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Disc Degeneration (disc + degeneration)
Kinds of Disc Degeneration Selected AbstractsDisc degeneration and bone density in monozygotic twins discordant for insulin-dependent diabetes mellitusJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2000T. Videman The effects of insulin-dependent diabetes mellitus on bone density and connective tissue degeneration have theoretical interest and practical relevance. Several experimental studies in animals have demonstrated the harmful effects of insulin deficiency on connective tissues. However, clinical studies in humans have produced somewhat contradictory results, most likely due to difficulties controlling for general degeneration and factors associated with diabetes. In nine pairs of monozygotic twins discordant for insulin-dependent diabetes mellitus, we compared femoral and lumbar bone mineral density (assessed by dualenergy x-ray absorptiometry) and spinal degeneration (assessed by magnetic resonance imaging). The bone densities were, on average, 0.1,0.3% lower (p = 0.87,0.96) in diabetic patients. However, after controlling for smoking, we found that the bone density in the femoral neck was 2.5% (0.025 g/cm2) lower in diabetic individuals than in their twins (p = 0.09). The five magnetic resonance imaging parameters used to evaluate discdegeneration did not differ between diabetic patients and their twins. In conclusion, our results provide no evidence that insulin-dependent diabetes mellitus has any major effect on bone density or disc degeneration. [source] A preliminary in vitro study into the use of IL-1Ra gene therapy for the inhibition of intervertebral disc degenerationINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2006Christine L. Le Maitre Summary Conventional therapies for low back pain (LBP) are purely symptomatic and do not target the cause of LBP, which in approximately 40% of cases is caused by degeneration of the intervertebral disc (DIVD). Targeting therapies to inhibit the process of degeneration would be a potentially valuable treatment for LBP. There is increasing evidence for a role for IL-1 in DIVD. A natural inhibitor of IL-1 exists, IL-1Ra, which would be an ideal molecular target for inhibiting IL-1-mediated effects involved in DIVD and LBP. In this study, the feasibility of ex vivo gene transfer of IL-1Ra to the IVD was investigated. Monolayer and alginate cultures of normal and degenerate human intervertebral disc (IVD) cells were infected with an adenoviral vector carrying the IL-1Ra gene (Ad-IL-1Ra) and protein production measured using an enzyme-linked immunosorbent assay. The ability of these infected cells to inhibit the effects of IL-1 was also investigated. In addition, normal and degenerate IVD cells infected with Ad-IL-1Ra were injected into degenerate disc tissue explants and IL-1Ra production in these discs was assessed. This demonstrated that both nucleus pulposus and annulus fibrosus cells infected with Ad-IL-1Ra produced elevated levels of IL-1Ra for prolonged time periods, and these infected cells were resistant to IL-1. When the infected cells were injected into disc explants, IL-1Ra protein expression was increased which was maintained for 2 weeks of investigation. This in vitro study has shown that the use of ex vivo gene transfer to degenerate disc tissue is a feasible therapy for the inhibition of IL-1-mediated events during disc degeneration. [source] Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration modelJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 10 2010Kenji Serigano Abstract Transplantation of mesenchymal stem cells (MSCs) inhibits the progression of disc degeneration in animal models. We know of no study to determine the optimal number of cells to transplant into the degenerated intervertebral disc (IVD). To determine the optimal donor cell number for maximum benefit, we conducted an in vivo study using a canine disc degeneration model. Autologous MSCs were transplanted into degenerative discs at 105, 106, or 107,cells per disc. The MSC-transplanted discs were evaluated for 12 weeks using plain radiography, magnetic resonance imaging, and gross and microscopic evaluation. Preservation of the disc height, annular structure was seen in MSC-transplantation groups compared to the operated control group with no MSC transplantation. Result of the number of remaining transplanted MSCs, the survival rate of NP cells, and apoptosis of NP cells in transplanted discs showed both structural microenvironment and abundant extracellular matrix maintained in 106 MSCs transplanted disc, while less viable cells were detected in 105 MSCs transplanted and more apoptotic cells in 107 MSCs transplanted discs. The results of this study demonstrate that the number of cells transplanted affects the regenerative capability of MSC transplants in experimentally induced degenerating canine discs. It is suggested that maintenance of extracellular matrix by its production from transplanted cells and/or resident cells is important for checking the progression of structural disruption that leads to disc degeneration. Published by Wiley Periodicals, Inc. J Orthop Res 28:1267,1275, 2010 [source] Intervertebral disc cell response to dynamic compression is age and frequency dependent,JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2009Casey L. Korecki Abstract The maintenance of the intervertebral disc extracellular matrix is regulated by mechanical loading, nutrition, and the accumulation of matrix proteins and cytokines that are affected by both aging and degeneration. Evidence suggests that cellular aging may lead to alterations in the quantity and quality of extracellular matrix produced. The aims of this study were to examine the role of loading and maturation (a subset of aging), and the interaction between these two factors in intervertebral disc cell gene expression and biosynthesis in a controlled 3D culture environment. Cells were isolated from young (4,6 months) and mature (18,24 months) bovine caudal annulus fibrosus and nucleus pulposus tissue. Isolated cells were seeded into alginate and dynamically compressed for 7 days at either 0.1, 1, or 3 Hz or maintained as a free-swelling control. After 7 days, DNA and sulfated glycosaminoglycan contents were analyzed along with real time, quantitative reverse transcription-polymerase chain reaction analysis for collagen types I and II, aggrecan, and matrix metalloproteinase-3 gene expression. Results suggest that maturation plays an important role in intervertebral disc homeostasis and influences the cell response to mechanical loading. While isolated intervertebral disc cells responded to mechanical compression in 3D culture, the effect of loading frequency was minimal. Altered cellular phenotype and biosynthesis rates appear to be an attribute of the cell maturation process, potentially independent of changes in cellular microenvironment associated with lost nutrition and disc degeneration. Mature cells may have a decreased capacity to create or retain extracellular matrix components in response to mechanical loading compared to young cells. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 800,806, 2009 [source] The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2009Aiqun Wei Abstract Intervertebral disc degeneration is a major cause and a risk factor for chronic low back pain. The potential of using stem cells to treat disc degeneration has been raised. The aims of our study were to assess whether xenogeneic bone-marrow derived stem cells could survive in a rat disc degeneration model and to determine which cell types, if any, survived and differentiated into disc-like cells. Human bone-marrow derived CD34+ (hematopoietic progenitor cells) and CD34, (nonhematopoietic progenitor cells, including mesenchymal stem cells) cells were isolated, fluorescent-labeled, and injected into rat coccygeal discs. The rats were sacrificed at day 1, 10, 21, and 42. Treated discs were examined by histological and immunostaining techniques and compared to control discs. The survival of transplanted cells was further confirmed with a human nuclear specific marker. Fluorescent labeled CD34, cells were detected until day 42 in the nucleus pulposus of the injected discs. After 3 weeks these cells had differentiated into cells expressing chondrocytic phenotype (Collagen II and Sox-9). In contrast, the fluorescent labeled CD34+ cells could not be detected after day 21. No fluorescence-positive cells were detected in the noninjected control discs. Further, no inflammatory cells infiltrated the nucleus pulposus, even though these animals had not received immunosuppressive treatment. Our data provide evidence that transplanted human BM CD34, cells survived and differentiated within the relative immune privileged nucleus pulposus of intervertebral disc degeneration. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:374,379, 2009 [source] Experimental and model determination of human intervertebral disc osmoviscoelasticityJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 8 2008Y. Schroeder Abstract Finite element (FE) models have become an important tool to study load distribution in the healthy and degenerated disc. However, model predictions require accurate constitutive laws and material properties. As the mechanical properties of the intervertebral disc are regulated by its biochemical composition and fiber-reinforced structure, the relationship between the constitutive behavior of the tissue and its composition requires careful consideration. While numerous studies have investigated the annulus fibrosus compressive and tensile properties, specific conditions required to determine model parameters for the osmoviscoelastic model are unavailable. Therefore, the objectives of this study were (1) to complement the existing material testing in the literature with confined compression and tensile tests on human annulus fibrosus and (2) to use these data, together with existing nucleus pulposus compression data to tune a composition-based, osmoviscoelastic material constitutive law. The osmoviscoelastic material constitutive law and the experimental data were used to describe the fiber and nonfiber properties of the human disc. The compressive material properties of normal disc tissue were Gm,=,1.23 MPa, M,=,1.57, and ,,=,1.964,×,10,16 m4/Ns; the tensile fiber material parameters were E0,=,77.0 MPa; E,,=,500 MPa, and ,,=,1.8,×,103 MPa,s. The goodness of fit ranged from 0.88 to 0.96 for the four experimental conditions evaluated. The constitutive law emphasized the interdependency of the strong swelling ability of the tissue and the viscoelastic nature of the collagen fibers. This is especially important for numerical models to further study the load sharing behavior with regard to disc degeneration and regeneration. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1141,1146, 2008 [source] p38 MAPK inhibition modulates rabbit nucleus pulposus cell response to IL-1,JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2008Rebecca K. Studer Abstract Analysis of disc gene expression implicated IL-1 in the development of intervertebral disc degeneration (IDD) in a rabbit stab model. The purpose of these studies is to determine the role of p38 Mitogen Activated Protein Kinase (p38 MAPK) signaling in nucleus pulposus cell response to IL-1, and to compare rabbit nucleus pulposus (rNP) cell responses to IL-1 activation with those in a stab model of disc degeneration. NP cells maintained in alginate bead culture were exposed to IL-1, with or without p38 MAPK inhibition. RNA was isolated for reverse transcription polymerase chain reaction (RT-PCR) analysis of gene expression, conditioned media analyzed for accumulation of nitric oxide (NO) and prostaglandin E-2 (PGE-2), and proteoglycan synthesis measured after 10 days. IL-1 upregulation of mRNA for cycloxygenase-2 (COX-2), matrix metalloproteinase-3 (MMP-3), IL-1, and IL-6, was blunted by p38 inhibition while downregulation of matrix proteins (collagen I, collagen II, aggrecan) and insulin-like-growth-factor I (IFG-1) was also reversed. mRNA for tissue inhibitor of matrixmetalloproteinase-1 (TIMP-1) was modestly increased by IL-1, while those for Transforming Growth Factor-, (TGF-,) SOX-9, and versican remained unchanged. Blocking p38 MAPK reduced IL-1 induced NO and PGE-2 accumulation and partially restored proteoglycan synthesis. p38 MAPK inhibition in control cells increased mRNA for matrix proteins (aggrecan, collagen II, versican, collagen I) and anabolic factors (IGF-1, TGF, and SOX-9) from 50% to 120%, decreased basal PGE-2 accumulation, but had no effect on message for TIMP-1, MMP-3, or COX-2. Inhibition of p38 MAPK in cytokine-activated disc cells blunts gene expression and production of factors associated with inflammation, pain, and disc matrix catabolism while reversing IL-1 downregulation of matrix protein gene expression and proteoglycan synthesis. The results support the hypothesis that IL-1 could be responsible for many of the mRNA changes seen in rabbit NP in the stab model of disc degeneration, and uphold the concept that development of molecular techniques to block p38 MAPK could provide a therapeutic approach to slow the course of intervertebral disc degeneration. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:991,998, 2008 [source] Apoptosis of human intervertebral discs after trauma compares to degenerated discs involving both receptor-mediated and mitochondrial-dependent pathwaysJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2008Sven K. Tschoeke Abstract Post-traumatic disc degeneration with consecutive loss of reduction and kyphosis remains a debatable issue within both the operative and nonoperative treatment regimen of thoracolumbar spine fractures. Intervertebral disc (IVD) cell apoptosis has been suggested to play a vital role in promoting the degeneration process. To evaluate and compare apoptosis-regulating signaling mechanisms, IVDs were obtained from patients with thoracolumbar spine fractures (n,=,21), patients suffering from symptomatic IVD degeneration (n,=,6), and from patients undergoing surgical resection of a primary vertebral tumor (n,=,3 used as control samples). All tissues were prospectively analyzed in regards to caspase-3/7, -8, and -9 activity, apoptosis-receptor expression levels, and gene expression of the mitochondria-bound apoptosis-regulating proteins Bax and Bcl-2. Morphologic changes characteristic for apoptotic cell death were confirmed by H&E staining. Statistical significance was designated at p,<,0.05 using the Student's t -test. Both traumatic and degenerative IVD demonstrated a significant increase of caspase-3/7 activity with evident apoptosis. Although caspase-3/7 activation was significantly greater in degenerated discs, both showed equally significant activation of the initiator caspases 8 and 9. Traumatic IVD alone demonstrated a significant increase of the Fas receptor (FasR), whereas the TNF receptor I (TNFR I) was equally up-regulated in both morbid IVD groups. Only traumatic IVD showed distinct changes in up-regulated TNF expression, in addition to significantly down-regulated antiapoptotic Bcl-2 protein. Our results suggest that post-traumatic disc changes may be promoted and amplified by both the intrinsic mitochondria-mediated and extrinsic receptor-mediated apoptosis signaling pathways, which could be, in part, one possible explanation for developing subsequent disc degeneration. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:999,1006, 2008 [source] Transplantation of mesenchymal stem cells in a canine disc degeneration modelJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2008Akihiko Hiyama Abstract Transplantation of mesenchymal stem cells (MSCs) is effective in decelerating disc degeneration in small animals; much remains unknown about this new therapy in larger animals or humans. Fas-ligand (FasL), which is only found in tissues with isolated immune privilege, is expressed in IVDs, particularly in the nucleus pulposus (NP). Maintaining the FasL level is important for IVD function. This study evaluated whether MSC transplantation has an effect on the suppression of disc degeneration and preservation of immune privilege in a canine model of disc degeneration. Mature beagles were separated into a normal control group (NC), a MSC group, and the disc degeneration (nucleotomy-only) group. In the MSC group, 4 weeks after nucleotomy, MSCs were transplanted into the degeneration-induced discs. The animals were followed for 12 weeks after the initial operation. Subsequently, radiological, histological, biochemical, immunohistochemical, and RT-PCR analyses were performed. MSC transplantation effectively led to the regeneration of degenerated discs. FACS and RT-PCR analyses of MSCs before transplantation demonstrated that the MSCs expressed FasL at the genetic level, not at the protein level. GFP-positive MSCs detected in the NP region 8 weeks after transplantation expressed FasL protein. The results of this study suggest that MSC transplantation may contribute to the maintenance of IVD immune privilege by the differentiation of transplanted MSCs into cells expressing FasL. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:589,600, 2008 [source] Effect of aging and degeneration on disc volume and shape: A quantitative study in asymptomatic volunteersJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2006Christian W. A. Pfirrmann Abstract Debate continues on the effect of disc degeneration and aging on disc volume and shape. So far, no quantitative in vivo MRI data is available on the factors influencing disc volume and shape. The objective of this MRI study was to quantitatively investigate changes in disc height, volume, and shape as a result of aging and/or degeneration omitting pathologic (i.e., painful) disc alterations. Seventy asymptomatic volunteers (20,78 years) were investigated with sagittal T1- and T2-weighted MR-images encompassing the whole lumbar spine. Disc height was determined by the Dabbs method and the Farfan index. Disc volume was calculated by the Cavalieri method. For the disc shape the "disc convexity index" was calculated by the ratio of central disc height and mean anterior/posterior disc height. Disc height, disc volume, and the disc convexity index measurements were corrected for disc level and the individuals age, weight, height, and sex in a multilevel regression analysis. Multilevel regression analysis showed that disc volume was negatively influenced by disc degeneration (p,<,0.001) and positively correlated with body height (p,<,0.001) and age (p,<,0.01). Mean disc height and the disc convexity index were negatively influenced by disc degeneration but not by gender, weight, and height. Disc height was positively correlated with age (p,<,0.01). From the results of this study, it can be concluded that disc degeneration generally results in a decrease of disc height and volume as well as a less convex disc shape. In the absence of disc degeneration, however, age tends to result in an inverse relationship on disc height, volume, and shape. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res [source] The compressive creep properties of normal and degenerated murine intervertebral discsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 1 2004Erika I. Palmer Abstract Identifying mechanisms by which degeneration alters intervertebral disc material properties and biomechanical behavior is important for clarifying back pain risk factors as well as for evaluating the efficacy of novel interventions. Our goal was to quantify and characterize degeneration-dependent changes in the disc's response to compression using a previously established murine model of disc degeneration. We performed compressive creep tests on normal and degenerated murine intervertebral discs and parameterized the biomechanical response using a previously established fluid-transport model. Using a series of biochemical and histological assays, we sought to determine how biomechanical alterations were attributable to degeneration-related changes in tissue morphology. We observed that with moderate degeneration, discs lost height (mean ± std. dev. of 0.44 ± 0.01 vs. 0.36 ± 0.01 mm, p < 0.0001), increased in proteoglycan content (31 ± 4 vs. 43 ± 2 ,g/ml of extract, p < 0.0002), became less stiff (2.17 ± 0.66 vs. 1.56 ± 0.44 MPa, p < 0.053), and crept more. Model results suggested that the increased creep response was mainly due to a diminished strain-dependent nuclear swelling pressure. We also noted that the model-derived tissue properties varied with the applied load magnitude for both normal and degenerated discs. Overall, our data demonstrate that architectural remodeling stimulated by excessive loading diminishes the disc's ability to resist compression. These results are similar to degeneration-dependent changes reported for human discs. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Disc degeneration and bone density in monozygotic twins discordant for insulin-dependent diabetes mellitusJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2000T. Videman The effects of insulin-dependent diabetes mellitus on bone density and connective tissue degeneration have theoretical interest and practical relevance. Several experimental studies in animals have demonstrated the harmful effects of insulin deficiency on connective tissues. However, clinical studies in humans have produced somewhat contradictory results, most likely due to difficulties controlling for general degeneration and factors associated with diabetes. In nine pairs of monozygotic twins discordant for insulin-dependent diabetes mellitus, we compared femoral and lumbar bone mineral density (assessed by dualenergy x-ray absorptiometry) and spinal degeneration (assessed by magnetic resonance imaging). The bone densities were, on average, 0.1,0.3% lower (p = 0.87,0.96) in diabetic patients. However, after controlling for smoking, we found that the bone density in the femoral neck was 2.5% (0.025 g/cm2) lower in diabetic individuals than in their twins (p = 0.09). The five magnetic resonance imaging parameters used to evaluate discdegeneration did not differ between diabetic patients and their twins. In conclusion, our results provide no evidence that insulin-dependent diabetes mellitus has any major effect on bone density or disc degeneration. [source] The application of 23Na double-quantum-filter (DQF) NMR spectroscopy for the study of spinal disc degenerationMAGNETIC RESONANCE IN MEDICINE, Issue 2 2008Kristopher J. Ooms Abstract Degenerative disc disease is an irreversible process that leads to a loss of mechanical integrity and back pain in millions of people. In this report, 23Na double-quantum-filtered (DQF) NMR spectroscopy is used to study disc tissues in two stages of degeneration. Initial results indicate that the 23Na DQF signal may be useful for determining the degree of degeneration. The spectral analysis reveals the presence of sodium environments with different residual quadrupolar couplings and T2 relaxation times that we attribute to different regions, or compartments, corresponding to different biochemical regions in the tissue. In general it is found that there are compartments with no residual quadrupolar couplings, compartments with moderate couplings (200 to 1000 Hz), and compartments with couplings ranging from 1500 to 3000 Hz. The results indicate that 23Na DQF NMR spectroscopy provides a probe of the degenerative state of the intervertebral disc tissues, and might hold potential as a novel diagnostic method for detection of disc degeneration. Magn Reson Med 60:246,252, 2008. © 2008 Wiley-Liss, Inc. [source] MULTIDISCIPLINARY PAIN ABSTRACTS: 18PAIN PRACTICE, Issue 1 2004Article first published online: 15 MAR 200 A complex relationship exists between back pain and the presence of spinal disease. Particularly in chronic situations, back pain and its behavioral and emotional consequences are as likely to reflect the influence of psychosocial factors as any underlying spinal pathology. Nevertheless, physical factors are clearly important and it is significant that whereas in normal discs only the outer third of the annulus fibrosis is innervated, a much more extensive innervation develops in the presence of degeneration. Inflammation, as evidenced by leukocyte infiltration and expression of inflammatory mediators, is associated with disc degeneration and serves to alter the neural responses resulting in local and referred pain. It is probable that similar inflammatory processes, as well as direct root compression, contribute to radicular symptoms following disc herniation. An appreciation of these mechanisms encourages the search for novel treatments and permits a more rational and effective use of existing strategies for relieving pain. [source] Intervertebral disc degeneration: New insights based on "skipped" level disc pathologyARTHRITIS & RHEUMATISM, Issue 8 2010Kenneth M. C. Cheung Objective Typically, age and abnormal physical loading ("wear and tear") have been associated with the development of intervertebral disc degeneration. In the past decade, various additional etiologic factors for disc degeneration have been sporadically reported in the literature; however, many investigators continue to place tremendous emphasis on the effects of age and biomechanics associated with disc degeneration. The aim of this study was to provide additional insight into the notion that age and biomechanics are key factors in the development of disc degeneration. To this end, we addressed the prevalence of and risk factors associated with a unique pattern of disc degeneration of the lumbar spine, "skipped" level (nonconsecutive) disc degeneration (SLDD). Methods As part of a large genetics-based study in southern Chinese individuals (n = 1,989), a cross-sectional analysis was performed in subjects exhibiting disc degeneration in ,2 levels (n = 838) who were then categorized as having SLDD (n = 174) or non-SLDD (contiguous, multilevel; n = 664). Various radiographic parameters were assessed based on T2-weighted magnetic resonance imaging (MRI). Subject demographics were assessed, and univariate and multivariate logistic regression analyses were performed. Results Overall, 8.7% of the whole population (n = 1,989) had SLDD, while it was present in 20.8% of subjects with multilevel disc degeneration (n = 838). SLDD was more prevalent in male subjects (adjusted odds ratio [OR] 1.48, 95% confidence interval [95% CI] 1.04,2.10, P = 0.028). SLDD was significantly associated with the presence of Schmorl's nodes (adjusted OR 2.72, 95% CI 1.78,4.15, P < 0.001), which also presented in levels with no disc degeneration. A history of disc bulge/extrusion (P = 0.004) and/or a history of back injury (P = 0.010) was significantly associated with non-SLDD, and a greater degree of overall severity of disc degeneration was also associated with non-SLDD. Other demographic and MRI findings did not significantly differ between groups. Conclusion To our knowledge, this report is the first to describe the prevalence and risk factors associated with SLDD. Our study challenges the paradigm that age and biomechanics are the key factors associated with the development of disc degeneration. Although age and biomechanical factors may play a role in the manifestation of disc degeneration, our novel findings of SLDD patterns provide further awareness of and support for the notion that additional etiologic factors may play a role in the development of disc degeneration. Such factors warrant further investigation to shed light on the cause of disc degeneration. [source] Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissuesARTHRITIS & RHEUMATISM, Issue 7 2010Mohammed F. Shamji Objective Prior reports document macrophage and lymphocyte infiltration with proinflammatory cytokine expression in pathologic intervertebral disc (IVD) tissues. Nevertheless, the role of the Th17 lymphocyte lineage in mediating disc disease remains uninvestigated. We undertook this study to evaluate the immunophenotype of pathologic IVD specimens, including interleukin-17 (IL-17) expression, from surgically obtained IVD tissue and from nondegenerated autopsy control tissue. Methods Surgical IVD tissues were procured from patients with degenerative disc disease (n = 25) or herniated IVDs (n = 12); nondegenerated autopsy control tissue was also obtained (n = 8) from the anulus fibrosus and nucleus pulposus regions. Immunohistochemistry was performed for cell surface antigens (CD68 for macrophages, CD4 for lymphocytes) and various cytokines, with differences in cellularity and target immunoreactivity scores analyzed between surgical tissue groups and between autopsy control tissue regions. Results Immunoreactivity for IL-4, IL-6, IL-12, and interferon-, (IFN,) was modest in surgical IVD tissue, although expression was higher in herniated IVD samples and virtually nonexistent in control samples. The Th17 lymphocyte product IL-17 was present in >70% of surgical tissue fields, and among control samples was detected rarely in anulus fibrosus regions and modestly in nucleus pulposus regions. Macrophages were prevalent in surgical tissues, particularly herniated IVD samples, and lymphocytes were expectedly scarce. Control tissue revealed lesser infiltration by macrophages and a near absence of lymphocytes. Conclusion Greater IFN, positivity, macrophage presence, and cellularity in herniated IVDs suggests a pattern of Th1 lymphocyte activation in this pathology. Remarkable pathologic IVD tissue expression of IL-17 is a novel finding that contrasts markedly with low levels of IL-17 in autopsy control tissue. These findings suggest involvement of Th17 lymphocytes in the pathomechanism of disc degeneration. [source] The link between structural damage and pain in a genetic model of osteoarthritis and intervertebral disc degeneration: A joint misadventureARTHRITIS & RHEUMATISM, Issue 9 2009Mary B. Goldring No abstract is available for this article. [source] Decreased physical function and increased pain sensitivity in mice deficient for type IX collagenARTHRITIS & RHEUMATISM, Issue 9 2009Kyle D. Allen Objective In mice with Col9a1 gene inactivation (Col9a1,/,), osteoarthritis (OA) and intervertebral disc degeneration develop prematurely. The aim of this study was to investigate Col9a1,/, mice for functional and symptomatic changes that may be associated with these pathologies. Methods Col9a1,/, and wild-type mice were investigated for reflexes, functional impairment (beam walking, pole climbing, wire hang, grip strength), sensorimotor skills (rotarod), mechanical sensitivity (von Frey hair), and thermal sensitivity (hot plate/tail flick). Gait was also analyzed to determine velocity, stride frequency, symmetry, percentage stance time, stride length, and step width. Postmortem, sera obtained from the mice were analyzed for hyaluronan, and their knees and spines were graded histologically for degeneration. Results Col9a1,/, mice had compensatory gait changes, increased mechanical sensitivity, and impaired physical ability. Col9a1,/, mice ambulated with gaits characterized by increased percentage stance times and shorter stride lengths. These mice also had heightened mechanical sensitivity and were deficient in contact righting, wire hang, rotarod, and pole climbing tasks. Male Col9a1,/, mice had the highest mean serum hyaluronan levels and strong histologic evidence of cartilage erosion. Intervertebral disc degeneration was also detected, with Col9a1,/, mice having an increased incidence of disc tears. Conclusion These data describe a Col9a1,/, behavioral phenotype characterized by altered gait, increased mechanical sensitivity, and impaired function. These gait and functional differences suggest that Col9a1,/, mice select locomotive behaviors that limit joint loads. The nature and magnitude of behavioral changes were largest in male mice, which also had the greatest evidence of knee degeneration. These findings suggest that Col9a1,/, mice present behavioral changes consistent with anatomic signs of OA and intervertebral disc degeneration. [source] Notochordal intervertebral disc cells: Sensitivity to nutrient deprivationARTHRITIS & RHEUMATISM, Issue 4 2009Thorsten Guehring Objective The nucleus pulposus (NP) of the intervertebral disc develops from the notochord. Humans and other species in which notochordal cells (NCs) disappear to be replaced by chondrocyte-like mature NP cells (MNPCs) frequently develop disc degeneration, unlike other species that retain NCs. The reasons for NC disappearance are unknown. In humans, the change in cell phenotype (to MNPCs) coincides with changes that decrease nutrient supply to the avascular disc. We undertook this study to test the hypothesis that the consequent nutrient stress could be associated with NC disappearance. Methods We measured cell densities and metabolic rates in 3-dimensional cultures of porcine NCs and bovine MNPCs, and we determined survival rates under conditions of nutrient deprivation. We used scanning electron microscopy to examine end plate porosity of discs with NCs and those with MNPCs. Nutrient,metabolite profiles and cell viability were calculated as a function of cell density and disc size in a consumption/diffusion mathematical model. Results NCs were more active metabolically and more susceptible to nutrient deprivation than were MNPCs. Hypoxia increased rates of glycolysis in NCs but not in MNPCs. Higher end plate porosity in discs with NCs suggested greater nutrient supply in keeping with higher nutritional demands. Mathematical simulations and experiments using an analog disc diffusion chamber indicated that a fall in nutrient concentrations resulting from increased diffusion distance during growth and/or a fall in blood supply through end plate changes could instigate NC disappearance. Conclusion NCs demand more energy and are less resistant to nutritional stress than MNPCs, which may shed light on the fate of NCs in humans. This provides important information about prospective NC tissue engineering approaches. [source] Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowingARTHRITIS & RHEUMATISM, Issue 2 2009Tapio Videman Objective To examine the allelic diversity of structural, inflammatory, and matrix-modifying gene candidates and their association with disc degeneration. Methods Subjects were 588 men ages 35,70 years. We investigated associations of single-nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software. P values were derived from 1,000 permutations, and empirical P values for global significance also were applied. Results Twelve of the 99 variants in 25 selected candidate genes provided evidence of association (P < 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631; P = 0.001), COL1A1 (rs2075555; P = 0.005), COL9A1 (rs696990; P = 0.00008), and COL11A2 (rs2076311; P = 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P = 0.010) and COL9A1 (P = 0.014), as well as variants in the COL11A1 gene (rs1463035 [P = 0.004]; rs1337185 [P = 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797; P = 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P = 0.027]; rs1420100 in IL18RAP [P = 0.005]) were associated with disc signal intensity. Conclusion Genetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition. [source] Modified expression of the ADAMTS enzymes and tissue inhibitor of metalloproteinases 3 during human intervertebral disc degenerationARTHRITIS & RHEUMATISM, Issue 2 2009Aneta J. Pockert Objective Intervertebral disc degeneration is linked to loss of extracellular matrix (ECM), particularly the early loss of aggrecan. A group of metalloproteinases called aggrecanases are important mediators of aggrecan turnover. The present study was undertaken to investigate the expression of the recognized aggrecanases and their inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP-3), in human intervertebral disc tissue. Methods Twenty-four nondegenerated and 30 degenerated disc samples were analyzed for absolute messenger RNA (mRNA) copy number of ADAMTS 1, 4, 5, 8, 9, and 15 and TIMP-3 by real-time reverse transcription,polymerase chain reaction. Thirty-six formalin-fixed embedded intervertebral disc samples of varying grades of degeneration were used for immunohistochemical analyses. In addition, samples from 8 subjects were analyzed for the presence of matrix metalloproteinase (MMP), and aggrecanase-generated aggrecan products. Results Messenger RNA for all the aggrecanases other than ADAMTS-8 was identified in intervertebral disc tissue, as was mRNA for TIMP-3. Levels of mRNA expression of ADAMTS 1, 4, 5, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. All these aggrecanases and TIMP-3 were also detected immunohistochemically in disc tissue, and numbers of nucleus pulposus cells staining positive for ADAMTS 4, 5, 9, and 15 were significantly increased in degenerated tissue compared with nondegenerated tissue. Aggrecan breakdown products generated by MMP and aggrecanase activities were also detected in intervertebral disc tissue. Conclusion The aggrecanases ADAMTS 1, 4, 5, 9, and 15 may contribute to the changes occurring in the ECM during intervertebral disc degeneration. Targeting these enzymes may be a possible future therapeutic strategy for the prevention of intervertebral disc degeneration and its associated morbidity. [source] Disc space narrowing as a new risk factor for vertebral fracture: The OFELY studyARTHRITIS & RHEUMATISM, Issue 4 2006Elisabeth Sornay-Rendu Objective In a previous cross-sectional analysis, we found a positive association between disc space narrowing (DSN) and vertebral fracture. The aim of the present study was to analyze prospectively the risk of vertebral and nonvertebral fractures in women with spine osteoarthritis (OA). Methods Using radiographs, spine OA was evaluated in 634 postmenopausal women from the OFELY (Os des Femmes de Lyon) cohort (mean ± SD age 61.2 ± 9 years). Prevalence and severity of spine OA were assessed by scoring osteophytes and DSN. Incidental clinical fractures were prospectively registered during annual followup, and vertebral fractures were evaluated by radiography every 4 years. Results During an 11-year followup, fractures occurred in 121 women, including 42 with vertebral fractures. No association was found between osteophytes and the risk of fracture. In contrast, DSN was associated with an increased risk of vertebral fractures but not of nonvertebral fractures. After adjusting for confounding variables, the presence of DSN was associated with a marked increased risk of vertebral fractures, with an odds ratio of 6.59 (95% confidence interval 1.36,31.9). In addition, 95% of incident vertebral fractures were located above the disc with the most severe narrowing. Conclusion This longitudinal study shows that, despite a higher bone mineral density (BMD), women with spine OA do not have a reduced risk of fracture and that DSN is significantly associated with vertebral fracture risk. The location of DSN and of incident vertebral fractures suggests that disc degeneration impairs the biomechanics of the above spine, which leads to the increased risk of vertebral fractures, independent of BMD. We suggest that DSN is a newly identified risk factor for vertebral fracture that should be taken into consideration when assessing vertebral fracture risk in postmenopausal women. [source] | ||||||||||