can be predicted using a very simple set of criteria. This type of screening could reduce the need for surgery in isolated communities through prevention within primary health care.

Case-Control Studies↗
PubMed2002

[Autopsy evaluation of the extent of degeneration of the lumbar intervertebral discs].

The aim of study was to evaluate the degree of lumbar intervertebral disc degeneration during post-mortem studies, and its relation to the age and gender of cadavers. The changes of intervertebral disc were classified according to Nachemson [13]. The study included 308 lumbar intervertebral discs taken during autopsy from 57 females (mean age 41.83) and 79 males (mean age 42.06). Two hundred and forty discs showed degenerative changes. The statistic analysis revealed that the degeneration is more pronounced with age (ANOVA p < 0.05). The study demonstrated that in males degeneration occurs a decade earlier than in females, and could be observed in the second decade of life. Similarly, the degeneration of 3rd or 4th grade could be observed a decade earlier in men than in women. The statistical analysis revealed the differences (p < 0.05) in degeneration between upper (levels L2 and L3), and lower (levels L4 and L5) lumbar spine. Analysing the discs as single levels, no statistical differences in degeneration were observed.

Adolescent↗
PubMed1991

1991 Volvo Award in basic sciences. Collagen types around the cells of the intervertebral disc and cartilage end plate: an immunolocalization study.

Several types of collagen are known to exist in the intervertebral disc in addition to the fibrillar collagens, Types I and II. Although they constitute only a small percentage of the total collagen content, these minor collagens may have important functions. This study was designed to investigate the presence of Types I, II, III, IV, VI, and IX collagens in the intervertebral disc and cartilage end plate by immunohistochemistry, thereby establishing their location within the tissues. Types III and VI collagen have a pericellular distribution in animal and human tissue. No staining for Type IX collagen was present in normal human disc, but in rat and bovine intervertebral disc, it was also located pericellularly. These results show that cells of the intervertebral disc and cartilage end plate sit in fibrous capsules, forming chondrons similar to those described in articular cartilage. In pathologic tissue the amount and distribution of the collagen types, and the organization of the pericellular capsule, differ from that seen in control material.

Adult↗
PubMed1997

1997 Volvo Award winner in basic science studies. Immunohistologic markers for age-related changes of human lumbar intervertebral discs.

STUDY DESIGN: The authors performed a correlative macroscopic, histologic, and immunohistochemical investigation on human lumbar intervertebral discs using complete motion segment slices, including all age groups and stages of degeneration. OBJECTIVES: To identify markers for age-related changes of human lumbar intervertebral discs. In particular, to investigate changes in the distribution pattern of collagen Types I, II, III, IV, V, VI, IX, and X. In addition, to study posttranslational protein modification by the immunolocalization of N-(carboxylmethyl)lysine (CML), which is regarded as a biomarker for oxidative stress. SUMMARY OF BACKGROUND DATA: Data on a correlation of age-related changes in disc morphology and disc matrix composition is sparse. So far, no comprehensive analysis considered a correlation of macroscopic, histologic, and biochemical age-related alterations using complete sections of intervertebral discs (i.e., including nucleus pulposus, anulus fibrosus, endplates, and vertebral bodies). In addition, there is need for specific markers for these disc changes to allow for a better correlation with disc function. METHODS: After photodocumentation of the macroscopic appearance, 229 sagittal lumbar motion segments obtained from 47 individuals (fetal to 86 years) during routine autopsy were processed for histologic and immunohistochemical analysis. All slices were investigated for histologic alterations of disc degeneration. A randomly selected subset of these specimens (n = 45) was used for a correlative analysis of interstitial collagens and molecular modifications of matrix proteins. RESULTS: The presence of CML-modification of extracellular matrix proteins, mainly collagen, was observed first in the nucleus pulposus of a 13-year-old individual and increased significantly with age. In elderly people, both the nucleus pulposus and the anulus fibrosus showed extensive CML deposition. This CML deposition was accentuated in areas of macroscopic and histologic disc degeneration. After the occurrence of CML in the nucleus pulposus, we found a change in the collagen type pattern. An initial increase in nuclear collagen Types II, III, and VI staining was followed by a loss of collagen Type II, the occurrence of collagen Type I, and the persistence of high collagen Type III and VI levels, which were finally decreased again. The nuclear chondrocytes revealed significant changes in their immediate pericellular matrix, indicating phenotypic changes. Thus, exclusively in the nucleus pulposus of adolescents and young adults a significant proportion of cells positively stained for the basement membrane collagen Type IV. Collagen Type X was expressed by nuclear chondrocytes at a higher age and was associated with advanced degenerative disc alterations. CONCLUSIONS: The authors present the first study in which age-related changes are correlated on a macroscopic, histologic, and molecular level using complete sections of lumbar motion segments. They reconfirm the notion that disc degeneration starts as early as in the second decade of life. Therefore, only early prevention of disc damage may inhibit disc degeneration and its sequelae. Phenotypic alterations of nuclear chondrocytes as monitored by collagen Type IV in young adults with minor lesions and collagen Type X in advanced lesions indicate distinct cellular reactions, possibly as a reaction to enhanced oxidative stress. The degree of this oxidative stress is reflected by the CML-staining pattern which, in turn, indicates that the disc undergoes an accumulative stress, possibly leading to altered properties of the collagen fibrils and, thereby, tissue destruction. The deposition of CML proved to be the best marker for ongoing age-related changes in the intervertebral disc.

Adolescent↗
PubMed1984

Elastic fibers in the anulus fibrosus of the dog intervertebral disc.

A light microscopic investigation of the anulus fibrosus in cervical intervertebral discs of the dog was conducted to ascertain the arrangement and distribution of elastic fibers. Elastic fibers were observed in all lamellae of the anulus fibrosus. However, collagenous fibers were the predominant type of connective tissue fiber, and elastic fibers were randomly dispersed among them. Intralamellar (collagenous and elastic) fibers were vertically and obliquely oriented in both superficial and deep lamellae of the anulus fibrosus. All intralamellar fibers were densely and regularly arranged in superficial lamellae, but they were more loosely organized in deep lamellae. A narrow border of interlamellar, elastic fibers was observed between broader, contiguous lamellae in the superficial zone of the anulus fibrosus. Interlamellar elastic fibers wer vertically and obliquely arranged in superficial lamellae; however, they were radially oriented in deep lamellae. The deepest lamella of the anulus fibrosus consisted of a loose, three-dimensional network of intermeshing collagenous and elastic fibers. These observations suggest that elastic fibers are integral components of the articular and shock absorption mechanisms of the anulus fibrosus, and the cervical intervertebral disc of the dog is a suitable model for experimental investigation of the role of elastic fibers in intervertebral disc herniation.

Animals↗