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Sample records for disc degeneration model

  1. Modeling and optimization of an elastic arthroplastic disc for a degenerated disc

    NASA Astrophysics Data System (ADS)

    Ghouchani, Azadeh; Ravari, Mohammad; Mahmoudi, Farid

    2011-10-01

    A three-dimensional finite element model (FEM) of the L3-L4 motion segment using ABAQUS v 6.9 has been developed. The model took into account the material nonlinearities and is imposed different loading conditions. In this study, we validated the model by comparison of its predictions with several sets of experimental data. Disc deformation under compression and segmental rotational motions under moment loads for the normal disc model agreed well with the corresponding in vivo studies. By linking ABAQUS with MATLAB 2010.a, we determined the optimal Young s modulus as well as the Poisson's ratio for the artificial disc under different physiologic loading conditions. The results of the present study confirmed that a well-designed elastic arthroplastic disc preferably has an annulus modulus of 19.1 MPa and 1.24 MPa for nucleus section and Poisson ratio of 0.41 and 0.47 respectively. Elastic artificial disc with such properties can then achieve the goal of restoring the disc height and mechanical function of intact disc under different loading conditions and so can reduce low back pain which is mostly caused due to disc degeneration.

  2. A Review of Animal Models of Intervertebral Disc Degeneration: Pathophysiology, Regeneration, and Translation to the Clinic.

    PubMed

    Daly, Chris; Ghosh, Peter; Jenkin, Graham; Oehme, David; Goldschlager, Tony

    2016-01-01

    Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored. PMID:27314030

  3. A Review of Animal Models of Intervertebral Disc Degeneration: Pathophysiology, Regeneration, and Translation to the Clinic

    PubMed Central

    Ghosh, Peter

    2016-01-01

    Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored. PMID:27314030

  4. Biomechanics of Disc Degeneration

    PubMed Central

    Palepu, V.; Kodigudla, M.; Goel, V. K.

    2012-01-01

    Disc degeneration and associated disorders are among the most debated topics in the orthopedic literature over the past few decades. These may be attributed to interrelated mechanical, biochemical, and environmental factors. The treatment options vary from conservative approaches to surgery, depending on the severity of degeneration and response to conservative therapies. Spinal fusion is considered to be the “gold standard” in surgical methods till date. However, the association of adjacent level degeneration has led to the evolution of motion preservation technologies like spinal arthroplasty and posterior dynamic stabilization systems. These new technologies are aimed to address pain and preserve motion while maintaining a proper load sharing among various spinal elements. This paper provides an elaborative biomechanical review of the technologies aimed to address the disc degeneration and reiterates the point that biomechanical efficacy followed by long-term clinical success will allow these nonfusion technologies as alternatives to fusion, at least in certain patient population. PMID:22745914

  5. In Vivo Mouse Intervertebral Disc Degeneration Model Based on a New Histological Classification

    PubMed Central

    Ohnishi, Takashi; Sudo, Hideki; Iwasaki, Koji; Tsujimoto, Takeru; Ito, Yoichi M.; Iwasaki, Norimasa

    2016-01-01

    Although human intervertebral disc degeneration can lead to several spinal diseases, its pathogenesis remains unclear. This study aimed to create a new histological classification applicable to an in vivo mouse intervertebral disc degeneration model induced by needle puncture. One hundred six mice were operated and the L4/5 intervertebral disc was punctured with a 35- or 33-gauge needle. Micro-computed tomography scanning was performed, and the punctured region was confirmed. Evaluation was performed by using magnetic resonance imaging and histology by employing our classification scoring system. Our histological classification scores correlated well with the findings of magnetic resonance imaging and could detect degenerative progression, irrespective of the punctured region. However, the magnetic resonance imaging analysis revealed that there was no significant degenerative intervertebral disc change between the ventrally punctured and non-punctured control groups. To induce significant degeneration in the lumbar intervertebral discs, the central or dorsal region should be punctured instead of the ventral region. PMID:27482708

  6. Glucosamine Supplementation Demonstrates a Negative Effect On Intervertebral Disc Matrix in an Animal Model of Disc Degeneration

    PubMed Central

    Jacobs, Lloydine; Vo, Nam; Coehlo, J. Paulo; Dong, Qing; Bechara, Bernard; Woods, Barrett; Hempen, Eric; Hartman, Robert; Preuss, Harry; Balk, Judith; Kang, James; Sowa, Gwendolyn

    2013-01-01

    Study Design Laboratory based controlled in vivo study Objective To determine the in vivo effects of oral glucosamine sulfate on intervertebral disc degeneration Summary of Background Data Although glucosamine has demonstrated beneficial effect in articular cartilage, clinical benefit is uncertain. A CDC report from 2009 reported that many patients are using glucosamine supplementation for low back pain (LBP), without significant evidence to support its use. Because disc degeneration is a major contributor of LBP, we explored the effects of glucosamine on disc matrix homeostasis in an animal model of disc degeneration. Methods Eighteen skeletally mature New Zealand White rabbits were divided into four groups: control, annular puncture, glucosamine, and annular puncture+glucosamine. Glucosamine treated rabbits received daily oral supplementation with 107mg/day (weight based equivalent to human 1500mg/day). Annular puncture surgery involved puncturing the annulus fibrosus (AF) of 3 lumbar discs with a 16G needle to induce degeneration. Serial MRIs were obtained at 0, 4, 8, 12, and 20 weeks. Discs were harvested at 20 weeks for determination of glycosaminoglycan(GAG) content, relative gene expression measured by RT-PCR, and histological analyses. Results The MRI index and NP area of injured discs of glucosamine treated animals with annular puncture was found to be lower than that of degenerated discs from rabbits not supplemented with glucosamine. Consistent with this, decreased glycosaminoglycan was demonstrated in glucosamine fed animals, as determined by both histological and GAG content. Gene expression was consistent with a detrimental effect on matrix. Conclusions These data demonstrate that the net effect on matrix in an animal model in vivo, as measured by gene expression, MRI, histology, and total proteoglycan is anti-anabolic. This raises concern over this commonly used supplement, and future research is needed to establish the clinical relevance of these

  7. Lumbar intervertebral disc puncture under C-arm fluoroscopy: a new rat model of lumbar intervertebral disc degeneration.

    PubMed

    Li, Dapeng; Yang, Huilin; Huang, Yonghui; Wu, Yan; Sun, Taicun; Li, Xuefeng

    2014-01-01

    To establish a minimally invasive rat model of lumbar intervertebral disc degeneration (IDD) to better understand the pathophysiology of the human condition. The annulus fibrosus of lumbar level 4-5 (L4-5) and L5-6 discs were punctured by 27-gauge needles using the posterior approach under C-arm fluoroscopic guidance. Magnetic resonance imaging (MRI), histological examination by hematoxylin and eosin (H&E) staining, and reverse transcription polymerase chain reaction (RT-PCR) were performed at baseline and 2, 4, and 8 weeks after disc puncture surgery to determine the degree of degeneration. All sixty discs (thirty rats) were punctured successfully. Only two of thirty rats subjected to the procedure exhibited immediate neurological symptoms. The MRI results indicated a gradual increase in Pfirrmann grade from 4 to 8 weeks post-surgery (P<0.05), and H&E staining demonstrated a parallel increase in histological grade (P<0.05). Expression levels of aggrecan, type II collagen (Col2), and Sox9 mRNAs, which encode disc components, decreased gradually post-surgery. In contrast, mRNA expression of type I collagen (Col1), an indicator of fibrosis, increased (P<0.05). The procedure of annular puncture using a 27-gauge needle under C-arm fluoroscopic guidance had a high success rate. Histological, MRI, and RT-PCR results revealed that the rat model of disc degeneration is a progressive pathological process that is similar to human IDD. PMID:24770648

  8. STUDIES OF MOLECULAR CHANGES IN INTERVERTEBRAL DISC DEGENERATION IN ANIMAL MODEL

    PubMed Central

    de Campos, Marcelo Ferraz; de Oliveira, Cintia Pereira; Neff, Charles Benjamin; Correa, Olga Maria de Toledo; Pinhal, Maria Aparecida Silva; Rodrigues, Luciano Miller Reis

    2016-01-01

    ABSTRACT Objective: To evaluate the structural and molecular changes in the extracellular matrix (ECM) during the process of intervertebral disc degeneration, using animal model. Methods: Wistar rats underwent intervertebral disc degeneration through 20-gauge needle puncture, and 360° rotation applied for 30 sec, representing the degenerated group, while control group was not submitted to this procedure. Histological parameters and expression of extracellular matrix molecules were evaluated in the 15th and 28th days after degenerative induction. Results: Fifteen days after the induction of intervertebral disc degeneration, significant changes were observed, such as reduction in the expression metalloprotease-9 (MMP9) and interleukins (IL-6 and IL-10). There was a significant increase in the expression of vascular endothelial growth factor (VEGF) and caspase-3. However, different alterations in the ECM were observed at 28 days, the level of collagen I, metalloprotease-2 (MMP2) and caspase-3 were enhanced. Furthermore, expression of heparanase isoforms (HPSE1 and HPSE2) mRNA were increased in the degenerative intervertebral disc. Conclusion: The different profiles of ECM molecules observed during the intervertebral disc degeneration suggest that molecular processes such as ECM remodeling, neovascularization, apoptosis and inflammation occur. Experimental Study. PMID:26997908

  9. Quantitative Analysis of Disc Degeneration Using Axial T2 Mapping in a Percutaneous Annular Puncture Model in Rabbits

    PubMed Central

    Chai, Jee Won; Lee, Joon Woo; Kim, Su-Jin; Hong, Sung Hwan

    2016-01-01

    Objective To evaluate T2 relaxation time change using axial T2 mapping in a rabbit degenerated disc model and determine the most correlated variable with histologic score among T2 relaxation time, disc height index, and Pfirrmann grade. Materials and Methods Degenerated disc model was made in 4 lumbar discs of 11 rabbits (n = 44) by percutaneous annular puncture with various severities of an injury. Lumbar spine lateral radiograph, MR T2 sagittal scan and MR axial T2 mapping were obtained at baseline and 2 weeks and 4 weeks after the injury in 7 rabbits and at baseline and 2 weeks, 4 weeks, and 6 weeks after the injury in 4 rabbits. Generalized estimating equations were used for a longitudinal analysis of changes in T2 relaxation time in degenerated disc model. T2 relaxation time, disc height index and Pfirrmann grade were correlated with the histologic scoring of disc degeneration using Spearman's rho test. Results There was a significant difference in T2 relaxation time between uninjured and injured discs after annular puncture. Progressive decrease in T2 relaxation time was observed in injured discs throughout the study period. Lower T2 relaxation time was observed in the more severely injured discs. T2 relaxation time showed the strongest inverse correlation with the histologic score among the variables investigated (r = -0.811, p < 0.001). Conclusion T2 relaxation time measured with axial T2 mapping in degenerated discs is a potential method to assess disc degeneration. PMID:26798222

  10. Intervertebral Disc Degeneration

    PubMed Central

    Rannou, François; Lee, Tzong-Shyuan; Zhou, Rui-Hai; Chin, Jennie; Lotz, Jeffrey C.; Mayoux-Benhamou, Marie-Anne; Barbet, Jacques Patrick; Chevrot, Alain; Shyy, John Y.-J.

    2004-01-01

    Degeneration of the intervertebral disk (IVD) is a major pathological process implicated in low back pain and is a prerequisite to disk herniation. Although mechanical stress is an important modulator of the degeneration, the underlying molecular mechanism remains unclear. The association of human IVD degeneration, assessed by magnetic resonance imaging, with annulus fibrosus cell apoptosis and anti-cytochrome c staining revealed that the activation of the mitochondria-dependent apoptosome was a major event in the degeneration process. Mouse models of IVD degeneration were used to investigate the role of the mechanical stress in this process. The application of mechanical overload (1.3 MPa) for 24 hours induced annulus fibrosus cell apoptosis and led to severe degeneration of the mouse disks. Immunostaining revealed cytochrome c release but not Fas-L generation. The role of the caspase-9-dependent mitochondrial pathway in annulus fibrosus cell apoptosis induced by overload was investigated further with the use of cultured rabbit IVD cells in a stretch device. Mechanical overload (15% area change) induced apoptosis with increased caspase-9 activity and decreased mitochondrial membrane potential. Furthermore, Z-LEHD-FMK, a caspase-9 inhibitor, but not Z-IETD-FMK, a caspase-8 inhibitor, attenuated the overload-induced apoptosis. Our results from human samples, mouse models, and annulus fibrosus culture experiments demonstrate that the mechanical overload-induced IVD degeneration is mediated through the mitochondrial apoptotic pathway in IVD cells. PMID:14982845

  11. Are animal models useful for studying human disc disorders/degeneration?

    PubMed

    Alini, Mauro; Eisenstein, Stephen M; Ito, Keita; Little, Christopher; Kettler, A Annette; Masuda, Koichi; Melrose, James; Ralphs, Jim; Stokes, Ian; Wilke, Hans Joachim

    2008-01-01

    Intervertebral disc (IVD) degeneration is an often investigated pathophysiological condition because of its implication in causing low back pain. As human material for such studies is difficult to obtain because of ethical and government regulatory restriction, animal tissue, organs and in vivo models have often been used for this purpose. However, there are many differences in cell population, tissue composition, disc and spine anatomy, development, physiology and mechanical properties, between animal species and human. Both naturally occurring and induced degenerative changes may differ significantly from those seen in humans. This paper reviews the many animal models developed for the study of IVD degeneration aetiopathogenesis and treatments thereof. In particular, the limitations and relevance of these models to the human condition are examined, and some general consensus guidelines are presented. Although animal models are invaluable to increase our understanding of disc biology, because of the differences between species, care must be taken when used to study human disc degeneration and much more effort is needed to facilitate research on human disc material. PMID:17632738

  12. Regeneration of nucleus pulposus tissue in an ovine intervertebral disc degeneration model by cell-free resorbable polymer scaffolds.

    PubMed

    Woiciechowsky, Christian; Abbushi, Alexander; Zenclussen, Maria L; Casalis, Pablo; Krüger, Jan Philipp; Freymann, Undine; Endres, Michaela; Kaps, Christian

    2014-10-01

    Degeneration of intervertebral discs (IVDs) occurs frequently and is often associated with lower back pain. Recent treatment options are limited and treat the symptoms rather than regenerate the degenerated disc. Cell-free, freeze-dried resorbable polyglycolic acid (PGA)-hyaluronan implants were used in an ovine IVD degeneration model. The nucleus pulposus of the IVD was partially removed, endoscopically. PGA-hyaluronan implants were immersed in autologous sheep serum and implanted into the disc defect. Animals with nucleotomy only served as controls. The T2-weighted/fat suppression sequence signal intensity index of the operated discs, as assessed by magnetic resonance imaging (MRI), showed that implantation of the PGA-hyaluronan implant improved (p = 0.0066) the MRI signal compared to controls at 6 months after surgery. Histological analysis by haematoxylin and eosin and safranin O staining showed the ingrowth of cells with typical chondrocytic morphology, even cell distribution, and extracellular matrix rich in proteoglycan. Histomorphometric analyses confirmed that the implantation of the PGA-hyaluronan scaffolds improved (p = 0.027) the formation of regenerated tissue after nucleotomy. Disc heights remained stable in discs with nucleotomy only as well as after implantation of the implant. In conclusion, implantation of cell-free polymer-based implants after nucleotomy induces nucleus pulposus tissue regeneration and improves disc water content in the ovine model. PMID:22865642

  13. A rat tail temporary static compression model reproduces different stages of intervertebral disc degeneration with decreased notochordal cell phenotype.

    PubMed

    Hirata, Hiroaki; Yurube, Takashi; Kakutani, Kenichiro; Maeno, Koichiro; Takada, Toru; Yamamoto, Junya; Kurakawa, Takuto; Akisue, Toshihiro; Kuroda, Ryosuke; Kurosaka, Masahiro; Nishida, Kotaro

    2014-03-01

    The intervertebral disc nucleus pulposus (NP) has two phenotypically distinct cell types-notochordal cells (NCs) and non-notochordal chondrocyte-like cells. In human discs, NCs are lost during adolescence, which is also when discs begin to show degenerative signs. However, little evidence exists regarding the link between NC disappearance and the pathogenesis of disc degeneration. To clarify this, a rat tail disc degeneration model induced by static compression at 1.3 MPa for 0, 1, or 7 days was designed and assessed for up to 56 postoperative days. Radiography, MRI, and histomorphology showed degenerative disc findings in response to the compression period. Immunofluorescence displayed that the number of DAPI-positive NP cells decreased with compression; particularly, the decrease was notable in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, identified as NCs. The proportion of TUNEL-positive cells, which predominantly comprised non-NCs, increased with compression. Quantitative PCR demonstrated isolated mRNA up-regulation of ADAMTS-5 in the 1-day loaded group and MMP-3 in the 7-day loaded group. Aggrecan-1 and collagen type 2α-1 mRNA levels were down-regulated in both groups. This rat tail temporary static compression model, which exhibits decreased NC phenotype, increased apoptotic cell death, and imbalanced catabolic and anabolic gene expression, reproduces different stages of intervertebral disc degeneration. PMID:24285589

  14. Notochordal cell disappearance and modes of apoptotic cell death in a rat tail static compression-induced disc degeneration model

    PubMed Central

    2014-01-01

    Introduction The intervertebral disc has a complex structure originating developmentally from both the mesenchyme and notochord. Notochordal cells disappear during adolescence, which is also when human discs begin to show degenerative signs. During degeneration later in life, disc cells decline because of apoptosis. Although many animal models have been developed to simulate human disc degeneration, few studies have explored the long-term changes in cell population and phenotype. Our objective was to elucidate the time-dependent notochordal cell disappearance and apoptotic cell death in a rat tail static compression-induced disc degeneration model. Methods Twenty-four 12-week-old male Sprague–Dawley rat tails were instrumented with an Ilizarov-type device and loaded statically at 1.3 MPa for up to 56 days. Loaded and distal-unloaded discs were harvested. Changes in cell number and phenotype were assessed with histomorphology and immunofluorescence. Apoptosis involvement was determined with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunohistochemistry. Results The number of disc nucleus pulposus and annulus fibrosus cells decreased with the loading period; particularly, the decrease was notable at day 7 in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, indicating notochordal origin. Subsequently, the proportion of cells positive for TUNEL and cleaved caspase-3, markers of apoptosis induction, increased from day 7 through day 56. Although the percentage of cells immunopositive for cleaved caspase-8, a marker of apoptosis initiation through the death-receptor pathway, increased only at day 7, the percentage of cells immunopositive for cleaved caspase-9 and p53-regulated apoptosis-inducing protein 1 (p53AIP1), markers of apoptosis initiation through the p53-mediated mitochondrial pathway, increased from day 7 through day 56. The percentage of cells immunopositive for B-cell lymphoma 2 (Bcl-2) and silent

  15. The Effects of Simulated Microgravity on Intervertebral Disc Degeneration

    PubMed Central

    Jin, Li; Feng, Gang; Reames, Davis L; Shimer, Adam L; Shen, Francis H; Li, Xudong

    2012-01-01

    BACKGROUND CONTEXT Astronauts experience back pain, particularly low back pain, during and after spaceflight. Recent studies have described histological and biochemical changes in rat intervertebral discs after space travel, but there is still no in vitro model to investigate the effects of microgravity on disc metabolism. PURPOSE To study the effects of microgravity on disc degeneration and to establish an in vitro simulated microgravity study model STUDY DESIGN Discs were cultured in static and rotating conditions in bioreactor, and the characteristics of disc degeneration were evaluated METHODS The mice discs were cultured in a rotating wall vessel bioreactor where the microgravity condition was simulated. Intervertebral discs were cultured in static and microgravity condition. Histology, biochemistry, and immunohistochemical assays were performed to evaluate the characteristics of the discs in microgravity condition. RESULTS Intervertebral discs cultured in rotating bioreactors were found to develop changes of disc degeneration manifested by reduced red Safranin-o staining within the annulus fibrosus, downregulated GAG content and GAG/Hypro ratio, increased MMP-3 expression, and upregulated apoptosis. CONCLUSIONS We conclude that simulated microgravity induces the molecular changes of disc degeneration. The rotating bioreactor model will provide a foundation to investigate the effects of microgravity on disc metabolism. PMID:23537452

  16. Inflammation in intervertebral disc degeneration and regeneration

    PubMed Central

    Molinos, Maria; Almeida, Catarina R.; Caldeira, Joana; Cunha, Carla; Gonçalves, Raquel M.; Barbosa, Mário A.

    2015-01-01

    Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players. PMID:25673296

  17. Quantitative Pfirrmann Disc Degeneration Grading System to Overcome the Limitation of Pfirrmann Disc Degeneration Grade

    PubMed Central

    2016-01-01

    Objective Pfirrmann disc degeneration grade is one of morphologic disc degeneration grading system and it was reliable on routine T2-weighted magnetic resonance (MR) images. The purpose of this study was to evaluate the agreement of Pfirrmann disc degeneration grade, and check the alternative technique of disc degeneration grading system. Methods Fifteen volunteers (4 medical doctors related to spinal disease, 2 medical doctors not related to spinal disease, 6 nurses in spinal hospital, and 3 para-medicines) were included in this study. Three different digitalized MR images were provided all volunteers, and they checked Pfirrmann disc degeneration grade of each disc levels after careful listening to explanation. Indeed, all volunteers checked the signal intensity of disc degeneration at the points of nucleus pulposus (NP), disc membrane, ligaments, fat, and air to modify the quantitative Pfirrmann disc degeneration grade. Results Total 225 grade results of Pfirrmann disc degeneration grade and 405 signal intensity results of quantitative Pfirrmann disc degeneration grade were analyzed. Average interobserver agreement was "moderate (mean±standard deviation, 0.575±0.251)" from poor to excellent. Completely agreed levels of Pfirrmann disc degeneration grade were only 4 levels (26.67%), and the disagreement levels were observed in 11 levels; two different grades in 8 levels (53.33%) and three different grades in 3 levels (20%). Quantitative Pfirrmann disc degeneration showed relatively cluster distribution with the interobserver deviations of 0.41-1.56 at the ratio of NP and disc membrane, and it showed relatively good cluster and distribution indicating that the proposed grading system has good discrimination ability. Conclusion Pfirrmann disc degeneration grade showed the limitation of different interobserver results, but this limitation could be overcome by using quantitative techniques of MR signal intensity. Further evaluation is needed to access its advantage

  18. BMP7 enhances the effect of BMSCs on extracellular matrix remodeling in a rabbit model of intervertebral disc degeneration.

    PubMed

    Xu, Jun; E, Xiao-Qiang; Wang, Nan-Xiang; Wang, Mo-Nan; Xie, Huan-Xin; Cao, Yan-Hui; Sun, Li-Hua; Tian, Jun; Chen, Hua-Jiang; Yan, Jing-Long

    2016-05-01

    Intervertebral discs (IVDs) provide stability and flexibility to the spinal column; however, IVDs, and in particular the nucleus pulposus (NP), undergo a degenerative process characterized by changes in the disc extracellular matrix (ECM), decreased cell viability, and reduced synthesis of proteoglycan and type II collagen. Here, we investigated the efficacy and feasibility of stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) over-expressing bone morphogenetic protein 7 (BMP7) to promote ECM remodeling of degenerated IVDs. Lentivirus-mediated BMP7 over-expression induced differentiation of BMSCs into an NP phenotype, as indicated by expression of the NP markers collagen type II, aggrecan, SOX9 and keratins 8 and 19, increased the content of glycosaminoglycan, and up-regulated β-1,3-glucuronosyl transferase 1, a regulator of chondroitin sulfate synthesis in NP cells. These effects were suppressed by Smad1 silencing, indicating that the effect of BMP7 on ECM remodeling was mediated by the Smad pathway. In vivo analysis in a rabbit model of disc degeneration showed that implantation of BMSCs over-expressing BMP7 promoted cell differentiation and proliferation in the NP, as well as their own survival, and these effects were mediated by the Smad pathway. The results of the present study indicate the beneficial effects of BMP7 on restoring ECM homeostasis in NP cells, and suggest potential strategies for improving cell therapy for the treatment of disc diseases. PMID:26929154

  19. Notochord Cells in Intervertebral Disc Development and Degeneration

    PubMed Central

    McCann, Matthew R.; Séguin, Cheryle A.

    2016-01-01

    The intervertebral disc is a complex structure responsible for flexibility, multi-axial motion, and load transmission throughout the spine. Importantly, degeneration of the intervertebral disc is thought to be an initiating factor for back pain. Due to a lack of understanding of the pathways that govern disc degeneration, there are currently no disease-modifying treatments to delay or prevent degenerative disc disease. This review presents an overview of our current understanding of the developmental processes that regulate intervertebral disc formation, with particular emphasis on the role of the notochord and notochord-derived cells in disc homeostasis and how their loss can result in degeneration. We then describe the role of small animal models in understanding the development of the disc and their use to interrogate disc degeneration and associated pathologies. Finally, we highlight essential development pathways that are associated with disc degeneration and/or implicated in the reparative response of the tissue that might serve as targets for future therapeutic approaches. PMID:27252900

  20. RADIOLOGICAL ANALYSIS OF EXPERIMENTAL DISC DEGENERATION IN RABBITS

    PubMed Central

    Vialle, Emiliano; Vialle, Luiz Roberto; Arruda, André de Oliveira; Riet, Ricardo Nascimento; Krieger, Antônio Bernardo de Queiroz

    2015-01-01

    Objective: To validate radiographic evaluation of a rabbit model for disc degeneration. Methods: Lumbar intervertebral discs of New Zealand rabbits were stabbed three times with a 18G needle at a limited depth of 5mm, through lateral approach. Serial radiographic images were taken on the early pre-and postoperative periods, and after four, eight and 12 weeks of the procedure, with subsequent analysis of disc height, osteophyte formation, endplate sclerosis, and presence of disc degeneration. The statistical analysis of data was validated by the Kappa coefficient, with a confidence interval (CI) of 95%. Results: A significant reduction of disc space was found on AP X-ray images after 12 postoperative weeks, with Kappa = 0.489 for CI 95% (0.25-0.72) with p < 0.001. X-ray signs of disc degeneration also presented Kappa = 0.63 for CI 95% (0.39-0.86) with p < 0.001. The remaining assessed criteria showed positive results, but with a lower Kappa value. Conclusion: The disc degeneration model using rabbits as proposed in this study was shown to be feasible, with positive X-ray correlation between pre- and postoperative images, validating the potential to induce disc degeneration in this animal model for future studies. PMID:27022512

  1. MRI evaluation of spontaneous intervertebral disc degeneration in the alpaca cervical spine.

    PubMed

    Stolworthy, Dean K; Bowden, Anton E; Roeder, Beverly L; Robinson, Todd F; Holland, Jacob G; Christensen, S Loyd; Beatty, Amanda M; Bridgewater, Laura C; Eggett, Dennis L; Wendel, John D; Stieger-Vanegas, Susanne M; Taylor, Meredith D

    2015-12-01

    Animal models have historically provided an appropriate benchmark for understanding human pathology, treatment, and healing, but few animals are known to naturally develop intervertebral disc degeneration. The study of degenerative disc disease and its treatment would greatly benefit from a more comprehensive, and comparable animal model. Alpacas have recently been presented as a potential large animal model of intervertebral disc degeneration due to similarities in spinal posture, disc size, biomechanical flexibility, and natural disc pathology. This research further investigated alpacas by determining the prevalence of intervertebral disc degeneration among an aging alpaca population. Twenty healthy female alpacas comprised two age subgroups (5 young: 2-6 years; and 15 older: 10+ years) and were rated according to the Pfirrmann-grade for degeneration of the cervical intervertebral discs. Incidence rates of degeneration showed strong correlations with age and spinal level: younger alpacas were nearly immune to developing disc degeneration, and in older animals, disc degeneration had an increased incidence rate and severity at lower cervical levels. Advanced disc degeneration was present in at least one of the cervical intervertebral discs of 47% of the older alpacas, and it was most common at the two lowest cervical intervertebral discs. The prevalence of intervertebral disc degeneration encourages further investigation and application of the lower cervical spine of alpacas and similar camelids as a large animal model of intervertebral disc degeneration. PMID:26135031

  2. Simulation of biological therapies for degenerated intervertebral discs.

    PubMed

    Zhu, Qiaoqiao; Gao, Xin; Temple, H Thomas; Brown, Mark D; Gu, Weiyong

    2016-04-01

    The efficacy of biological therapies on intervertebral disc repair was quantitatively studied using a three-dimensional finite element model based on a cell-activity coupled multiphasic mixture theory. In this model, cell metabolism and matrix synthesis and degradation were considered. Three types of biological therapies-increasing the cell density (Case I), increasing the glycosaminoglycan (GAG) synthesis rate (Case II), and decreasing the GAG degradation rate (Case III)-to the nucleus pulposus (NP) of each of two degenerated discs [one mildly degenerated (e.g., 80% viable cells in the NP) and one severely degenerated (e.g., 30% viable cells in the NP)] were simulated. Degenerated discs without treatment were also simulated as a control. The cell number needed, nutrition level demanded, time required for the repair, and the long-term outcomes of these therapies were analyzed. For Case I, the repair process was predicted to be dependent on the cell density implanted and the nutrition level at disc boundaries. With sufficient nutrition supply, this method was predicted to be effective for treating both mildly and severely degenerated discs. For Case II, the therapy was predicted to be effective for repairing the mildly degenerated disc, but not for the severely degenerated disc. Similar results were predicted for Case III. No change in cell density for Cases II and III were predicted under normal nutrition level. This study provides a quantitative guide for choosing proper strategies of biological therapies for different degenerated discs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:699-708, 2016. PMID:26425965

  3. Lentivirus-mediated TGF-β3, CTGF and TIMP1 gene transduction as a gene therapy for intervertebral disc degeneration in an in vivo rabbit model

    PubMed Central

    LIU, YONG; YU, TAO; MA, XUE-XIAO; XIANG, HONG-FEI; HU, YOU-GU; CHEN, BO-HUA

    2016-01-01

    The present study examined the effects of transforming growth factor (TGF)-β3, connective tissue growth factor (CTGF) and tissue inhibitor of metalloproteinase 1 (TIMP1) gene transduction, using a lentiviral vector, on rabbit intervertebral disc degeneration in vivo, with the intention of investigating their potential use in gene therapy. A model of lumbar intervertebral disc degeneration was created by needle puncture into the annulus fibrosus of 15 New Zealand white rabbits. Empty lentivirus or recombinant lentiviral plasmid lenti-TGFβ3-P2A-CTGF-T2A-TIMP1 was injected into degenerative lumbar intervertebral discs (representing the control and experimental groups, respectively), whilst untreated degenerative lumbar intervertebral discs served as the puncture group. After 16 and 20 weeks, magnetic resonance imaging (MRI) was conducted and the changes in intensity on micrographs of degenerative intervertebral discs were measured. The mRNA levels of aggrecan and type II collagen in nucleus pulposus tissue were determined by reverse transcription-polymerase chain reaction, and protein expression levels of type II collagen and aggrecan were determined by western blot analysis. MRI results indicated that intervertebral disc degeneration was ameliorated in the experimental group when compared with the control and the puncture group. Furthermore, the expression levels of type II collagen and aggrecan in the puncture and control groups were significantly lower than in the experimental group (P<0.05). In conclusion, lenti-TGFβ3-P2A-CTGF-T2A-TIMP1 co-transduction can promote synthesis of aggrecan and type II collagen in degenerative intervertebral discs, thereby delaying intervertebral disc degeneration. These results indicate the potential of gene therapy in treatment of intervertebral disc degeneration. PMID:27073456

  4. Decellularized allogeneic intervertebral disc: natural biomaterials for regenerating disc degeneration

    PubMed Central

    Hu, Zhijun; Chen, Kai; Shan, Zhi; Chen, Shuai; Wang, Jiying; Mo, Jian; Ma, Jianjun; Xu, Wenbing; Qin, An; Fan, Shunwu

    2016-01-01

    Intervertebral disc degeneration is associated with back pain and disc herniation. This study established a modified protocol for intervertebral disc (IVD) decellularization and prepared its extracellular matrix (ECM). By culturing mesenchymal stem cells (MSCs)(3, 7, 14 and 21 days) and human degenerative IVD cells (7 days) in the ECM, implanting it subcutaneously in rabbit and injecting ECM microparticles into degenerative disc, the biological safety and efficacy of decellularized IVD was evaluated both in vitro and in vivo. Here, we demonstrated that cellular components can be removed completely after decellularization and maximally retain the structure and biomechanics of native IVD. We revealed that allogeneic ECM did not evoke any apparent inflammatory reaction in vivo and no cytotoxicity was found in vitro. Moreover, IVD ECM can induce differentiation of MSCs into IVD-like cells in vitro. Furthermore, allogeneic ECM microparticles are effective on the treatment of rabbit disc degeneration in vivo. In conclusion, our study developed an optimized method for IVD decellularization and we proved decellularized IVD is safe and effective for the treatment of degenerated disc diseases. PMID:26933821

  5. 1990 Volvo Award in experimental studies. Anulus tears and intervertebral disc degeneration. An experimental study using an animal model.

    PubMed

    Osti, O L; Vernon-Roberts, B; Fraser, R D

    1990-08-01

    An animal model was developed to test the hypothesis that discrete peripheral tears within the anulus lead to secondary degenerative changes in other disc components. In 21 adult sheep, a cut was made in the left anterolateral anulus of three randomly selected lumbar discs. The cut was parallel and adjacent to the inferior end-plate, and had a controlled depth of 5 mm. This left the inner third of the anulus and the nucleus pulposus intact and closely reproduced the rim Lear lesion described by Schmorl. Animals were randomly allocated to different groups in relation to the length of time interval between operation and death, varying from 1 to 18 months. At death, the lumbar spine was cut into individual joint units and each disc sectioned into six parasagittal slabs. After observation of the slabs under the dissecting microscope, two of the six slabs, the one containing the anulus lesion and a contralateral, were processed for histology. The results of this study suggest that, despite the great care taken at operation to ensure that the inner anulus was left intact, progressive failure of the inner anulus was seen in all sheep and occurred in the majority of discs between 4 and 12 months after the operation. Although the outermost anulus showed the ability to heal, the defect induced by the cut led initially to deformation and bulging of the collagen bundles, and eventually to inner extension of the tear and complete failure. These findings suggest that discrete tears of the outer anulus may have a role in the formation of concentric clefts and in accelerating the development of radiating clefts. Peripheral tears of the anulus fibrosus therefore may play an important role in the degeneration of the intervertebral joint complex. PMID:2237626

  6. A papain-induced disc degeneration model for the assessment of thermo-reversible hydrogel-cells therapeutic approach.

    PubMed

    Malonzo, C; Chan, S C W; Kabiri, A; Eglin, D; Grad, S; Bonél, H M; Benneker, L M; Gantenbein-Ritter, B

    2015-12-01

    Nucleus pulposus (NP) regeneration by the application of injectable cell-embedded hydrogels is an appealing approach for tissue engineering. We investigated a thermo-reversible hydrogel (TR-HG), based on a modified polysaccharide with a thermo-reversible polyamide [poly(N-isopropylacrylamide), pNIPAM], which is made to behave as a liquid at room temperature and hardens at > 32 °C. In order to test the hydrogel, a papain-induced bovine caudal disc degeneration model (PDDM), creating a cavity in the NP, was employed. Human mesenchymal stem cells (hMSCs) or autologous bovine NP cells (bNPCs) were seeded in TR-HG; hMSCs were additionally preconditioned with rhGDF-5 for 7 days. Then, TR-HG was reversed to a fluid and the cell suspension injected into the PDDM and kept under static loading for 7 days. Experimental design was: (D1) fresh disc control + PBS injection; (D2) PDDM + PBS injection; (D3) PDDM + TR-HG (material control); (D4) PDDM + TR-HG + bNPCs; (D5) PDDM + TR-HG + hMSCs. Magnetic resonance imaging performed before and after loading, on days 9 and 16, allowed imaging of the hydrogel-filled PDDM and assessment of disc height and volume changes. In gel-injected discs the NP region showed a major drop in volume and disc height during culture under static load. The RT-PCR results of injected hMSCs showed significant upregulation of ACAN, COL2A1, VCAN and SOX9 during culture in the disc cavity, whereas the gene expression profile of NP cells remained unchanged. The cell viability of injected cells (NPCs or hMSCs) was maintained at over 86% in 3D culture and dropped to ~72% after organ culture. Our results underline the need for load-bearing hydrogels that are also cyto-compatible. PMID:23303720

  7. Potential regenerative treatment strategies for intervertebral disc degeneration in dogs

    PubMed Central

    2014-01-01

    Pain due to spontaneous intervertebral disc (IVD) disease is common in dogs. In chondrodystrophic (CD) dogs, IVD disease typically develops in the cervical or thoracolumbar spine at about 3–7 years of age, whereas in non-chondrodystrophic (NCD) dogs, it usually develops in the caudal cervical or lumbosacral spine at about 6–8 years of age. IVD degeneration is characterized by changes in the biochemical composition and mechanical integrity of the IVD. In the degenerated IVD, the content of glycosaminoglycan (GAG, a proteoglycan side chain) decreases and that of denatured collagen increases. Dehydration leads to tearing of the annulus fibrosus (AF) and/or disc herniation, which is clinically characterized by pain and/or neurological signs. Current treatments (physiotherapy, anti-inflammatory/analgesic medication, surgery) for IVD disease may resolve neurological deficits and reduce pain (although in many cases insufficient), but do not lead to repair of the degenerated disc. For this reason, there is interest in new regenerative therapies that can repair the degenerated disc matrix, resulting in restoration of the biomechanical function of the IVD. CD dogs are considered a suitable animal model for human IVD degeneration because of their spontaneous IVD degeneration, and therefore studies investigating cell-, growth factor-, and/or gene therapy-based regenerative therapies with this model provide information relevant to both human and canine patients. The aim of this article is to review potential regenerative treatment strategies for canine IVD degeneration, with specific emphasis on cell-based strategies. PMID:24387033

  8. BMP-2 and BMP-2/7 Heterodimers Conjugated to a Fibrin/Hyaluronic Acid Hydrogel in a Large Animal Model of Mild Intervertebral Disc Degeneration.

    PubMed

    Peeters, Mirte; Detiger, Suzanne E L; Karfeld-Sulzer, Lindsay S; Smit, Theo H; Yayon, Avner; Weber, Franz E; Helder, Marco N

    2015-01-01

    Intervertebral disc (IVD) degeneration is etiologically associated with low back pain and is currently only treated in severe cases with spinal fusion. Regenerative medicine attempts to restore degenerated tissue by means of cells, hydrogels, and/or growth factors and can therefore be used to slow, halt, or reverse the degeneration of the IVD in a minimally invasive manner. Previously, the growth factors bone morphogenetic proteins 2 and 7 (BMP-2, -7) were shown to enhance disc regeneration, in vitro and in vivo. Since BMPs have only a short in vivo half-life, and to prevent heterotopic ossification, we evaluated the use of a slow release system for BMP-2 homodimers and BMP-2/7 heterodimers for IVD regeneration. BMP growth factors were conjugated to a fibrin/hyaluronic acid (FB/HA) hydrogel and intradiscally injected in a goat model of mild IVD degeneration to study safety and efficacy. Mild degeneration was induced in five lumbar discs of seven adult Dutch milk goats, by injections with the enzyme chondroitinase ABC. After 12 weeks, discs were treated with either FB/HA-hydrogel only or supplemented with 1 or 5 μg/mL of BMP-2 or BMP-2/7. BMPs were linked to the FB/HA hydrogels using a transglutaminase moiety, to be released through an incorporated plasmin cleavage site. After another 12 weeks, goats were sacrificed and discs were assessed using radiography, MRI T2* mapping, and biochemical and histological analyses. All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up. Radiographs showed significant disc height loss upon induction of mild degeneration. MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before. Surprisingly, no differences could be demonstrated in any parameter between intervention groups. To our knowledge, this is the first large animal study evaluating BMPs conjugated to an FB/HA-hydrogel for the treatment of

  9. BMP-2 and BMP-2/7 Heterodimers Conjugated to a Fibrin/Hyaluronic Acid Hydrogel in a Large Animal Model of Mild Intervertebral Disc Degeneration

    PubMed Central

    Peeters, Mirte; Detiger, Suzanne E.L.; Karfeld-Sulzer, Lindsay S.; Smit, Theo H.; Yayon, Avner; Weber, Franz E.; Helder, Marco N.

    2015-01-01

    Abstract Intervertebral disc (IVD) degeneration is etiologically associated with low back pain and is currently only treated in severe cases with spinal fusion. Regenerative medicine attempts to restore degenerated tissue by means of cells, hydrogels, and/or growth factors and can therefore be used to slow, halt, or reverse the degeneration of the IVD in a minimally invasive manner. Previously, the growth factors bone morphogenetic proteins 2 and 7 (BMP-2, -7) were shown to enhance disc regeneration, in vitro and in vivo. Since BMPs have only a short in vivo half-life, and to prevent heterotopic ossification, we evaluated the use of a slow release system for BMP-2 homodimers and BMP-2/7 heterodimers for IVD regeneration. BMP growth factors were conjugated to a fibrin/hyaluronic acid (FB/HA) hydrogel and intradiscally injected in a goat model of mild IVD degeneration to study safety and efficacy. Mild degeneration was induced in five lumbar discs of seven adult Dutch milk goats, by injections with the enzyme chondroitinase ABC. After 12 weeks, discs were treated with either FB/HA-hydrogel only or supplemented with 1 or 5 μg/mL of BMP-2 or BMP-2/7. BMPs were linked to the FB/HA hydrogels using a transglutaminase moiety, to be released through an incorporated plasmin cleavage site. After another 12 weeks, goats were sacrificed and discs were assessed using radiography, MRI T2* mapping, and biochemical and histological analyses. All animals maintained weight throughout the study and no heterotopic bone formation or other adverse effects were noted during follow-up. Radiographs showed significant disc height loss upon induction of mild degeneration. MRI T2* mapping showed strong and significant correlations with biochemistry and histology as shown before. Surprisingly, no differences could be demonstrated in any parameter between intervention groups. To our knowledge, this is the first large animal study evaluating BMPs conjugated to an FB/HA-hydrogel for the

  10. Assessment of Functional and Behavioral Changes Sensitive to Painful Disc Degeneration

    PubMed Central

    Lai, Alon; Moon, Andrew; Purmessur, Devina; Skovrlj, Branko; Winkelstein, Beth A.; Cho, Samuel K.; Hecht, Andrew C.; Iatridis, James C.

    2015-01-01

    The development of an in vivo rodent discogenic pain model can provide insight into mechanisms for painful disc degeneration. Painful disc degeneration in rodents can be inferred by examining responses to external stimuli, observing pain-related behaviors, and measuring functional performance. This study compared the sensitivity of multiple pain and functional assessment methods to disc disruption for identifying the parameters sensitive to painful disc degeneration in rats. Disc degeneration was induced in rats by annular injury with saline injection. The severity of disc degeneration, pain sensitivity, and functional performance were compared to sham and näve control rats. Saline injection induced disc degeneration with decreased disc height and MRI signal intensity as well as more fibrous nucleus pulposus, disorganized annular lamellae and decreased proteoglycan. Rats also demonstrated increased painful behaviors including decreased hindpaw mechanical and thermal sensitivities, increased grooming, and altered gait patterns with hindpaw mechanical hyperalgesia and duration of grooming tests being most sensitive. This is the first study to compare sensitivities of different pain assessment methods in an in vivo rat model of disc degeneration. Hindpaw mechanical sensitivity and duration of grooming were the most sensitive parameters to surgically induced degenerative changes and overall results were suggestive of disc degeneration associated pain. PMID:25731955

  11. ISSLS PRIZE WINNER: INHIBITION OF NF-κB ACTIVITY AMELIORATES AGE-ASSOCIATED DISC DEGENERATION IN A MOUSE MODEL OF ACCELERATED AGING

    PubMed Central

    Nasto, Luigi A.; Seo, Hyoung-Yeon; Robinson, Andria R.; Tilstra, Jeremy S.; Clauson, Cheryl L.; Sowa, Gwendolyn A.; Ngo, Kevin; Dong, Qing; Pola, Enrico; Lee, Joon Y.; Niedernhofer, Laura J.; Kang, James D.; Robbins, Paul D.; Vo, Nam V.

    2012-01-01

    Study Design NF-κB activity was pharmacologically and genetically blocked in an accelerated aging mouse model to mitigate age-related disc degenerative changes. Objective To study the mediatory role of NF-κB signaling pathway in age-dependent intervertebral disc degeneration. Summary of Background Data Aging is a major contributor to intervertebral disc degeneration (IDD), but the molecular mechanism behind this process is poorly understood. NF-κB is a family of transcription factors which play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic NF-κB activation as a culprit in many aging-related diseases, but its role in aging-related IDD has not been adequately explored. We studied the effects of NF-κB inhibition on IDD using a DNA repair-deficient mouse model of accelerated aging (Ercc1-/Δ mice) previously been reported to exhibit age-related IDD. Methods Systemic inhibition of NF-κB activation was achieved either genetically by deletion of one allele of the NF-κB subunit p65 (Ercc1-/Δp65+/- mice) or pharmacologically by chronic intra-peritoneal administration of the Nemo Binding Domain (8K-NBD) peptide to block the formation of the upstream activator of NF-κB, IκB Inducible Kinase (IKK), in Ercc1-/Δ mice. Disc cellularity, total proteoglycan content and proteoglycan synthesis of treated mice and untreated controls were assessed. Results Decreased disc matrix proteoglycan content, a hallmark feature of IDD, and elevated disc NF-κB activity were observed in discs of progeroid Ercc1-/Δ mice and naturally aged wild-type compared to young WT mice. Systemic inhibition of NF-κB by the 8K-NBD peptide in Ercc1-/Δ mice increased disc proteoglycan synthesis and ameriolated loss disc cellularity and matrix proteoglycan. These results were confirmed genetically by using the p65 haploinsufficient Ercc1-/Δp65+/- mice. Conclusion These findings demonstrate that the IKK/NF-κB signaling pathway

  12. Glucosamine loaded injectable silk-in-silk integrated system modulate mechanical properties in bovine ex-vivo degenerated intervertebral disc model.

    PubMed

    Murab, Sumit; Samal, Juhi; Shrivastava, Akshay; Ray, Alok Ranjan; Pandit, Abhay; Ghosh, Sourabh

    2015-07-01

    Injectable hydrogels offer a tremendous potential for treatment of degenerated intervertebral disc due to their ability to withstand complex loading, conforming precisely to the defect spaces and eliminating the need for invasive surgical procedures. We have developed an injectable hydrogel platform of N-acetyl-glucosamine (GlcNAc) loaded silk hollow spheres embedded in silk hydrogel for in situ therapeutic release and enhanced mechanical strength. The assembled silk hydrogel provided adequate structural support to the ex vivo degenerated disc model in a cyclic compression test at par with the native tissue. Spatiotemporal release of GlcNAc in a controlled manner from the silk hollow microspheres trigger enhanced proteoglycan production from ADSCs embedded in the composite system. Role of MAPK and SMAD pathways in increasing proteoglycan production have been explored by immunohistological analysis as a result of the action of GlcNAc on the cells, elucidating the potential of injectable silk microsphere-in-silk hydrogel for the regeneration of degenerated disc tissue. PMID:25934453

  13. Injection of AAV2-BMP2 and AAV2-TIMP1 into the nucleus pulposus slows the course of intervertebral disc degeneration in an in vivo rabbit model

    PubMed Central

    Leckie, Steven K.; Bechara, Bernard P.; Hartman, Robert A.; Sowa, Gwendolyn A.; Woods, Barrett I.; Coelho, Joao P.; Witt, William T.; Dong, Qing D.; Bowman, Brent W.; Bell, Kevin M.; Vo, Nam V.; Wang, Bing; Kang, James D.

    2016-01-01

    BACKGROUND CONTEXT Intervertebral disc degeneration (IDD) is a common cause of back pain. Patients who fail conservative management may face the morbidity of surgery. Alternative treatment modalities could have a significant impact on disease progression and patients’ quality of life. PURPOSE To determine if the injection of a virus vector carrying a therapeutic gene directly into the nucleus pulposus improves the course of IDD. STUDY DESIGN Prospective randomized controlled animal study. METHODS Thirty-four skeletally mature New Zealand white rabbits were used. In the treatment group, L2–L3, L3–L4, and L4–L5 discs were punctured in accordance with a previously validated rabbit annulotomy model for IDD and then subsequently treated with adeno-associated virus serotype 2 (AAV2) vector carrying genes for either bone morphogenetic protein 2 (BMP2) or tissue inhibitor of metalloproteinase 1 (TIMP1). A nonoperative control group, nonpunctured sham surgical group, and punctured control group were also evaluated. Serial magnetic resonance imaging (MRI) studies at 0, 6, and 12 weeks were obtained, and a validated MRI analysis program was used to quantify degeneration. The rabbits were sacrificed at 12 weeks, and L4–L5 discs were analyzed histologically. Viscoelastic properties of the L3–L4 discs were analyzed using uniaxial load normalized displacement testing. Creep curves were mathematically modeled according to a previously validated two-phase exponential model. Serum samples obtained at 0, 6, and 12 weeks were assayed for biochemical evidence of degeneration. RESULTS The punctured group demonstrated MRI and histologic evidence of degeneration as expected. The treatment groups demonstrated less MRI and histologic evidence of degeneration than the punctured group. The serum biochemical marker C-telopeptide of collagen type II increased rapidly in the punctured group, but the treated groups returned to control values by 12 weeks. The treatment groups

  14. MicroRNA in intervertebral disc degeneration.

    PubMed

    Li, Zheng; Yu, Xin; Shen, Jianxiong; Chan, Matthew T V; Wu, William Ka Kei

    2015-06-01

    Aetiology of intervertebral disc degeneration (IDD) is complex, with genetic, developmental, biochemical and biomechanical factors contributing to the disease process. It is becoming obvious that epigenetic processes influence evolution of IDD as strongly as the genetic background. Deregulated phenotypes of nucleus pulposus cells, including differentiation, migration, proliferation and apoptosis, are involved in all stages of progression of human IDD. Non-coding RNAs, including microRNAs, have recently been recognized as important regulators of gene expression. Research into roles of microRNAs in IDD has been very active over the past 5 years. Our review summarizes current research enlightenment towards understanding roles of microRNAs in regulating nucleus pulposus cell functions in IDD. These exciting findings support the notion that specific modulation of microRNAs may represent an attractive approach for management of IDD. PMID:25736871

  15. Gene expression profile analysis of human intervertebral disc degeneration

    PubMed Central

    Chen, Kai; Wu, Dajiang; Zhu, Xiaodong; Ni, Haijian; Wei, Xianzhao; Mao, Ningfang; Xie, Yang; Niu, Yunfei; Li, Ming

    2013-01-01

    In this study, we used microarray analysis to investigate the biogenesis and progression of intervertebral disc degeneration. The gene expression profiles of 37 disc tissue samples obtained from patients with herniated discs and degenerative disc disease collected by the National Cancer Institute Cooperative Tissue Network were analyzed. Differentially expressed genes between more and less degenerated discs were identified by significant analysis of microarray. A total of 555 genes were significantly overexpressed in more degenerated discs with a false discovery rate of < 3%. Functional annotation showed that these genes were significantly associated with membrane-bound vesicles, calcium ion binding and extracellular matrix. Protein-protein interaction analysis showed that these genes, including previously reported genes such as fibronectin, COL2A1 and β-catenin, may play key roles in disc degeneration. Unsupervised clustering indicated that the widely used morphology-based Thompson grading system was only marginally associated with the molecular classification of intervertebral disc degeneration. These findings indicate that detailed, systematic gene analysis may be a useful way of studying the biology of intervertebral disc degeneration. PMID:24130454

  16. Molecular mechanisms of cell death in intervertebral disc degeneration (Review).

    PubMed

    Zhang, Fan; Zhao, Xueling; Shen, Hongxing; Zhang, Caiguo

    2016-06-01

    Intervertebral discs (IVDs) are complex structures that consist of three parts, namely, nucleus pulposus, annulus fibrosus and cartilage endplates. With aging, IVDs gradually degenerate as a consequence of many factors, such as microenvironment changes and cell death. Human clinical trial and animal model studies have documented that cell death, particularly apoptosis and autophagy, significantly contribute to IVD degeneration. The mechanisms underlying this phenomenon include the activation of apoptotic pathways and the regulation of autophagy in response to nutrient deprivation and multiple stresses. In this review, we briefly summarize recent progress in understanding the function and regulation of apoptosis and autophagy signaling pathways. In particular, we focus on studies that reveal the functional mechanisms of these pathways in IVD degeneration. PMID:27121482

  17. Molecular mechanisms of cell death in intervertebral disc degeneration (Review)

    PubMed Central

    ZHANG, FAN; ZHAO, XUELING; SHEN, HONGXING; ZHANG, CAIGUO

    2016-01-01

    Intervertebral discs (IVDs) are complex structures that consist of three parts, namely, nucleus pulposus, annulus fibrosus and cartilage endplates. With aging, IVDs gradually degenerate as a consequence of many factors, such as microenvironment changes and cell death. Human clinical trial and animal model studies have documented that cell death, particularly apoptosis and autophagy, significantly contribute to IVD degeneration. The mechanisms underlying this phenomenon include the activation of apoptotic pathways and the regulation of autophagy in response to nutrient deprivation and multiple stresses. In this review, we briefly summarize recent progress in understanding the function and regulation of apoptosis and autophagy signaling pathways. In particular, we focus on studies that reveal the functional mechanisms of these pathways in IVD degeneration. PMID:27121482

  18. Effect of intervertebral disc degeneration on disc cell viability: a numerical investigation.

    PubMed

    Galbusera, Fabio; Mietsch, Antje; Schmidt, Hendrik; Wilke, Hans-Joachim; Neidlinger-Wilke, Cornelia

    2013-01-01

    Degeneration of the intervertebral disc may be initiated and supported by impairment of the nutrition processes of the disc cells. The effects of degenerative changes on cell nutrition are, however, only partially understood. In this work, a finite volume model was used to investigate the effect of endplate calcification, water loss, reduction of disc height and cyclic mechanical loading on the sustainability of the disc cell population. Oxygen, lactate and glucose diffusion, production and consumption were modelled with non-linear coupled partial differential equations. Oxygen and glucose consumption and lactate production were expressed as a function of local oxygen concentration, pH and cell density. The cell viability criteria were based on local glucose concentration and pH. Considering a disc with normal water content, cell death was initiated in the centre of the nucleus for oxygen, glucose, and lactate diffusivities in the cartilaginous endplate below 20% of the physiological values. The initial cell population could not be sustained even in the non-calcified endplates when a reduction of diffusion inside the disc due to water loss was modelled. Alterations in the disc shape such as height loss, which shortens the transport route between the nutrient sources and the cells, and cyclic mechanical loads, could enhance cell nutrition processes. PMID:21970697

  19. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration

    PubMed Central

    Le Maitre, Christine Lyn; Freemont, Anthony John; Hoyland, Judith Alison

    2007-01-01

    Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescence-associated β-galactosidase (SA-β-gal), and replicative potential. Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-β-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16INK4A and matrix-degrading enzyme gene expression. Our findings indicate that disc cell senescence occurs in vivo and is accelerated in IVD degeneration. Furthermore, the senescent phenotype is associated with increased catabolism, implicating cellular senescence in the pathogenesis of IVD degeneration. PMID:17498290

  20. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration.

    PubMed

    Le Maitre, Christine Lyn; Freemont, Anthony John; Hoyland, Judith Alison

    2007-01-01

    Current evidence implicates intervertebral disc degeneration as a major cause of low back pain, although its pathogenesis is poorly understood. Numerous characteristic features of disc degeneration mimic those seen during ageing but appear to occur at an accelerated rate. We hypothesised that this is due to accelerated cellular senescence, which causes fundamental changes in the ability of disc cells to maintain the intervertebral disc (IVD) matrix, thus leading to IVD degeneration. Cells isolated from non-degenerate and degenerate human tissue were assessed for mean telomere length, senescence-associated beta-galactosidase (SA-beta-gal), and replicative potential. Expression of P16INK4A (increased in cellular senescence) was also investigated in IVD tissue by means of immunohistochemistry. RNA from tissue and cultured cells was used for real-time polymerase chain reaction analysis for matrix metalloproteinase-13, ADAMTS 5 (a disintegrin and metalloprotease with thrombospondin motifs 5), and P16INK4A. Mean telomere length decreased with age in cells from non-degenerate tissue and also decreased with progressive stages of degeneration. In non-degenerate discs, there was an age-related increase in cellular expression of P16INK4A. Cells from degenerate discs (even from young patients) exhibited increased expression of P16INK4A, increased SA-beta-gal staining, and a decrease in replicative potential. Importantly, there was a positive correlation between P16INK4A and matrix-degrading enzyme gene expression. Our findings indicate that disc cell senescence occurs in vivo and is accelerated in IVD degeneration. Furthermore, the senescent phenotype is associated with increased catabolism, implicating cellular senescence in the pathogenesis of IVD degeneration. PMID:17498290

  1. Human cartilage endplate permeability varies with degeneration and intervertebral disc site.

    PubMed

    DeLucca, John F; Cortes, Daniel H; Jacobs, Nathan T; Vresilovic, Edward J; Duncan, Randall L; Elliott, Dawn M

    2016-02-29

    Despite the critical functions the human cartilage endplate (CEP) plays in the intervertebral disc, little is known about its structural and mechanical properties and their changes with degeneration. Quantifying these changes with degeneration is important for understanding how the CEP contributes to the function and pathology of the disc. Therefore the objectives of this study were to quantify the effect of disc degeneration on human CEP mechanical properties, determine the influence of superior and inferior disc site on mechanics and composition, and simulate the role of collagen fibers in CEP and disc mechanics using a validated finite element model. Confined compression data and biochemical composition data were used in a biphasic-swelling model to calculate compressive extrafibrillar elastic and permeability properties. Tensile properties were obtained by applying published tensile test data to an ellipsoidal fiber distribution. Results showed that with degeneration CEP permeability decreased 50-60% suggesting that transport is inhibited in the degenerate disc. CEP fibers are organized parallel to the vertebrae and nucleus pulposus and may contribute to large shear strains (0.1-0.2) and delamination failure of the CEP commonly seen in herniated disc tissue. Fiber-reinforcement also reduces CEP axial strains thereby enhancing fluid flux by a factor of 1.8. Collectively, these results suggest that the structure and mechanics of the CEP may play critical roles in the solute transport and disc mechanics. PMID:26874969

  2. Lumbar intervertebral disc degeneration and related factors in Korean firefighters

    PubMed Central

    Jang, Tae-Won; Ahn, Yeon-Soon; Byun, Junsu; Lee, Jong-In; Kim, Kun-Hyung; Kim, Youngki; Song, Han-Soo; Lee, Chul-Gab; Kwon, Young-Jun; Yoon, Jin-Ha; Jeong, Kyoungsook

    2016-01-01

    Objectives The job of firefighting can cause lumbar burden and low back pain. This study aimed to identify the association between age and lumbar intervertebral disc degeneration and whether the association differs between field and administrative (non-field) firefighters. Methods Subjects were selected using a stratified random sampling method. Firefighters were stratified by geographic area, gender, age and type of job. First, 25 fire stations were randomly sampled considering regional distribution. Then firefighters were stratified by gender, age and their job and randomly selected among the strata. A questionnaire survey and MRI scans were performed, and then four radiologists used Pfirrmann classification methods to determine the grade of lumbar intervertebral disc degeneration. Results Pfirrmann grade increased with lumbar intervertebral disc level. Analysis of covariance showed that age was significantly associated with lumbar intervertebral disc degeneration (p<0.05). The value of β (parameter estimate) was positive at all lumbar intervertebral disc levels and was higher in the field group than in the administrative group at each level. In logistic regression analysis, type of job was statistically significant only with regard to the L4–5 intervertebral disc (OR 3.498, 95% CI 1.241 to 9.860). Conclusions Lumbar intervertebral disc degeneration is associated with age, and field work such as firefighting, emergency and rescue may accelerate degeneration in the L4–5 intervertebral disc. The effects of field work on lumbar intervertebral disc degeneration were not clear in discs other than at the level L4–5. PMID:27354080

  3. Modic Changes and Disc Degeneration Caused by Inoculation of Propionibacterium acnes inside Intervertebral Discs of Rabbits: A Pilot Study.

    PubMed

    Chen, Zhe; Zheng, Yuehuan; Yuan, Ye; Jiao, Yucheng; Xiao, Jiaqi; Zhou, Zezhu; Cao, Peng

    2016-01-01

    Purpose. To investigate whether P. acnes could induce disc degeneration and Modic changes when inoculated into the discs of rabbits. Method. A wild-type strain of P. acnes isolated from a patient associated with Modic change and disc degeneration was inoculated into the intervertebral discs of rabbits. Meanwhile, S. aureus was injected into the discs to establish a model of discitis as the comparison and a standard strain of P. acnes was inoculated as the control. MRI and histological change were observed. Results. Both the P. acnes-inoculated and S. aureus-inoculated rabbits showed hyperintense signals at endplates and hypointense signals at nucleus pulposus on T2WI. However, P. acnes only resulted in moderate disc degeneration and endplates rupture in histological examination, which was different from the pathological change of discitis caused by S. aureus. In addition, higher death rates (2/3 versus 0/5) were observed in S. aureus-inoculated rabbits. Conclusion. Compared to S. aureus, the pathological change caused by P. acnes would be considered as Modic-I change and disc degeneration rather than a discitis. PMID:26925420

  4. Effect of autologous platelet-rich plasma-releasate on intervertebral disc degeneration in the rabbit anular puncture model: a preclinical study

    PubMed Central

    2012-01-01

    Introduction Platelet-rich plasma (PRP) is a fraction of plasma in which several growth factors are concentrated at high levels. The active soluble releasate isolated following platelet activation of PRP (PRP-releasate) has been demonstrated to stimulate the metabolism of IVD cells in vitro. The in vivo effect of PRP-releasate on degenerated IVD remains unknown. The purpose of this study was to determine the reparative effects of autologous PRP-releasate on degenerated intervertebral discs (IVDs). Methods To induce disc degeneration, New Zealand white rabbits (n = 12) received anular puncture in two noncontiguous discs. Autologous PRP and PPP (platelet-poor plasma) were isolated from fresh blood using two centrifugation techniques. Four weeks after the initial puncture, releasate isolated from clotted PPP or PRP (PPP- or PRP-releasate), or phosphate-buffered saline (PBS; control) was injected into the punctured discs. Disc height, magnetic resonance imaging (MRI) T2-mapping and histology were assessed. Results Anular puncture produced a consistent disc narrowing within four weeks. PRP-releasate induced a statistically significant restoration of disc height (PRP vs. PPP and PBS, P<0.05). In T2-quantification, the mean T2-values of the nucleus pulposus (NP) and anulus fibrosus (AF) of the discs were not significantly different among the three treatment groups. Histologically, the number of chondrocyte-like cells was significantly higher in the discs injected with PRP-releasate compared to that with PBS. Conclusions The administration of active PRP-releasate induced a reparative effect on rabbit degenerated IVDs. The results of this study suggest that the use of autologous PRP-releasate is safe and can lead to a clinical application for IVD degeneration. PMID:23127251

  5. Does lumbar facet arthrosis precede disc degeneration? A postmortem study.

    PubMed

    Eubanks, Jason David; Lee, Michael J; Cassinelli, Ezequiel; Ahn, Nicholas U

    2007-11-01

    It is believed lumbar degeneration begins in the disc, where desiccation and collapse lead to instability and compensatory facet arthrosis. We explored the contrary contention that facet degeneration precedes disc degeneration by examining 647 skeletal lumbar spines. Using facet osteophytosis as a measure of facet degeneration and vertebral rim osteophytosis as a measure of disc degeneration, we assumed bone degeneration in both locations equally reflected the progression of those in the soft tissues. We graded arthrosis Grade 0 to 4 on a continuum from no arthritis to ankylosis. The data were analyzed for different age groups to examine patterns of degeneration with age. Specimens younger than 30 years of age had a higher prevalence of facet osteophytosis compared with vertebral rim osteophotosis at L1-L2 and L2-L3. Specimens aged 30 to 39 years showed more facet osteophytosis than vertebral rim osteophytosis at L4-L5. Specimens older than 40 years, however, showed more vertebral rim osteophytosis compared with facet osteophytosis at all levels except L4-L5 and L5-S1. This skeletal study suggests facet osteophytosis appears early in the degenerative process, preceding vertebral rim osteophytosis of degenerating intervertebral discs. However, once facets begin deteriorating with age, vertebral rim osteophytosis overtakes continued facet osteophytosis. These data challenge the belief that facet osteophytosis follows vertebral rim osteophytosis; rather, it appears vertebral rim osteophytosis progresses more rapidly in later years, but facet osteophotosis occurs early, predominating in younger individuals. PMID:17767079

  6. Correlations between quantitative T2 and T1ρ MRI, mechanical properties and biochemical composition in a rabbit lumbar intervertebral disc degeneration model.

    PubMed

    Gullbrand, Sarah E; Ashinsky, Beth G; Martin, John T; Pickup, Stephen; Smith, Lachlan J; Mauck, Robert L; Smith, Harvey E

    2016-08-01

    Improved diagnostic measures for intervertebral disc degeneration are necessary to facilitate early detection and treatment. The aim of this study was to correlate changes in mechanical and biochemical properties with the quantitative MRI parameters T2 and T1ρ in rabbit lumbar discs using an ex vivo chymopapain digestion model. Rabbit lumbar spinal motion segments from animals less than 6 months of age were injected with 100 μl of saline (control) or chymopapain at 3, 15, or 100 U/ml (n = 5 per group). T2 and T1ρ MRI series were obtained at 4.7T. Specimens were mechanically tested in tension-compression and creep. Normalized nucleus pulposus (NP) water and GAG contents were quantified. Stepwise multiple linear regression was performed to determine which parameters contributed significantly to changes in NP T2 and T1ρ. When all groups were included, multiple regression yielded a model with GAG, compressive modulus, and the creep time constants as variables significantly impacting T2 (multiple r(2)  = 0.64, p = 0.006). GAG and neutral zone (NZ) modulus were identified as variables contributing to T1ρ (multiple r(2)  = 0.28, p = 0.08). When specimens with advanced degeneration were excluded from the multiple regression analysis, T2 was significantly predicted by compressive modulus, τ1, and water content (multiple r(2)  = 0.71, p = 0.009), while no variables were significant predictors in the model for T1ρ. These results indicate that quantitative MRI can detect changes in the mechanical and biochemical properties of the degenerated disc. T2 may be more sensitive to early stage degenerative changes than T1ρ, while both quantitative MRI parameters are sensitive to advanced degeneration. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1382-1388, 2016. PMID:27105019

  7. Effect of disc degeneration on the muscle recruitment pattern in upright posture: a computational analysis.

    PubMed

    Kim, Young Eun; Choi, Hae Won

    2015-01-01

    Based on the sensor driving control mechanism model, the effect of disc degeneration on the trunk muscle recruitment (TMR) pattern was analysed in erect standing posture. A previously developed computational model was used for this analysis, with modifications incorporating the T12-L1 motion segment and additional muscle fascicles. To generate disc degeneration at three different levels (L3-L4, L4-L5, or L5-S1), the material properties of the ground matrix of the annulus and bulk modulus of the nucleus were reduced. The finite element method combined with an optimization technique was applied to calculate the muscle forces. Minimization of deviations in the averaged tensile stress in the annulus fibres at the outermost layer in the five discs was selected for muscle force calculations. The results indicated that the disc degeneration noticeably increased the activation of the superficial muscle (IT and R) even though there was no clear change in the longissimus thoracis. Unlike some of the superficial muscles, activation in the deep muscles (multifidus (ML, MS, MT), LL and Q) was decreased. The change in TMR pattern generated an intervertebral disc angle difference and nucleus pressure increased in the upper level. These differences are expected to be functional in that they reduce the stress at the degenerated disc by changing the muscle activation, which slows down the progress of disc degeneration. PMID:25025614

  8. Rat tail static compression model mimics extracellular matrix metabolic imbalances of matrix metalloproteinases, aggrecanases, and tissue inhibitors of metalloproteinases in intervertebral disc degeneration

    PubMed Central

    2012-01-01

    Introduction The longitudinal degradation mechanism of extracellular matrix (ECM) in the interbertebral disc remains unclear. Our objective was to elucidate catabolic and anabolic gene expression profiles and their balances in intervertebral disc degeneration using a static compression model. Methods Forty-eight 12-week-old male Sprague-Dawley rat tails were instrumented with an Ilizarov-type device with springs and loaded statically at 1.3 MPa for up to 56 days. Experimental loaded and distal-unloaded control discs were harvested and analyzed by real-time reverse transcription-polymerase chain reaction (PCR) messenger RNA quantification for catabolic genes [matrix metalloproteinase (MMP)-1a, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5], anti-catabolic genes [tissue inhibitor of metalloproteinases (TIMP)-1, TIMP-2, and TIMP-3], ECM genes [aggrecan-1, collagen type 1-α1, and collagen type 2-α1], and pro-inflammatory cytokine genes [tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, and IL-6]. Immunohistochemistry for MMP-3, ADAMTS-4, ADAMTS-5, TIMP-1, TIMP-2, and TIMP-3 was performed to assess their protein expression level and distribution. The presence of MMP- and aggrecanase-cleaved aggrecan neoepitopes was similarly investigated to evaluate aggrecanolytic activity. Results Quantitative PCR demonstrated up-regulation of all MMPs and ADAMTS-4 but not ADAMTS-5. TIMP-1 and TIMP-2 were almost unchanged while TIMP-3 was down-regulated. Down-regulation of aggrecan-1 and collagen type 2-α1 and up-regulation of collagen type 1-α1 were observed. Despite TNF-α elevation, ILs developed little to no up-regulation. Immunohistochemistry showed, in the nucleus pulposus, the percentage of immunopositive cells of MMP-cleaved aggrecan neoepitope increased from 7 through 56 days with increased MMP-3 and decreased TIMP-1 and TIMP-2 immunopositivity. The percentage of immunopositive cells

  9. Human L3L4 intervertebral disc mean 3D shape, modes of variation, and their relationship to degeneration

    PubMed Central

    Peloquin, John M.; Yoder, Jonathon H.; Jacobs, Nathan T.; Moon, Sung M.; Wright, Alexander C.; Vresilovic, Edward J.; Elliott, Dawn M.

    2014-01-01

    Intervertebral disc mechanics are affected by both disc shape and disc degeneration, which in turn each affect the other; disc mechanics additionally have a role in the etiology of disc degeneration. Finite element analysis (FEA) is a favored tool to investigate these relationships, but limited data for intervertebral disc 3D shape has forced the use of simplified or single-subject geometries, with the effect of inter-individual shape variation investigated only in specialized studies. Similarly, most data on disc shape variation with degeneration is based on 2D mid-sagittal images, which incompletely define 3D shape changes. Therefore, the objective of this study was to quantify inter-individual disc shape variation in 3D, classify this variation into independently-occurring modes using a statistical shape model, and identify correlations between disc shape and degeneration. Three-dimensional disc shapes were obtained from MRI of 13 human male cadaver L3L4 discs. An average disc shape and four major modes of shape variation (representing 90% of the variance) were identified. The first mode represented disc axial area and was significantly correlated to degeneration (R2 = 0.44), indicating larger axial area in degenerate discs. Disc height variation occurred in three distinct modes, each also involving non-height variation. The statistical shape model provides an average L3L4 disc shape for FEA that is fully defined in 3D, and makes it convenient to generate a set of shapes with which to represent aggregate inter-individual variation. Degeneration grade-specific shapes can also be generated. To facilitate application, the model is included in this paper’s supplemental content. PMID:24792581

  10. Soft tissue ossification and condylar cartilage degeneration following TMJ disc perforation in a rabbit pilot study

    PubMed Central

    Embree, Mildred C.; Iwaoka, George M.; Kong, Danielle; Martin, Brittany N.; Patel, Ryan K.; Lee, Andrew; Nathan, John M.; Eisig, Sidney B.; Safarov, Aram; Koslovsky, David A; Koch, Alia; Romanov, Alex; Mao, Jeremy J

    2015-01-01

    Objective There are limited clinical treatments for temporomandibular joint pathologies, including degenerative disease, disc perforation and heterotopic ossification. One barrier hindering the development of new therapies is that animal models recapitulating TMJ diseases are poorly established. The objective of this study was to develop an animal model for TMJ cartilage degeneration and disc pathology, including disc perforation and soft tissue heterotopic ossification. Methods New Zealand white rabbits (n=9 rabbits) underwent unilateral TMJ disc perforation surgery and sham surgery on the contralateral side. A 2.5 mm defect was created using a punch biopsy in rabbit TMJ disc. The TMJ condyles and discs were evaluated macroscopically and histologically after 4, 8 and 12 weeks. Condyles were blindly scored by 4 independent observers using OARSI recommendations for macroscopic and histopathological scoring of osteoarthritis in rabbit tissues. Results Histological evidence of TMJ condylar cartilage degeneration was apparent in experimental condyles following disc perforation relative to sham controls after 4 and 8 weeks, including surface fissures and loss of Safranin O staining. At 12 weeks, OARSI scores indicated experimental condylar cartilage erosion into the subchondral bone. Most strikingly, heterotopic ossification occurred within the TMJ disc upon perforation injury in 6 rabbits after 8 and 12 weeks. Conclusion We report for the first time a rabbit TMJ injury model that demonstrates condylar cartilage degeneration and disc ossification, which is indispensible for testing the efficacy of potential TMJ therapies. PMID:25573797

  11. Progranulin Knockout Accelerates Intervertebral Disc Degeneration in Aging Mice

    PubMed Central

    Zhao, Yun-peng; Tian, Qing-yun; Liu, Ben; Cuellar, Jason; Richbourgh, Brendon; Jia, Tang-hong; Liu, Chuan-ju

    2015-01-01

    Intervertebral disc (IVD) degeneration is a common degenerative disease, yet much is unknown about the mechanisms during its pathogenesis. Herein we investigated whether progranulin (PGRN), a chondroprotective growth factor, is associated with IVD degeneration. PGRN was detectable in both human and murine IVD. The levels of PGRN were upregulated in murine IVD tissue during aging process. Loss of PGRN resulted in an early onset of degenerative changes in the IVD tissue and altered expressions of the degeneration-associated molecules in the mouse IVD tissue. Moreover, PGRN knockout mice exhibited accelerated IVD matrix degeneration, abnormal bone formation and exaggerated bone resorption in vertebra with aging. The acceleration of IVD degeneration observed in PGRN null mice was probably due to the enhanced activation of NF-κB signaling and β-catenin signaling. Taken together, PGRN may play a critical role in homeostasis of IVD, and may serve as a potential molecular target for prevention and treatment of disc degenerative diseases. PMID:25777988

  12. Protective Effects of Cannabidiol on Lesion-Induced Intervertebral Disc Degeneration

    PubMed Central

    Silveira, João W.; Issy, Ana Carolina; Castania, Vitor A.; Salmon, Carlos E. G.; Nogueira-Barbosa, Marcello H.; Guimarães, Francisco S.; Defino, Helton L. A.; Bel, Elaine Del

    2014-01-01

    Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabidiol on intervertebral disc degeneration have not been investigated yet. The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses. Disc injury was induced in the tail of male Wistar rats via a single needle puncture. The discs selected for injury were punctured percutaneously using a 21-gauge needle. MRI and histological evaluation were employed to assess the results. The effects of intradiscal injection of cannabidiol (30, 60 or 120 nmol) injected immediately after lesion were analyzed acutely (2 days) by MRI. The experimental group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses 15 days after lesion/cannabidiol injection. The needle puncture produced a significant disc injury detected both by MRI and histological analyses. Cannabidiol significantly attenuated the effects of disc injury induced by the needle puncture. Considering that cannabidiol presents an extremely safe profile and is currently being used clinically, these results suggest that this compound could be useful in the treatment of intervertebral disc degeneration. PMID:25517414

  13. Biologic Treatment of Mild and Moderate Intervertebral Disc Degeneration

    PubMed Central

    Vasiliadis, Elias S; Pneumaticos, Spyros G; Evangelopoulos, Demitrios S; Papavassiliou, Athanasios G

    2014-01-01

    Disc degeneration is the most common cause of back pain in adults and has enormous socioeconomic implications. Conservative management is ineffective in most cases, and results of surgical treatment have not yet reached desirable standards. Biologic treatment options are an alternative to the above conventional management and have become very attractive in recent years. The present review highlights the currently available biologic treatment options in mild and moderate disc degeneration, where a potential for regeneration still exists. Biologic treatment options include protein-based and cell-based therapies. Protein-based therapies involve administration of biologic factors into the intervertebral disc to enhance matrix synthesis, delay degeneration or impede inflammation. These factors can be delivered by an intradiscal injection, alone or in combination with cells or tissue scaffolds and by gene therapy. Cell-based therapies comprise treatment strategies that aim to either replace necrotic or apoptotic cells, or minimize cell death. Cell-based therapies are more appropriate in moderate stages of degenerated disc disease, when cell population is diminished; therefore, the effect of administration of growth factors would be insufficient. Although clinical application of biologic treatments is far from being an everyday practice, the existing studies demonstrate promising results that will allow the future design of more sophisticated methods of biologic intervention to treat intervertebral disc degeneration. PMID:25171110

  14. Degenerated human intervertebral discs contain autoantibodies against extracellular matrix proteins.

    PubMed

    Capossela, S; Schläfli, P; Bertolo, A; Janner, T; Stadler, B M; Pötzel, T; Baur, M; Stoyanov, J V

    2014-01-01

    Degeneration of intervertebral discs (IVDs) is associated with back pain and elevated levels of inflammatory cells. It has been hypothesised that discogenic pain is a direct result of vascular and neural ingrowth along annulus fissures, which may expose the avascular nucleus pulposus (NP) to the systemic circulation and induce an autoimmune reaction. In this study, we confirmed our previous observation of antibodies in human degenerated and post-traumatic IVDs cultured in vitro. We hypothesised that the presence of antibodies was due to an autoimmune reaction against specific proteins of the disc. Furthermore we identified antigens which possibly trigger an autoimmune response in degenerative disc diseases. We demonstrated that degenerated and post-traumatic IVDs contain IgG antibodies against typical extracellular proteins of the disc, particularly proteins of the NP. We identified IgGs against collagen type II and aggrecan, confirming an autoimmune reaction against the normally immune privileged NP. We also found specific IgGs against collagens types I and V, but not against collagen type III. In conclusion, this study confirmed the association between disc degeneration and autoimmunity, and may open the avenue for future studies on developing prognostic, diagnostic and therapy-monitoring markers for degenerative disc diseases. PMID:24706108

  15. Disc in Flames: Roles of TNF-α and IL-1β in Intervertebral Disc Degeneration

    PubMed Central

    Johnson, Zariel I.; Schoepflin, Zachary R.; Choi, Hyowon; Shapiro, Irving M.; Risbud, Makarand V.

    2016-01-01

    The intervertebral disc is an important mechanical structure that allows range of motion of the spinal column. Degeneration of the intervertebral disc, incited by aging, traumatic insult, genetic predisposition, or other factors, is often defined by functional and structural changes in the tissue, including excessive breakdown of the extracellular matrix, increased disc cell senescence and death, and compromised biomechanical function of the tissue. Intervertebral disc degeneration is strongly correlated with low back pain, which is a highly prevalent and costly condition, significantly contributing to loss in productivity and health care costs. Disc degeneration is a chronic, progressive condition, and current therapies are limited and often focused on symptomatic pain relief rather than curtailing the progression of the disease. Inflammatory processes, exacerbated by cytokines TNF-α and IL-1β are believed to be key mediators of disc degeneration and low back pain. In this review, we describe the contributions of TNF-α and IL-1β to changes seen during disc degeneration at the cellular and tissue level, new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes. PMID:26388614

  16. Delivery systems for the treatment of degenerated intervertebral discs.

    PubMed

    Blanquer, S B G; Grijpma, D W; Poot, A A

    2015-04-01

    The intervertebral disc (IVD) is the most avascular and acellular tissue in the body and therefore prone to degeneration. During IVD degeneration, the balance between anabolic and catabolic processes in the disc is deregulated, amongst others leading to alteration of extracellular matrix production, abnormal enzyme activities and production of pro-inflammatory substances like cytokines. The established treatment strategy for IVD degeneration consists of physiotherapy, pain medication by drug therapy and if necessary surgery. This approach, however, has shown limited success. Alternative strategies to increase and prolong the effects of bioactive agents and to reverse the process of IVD degeneration include the use of delivery systems for drugs, proteins, cells and genes. In view of the specific anatomy and physiology of the IVD and depending on the strategy of the therapy, different delivery systems have been developed which are reviewed in this article. PMID:25451138

  17. MicroRNAs: New players in intervertebral disc degeneration.

    PubMed

    Wang, Cheng; Wang, Wen-Jun; Yan, Yi-Guo; Xiang, Yong-Xiao; Zhang, Jian; Tang, Zhi-Han; Jiang, Zhi-Sheng

    2015-10-23

    Chronic low back pain is generally attributed to intervertebral disc (IVD) degeneration (IDD), which is closely associated with apoptosis, extracellular matrix (ECM) disruption, cell proliferation and inflammatory response. Currently, there is no clinical therapy targeting the pathophysiology of disc degeneration. microRNAs (miRNAs) are a class of small noncoding RNA molecules that negatively regulate gene expression at the post-transcriptional levels. miRNAs not only regulate many normal physiological processes, but also play an important role in the development of most disorders, including degenerative disc disease. A variety of miRNAs are differentially expressed in degenerative human IVD tissues and cells. Among these, some of the miRNAs have been shown to be involved in multiple pathological processes during disc degeneration, including apoptosis, ECM degradation, cell proliferation and inflammatory response. This review will mainly focus on the expression profiles, roles, and therapeutic implications of miRNAs in IDD. With continued efforts, restoration of dysregulated miRNA expression may represent a promising biological treatment approach for mitigating or reversing IVD degeneration. PMID:26368266

  18. Biological treatment strategies for disc degeneration: potentials and shortcomings

    PubMed Central

    Nerlich, Andreas G.; Boos, Norbert

    2006-01-01

    Recent advances in molecular biology, cell biology and material sciences have opened a new emerging field of techniques for the treatment of musculoskeletal disorders. These new treatment modalities aim for biological repair of the affected tissues by introducing cell-based tissue replacements, genetic modifications of resident cells or a combination thereof. So far, these techniques have been successfully applied to various tissues such as bone and cartilage. However, application of these treatment modalities to cure intervertebral disc degeneration is in its very early stages and mostly limited to experimental studies in vitro or in animal studies. We will discuss the potential and possible shortcomings of current approaches to biologically cure disc degeneration by gene therapy or tissue engineering. Despite the increasing number of studies examining the therapeutic potential of biological treatment strategies, a practicable solution to routinely cure disc degeneration might not be available in the near future. However, knowledge gained from these attempts might be applied in a foreseeable future to cure the low back pain that often accompanies disc degeneration and therefore be beneficial for the patient. PMID:16983559

  19. Clinical experience in cell-based therapeutics: disc chondrocyte transplantation A treatment for degenerated or damaged intervertebral disc.

    PubMed

    Meisel, Hans Jörg; Siodla, Vilma; Ganey, Timothy; Minkus, Yvonne; Hutton, William C; Alasevic, Olivera J

    2007-02-01

    Disc herniation treated by discectomy results in a significant loss of nucleus material and disc height. Biological restoration through the use of autologous disc chondrocyte transplantation offers a potential to achieve functional integration of disc metabolism and mechanics. Chondrocytes that have been removed from damaged cartilaginous tissues maintain a capacity to proliferate, produce and secrete matrix components and respond to physical stimuli such as dynamic loading. Nucleus regeneration using autologous cultured disc-derived chondrocytes (ADCT) has been demonstrated in a canine model and in clinical pilot studies. In 2002 a prospective, controlled, randomised, multi-center study, EuroDISC, comparing safety and efficacy of autologous disc chondrocyte transplant, chondrotransplant DISC, plus discectomy (ADCT), with discectomy alone was initiated. A dog model was used to investigate the hypothesis that autologous disc chondrocytes can be used to repair damaged intervertebral disc. Disc chondrocytes were harvested and expanded in culture under controlled and defined conditions, returned to the same animals from which they had been sampled (autologous transplantation) via percutaneous delivery. The animals were analyzed at specific times after transplantation by several methods to examine whether disc chondrocytes integrated with the surrounding tissue, produced the appropriate intervertebral disc extracellular matrix, and might provide a formative solution to disc repair. The clinical goals of the EuroDISC study, were to provide long-term pain relief, maintain disc height and prevent adjacent segment disease. Interim analysis was performed after 2 years; Oswestry (low back pain/disability), Quebec Back-Pain Disability Scale, as well as Prolo and VAS score were used for the evaluation. Disc height was assessed by MRI. In the context of degenerative changes in an injury model: () autologous disc chondrocytes were expended in culture and returned to the disc by a

  20. Angiogenesis in the degeneration of the lumbar intervertebral disc

    PubMed Central

    David, Gh; Iencean, SM; Mohan, A

    2010-01-01

    The goal of the study is to show the histological and biochemical changes that indicate the angiogenesis of the intervertebral disc in lumbar intervertebral disc hernia and the existence of epidemiological correlations between these changes and the risk factors of lumbar intervertebral disc hernia, as well as the patient's quality of life (QOL). We have studied 50 patients aged between 18 and 73 years old, who have undergone lumbar intervertebral disc hernia surgery, making fibroblast growth factor and vascular endothelial growth factor level measurements, as elements in the process of appreciating the disc angiogenesis. Also, pre–surgery and post–surgery QOL has been measured, as well as the intensity of the pain syndrome. We have identified factors capable of stimulating vascular endothelial growth (VEGF, FGF–2) for the examined disc material, but histological examination did not show angiogenesis. The process of angiogenesis at the degenerated intervertebral disc level affects the patient's quality of life both pre and postoperatively, and may be a predictive factor for the post–operative results. Patients can prevent the appearance of angiogenesis type degenerative processes of the intervertebral disc by avoiding angiogenesis correlated factors (weight control, physical effort, and smoking). PMID:20968201

  1. Disc cell senescence in intervertebral disc degeneration: Causes and molecular pathways

    PubMed Central

    Feng, Chencheng; Liu, Huan; Yang, Minghui; Zhang, Yang; Huang, Bo; Zhou, Yue

    2016-01-01

    ABSTRACT The accumulation of senescent disc cells in degenerative intervertebral disc (IVD) suggests the detrimental roles of cell senescence in the pathogenesis of intervertebral disc degeneration (IDD). Disc cell senescence decreased the number of functional cells in IVD. Moreover, the senescent disc cells were supposed to accelerate the process of IDD via their aberrant paracrine effects by which senescent cells cause the senescence of neighboring cells and enhance the matrix catabolism and inflammation in IVD. Thus, anti-senescence has been proposed as a novel therapeutic target for IDD. However, the development of anti-senescence therapy is based on our understanding of the molecular mechanism of disc cell senescence. In this review, we focused on the molecular mechanism of disc cell senescence, including the causes and various molecular pathways. We found that, during the process of IDD, age-related damages together with degenerative external stimuli activated both p53-p21-Rb and p16-Rb pathways to induce disc cell senescence. Meanwhile, disc cell senescence was regulated by multiple signaling pathways, suggesting the complex regulating network of disc cell senescence. To understand the mechanism of disc cell senescence better contributes to developing the anti-senescence-based therapies for IDD. PMID:27192096

  2. Role of Cytokines in Intervertebral Disc Degeneration: Pain and Disc-content

    PubMed Central

    Risbud, Makarand V.; Shapiro, Irving. M

    2014-01-01

    Degeneration of the intervertebral disc is the major contributor to back/neck and radicular pain. It is characterized by an elevation in levels of the inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 α/β, IL-6 and IL-17 secreted by the disc cells themselves; these cytokines promote matrix degradation, chemokine production and changes in cell phenotype. The resulting imbalance between catabolic and anabolic responses leads to degeneration, as well as herniation and radicular pain. Release of chemokines from degenerating discs promote infiltration and activation of T and B cells, macrophages, neutrophils, and mast cells further amplifying the inflammatory cascade. Immunocyte migration into the disc is accompanied by the appearance of microvasculature and nerve fibers arising from the dorsal root ganglion (DRG). In this inflammatory milieu, neurogenic factors in particular nerve growth factor (NGF) and brain-derive neurotrophic factor (BDNF) generated by disc and immune cells induce expression of pain associated cation channels in DRGs. Depolarization of these channels is likely to promote discogenic and radicular pain and reinforce the cytokine-mediated degenerative cascade. Taken together, the enhanced understanding of the contribution of cytokines and immune cells to catabolic and nociceptive processes provide new targets for treating symptomatic disc disease. PMID:24166242

  3. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc and characteristics of intervertebral disc degeneration.

    PubMed

    Bergknut, Niklas; Smolders, Lucas A; Grinwis, Guy C M; Hagman, Ragnvi; Lagerstedt, Anne-Sofie; Hazewinkel, Herman A W; Tryfonidou, Marianna A; Meij, Björn P

    2013-03-01

    Intervertebral disc (IVD) degeneration is common in dogs and can give rise to a number of diseases, such as IVD herniation, cervical spondylomyelopathy, and degenerative lumbosacral stenosis. Although there have been many reports and reviews on the clinical aspects of canine IVD disease, few reports have discussed and reviewed the process of IVD degeneration. In this first part of a two-part review, the anatomy, physiology, histopathology, and biochemical and biomechanical characteristics of the healthy and degenerated IVD are described. In Part 2, the aspects of IVD degeneration in chondrodystrophic and non-chondrodystrophic dog breeds are discussed in depth. PMID:23177522

  4. Chondroadherin Fragmentation Mediated by the Protease HTRA1 Distinguishes Human Intervertebral Disc Degeneration from Normal Aging*

    PubMed Central

    Akhatib, Bashar; Önnerfjord, Patrik; Gawri, Rahul; Ouellet, Jean; Jarzem, Peter; Heinegård, Dick; Mort, John; Roughley, Peter; Haglund, Lisbet

    2013-01-01

    Chondroadherin, a member of the leucine-rich repeat family, has previously been demonstrated to be fragmented in some juveniles with idiopathic scoliosis. This observation led us to investigate adults with disc degeneration. Immunoblotting analysis demonstrated that non-degenerate discs from three different age groups show no chondroadherin fragmentation. Furthermore, the chondroadherin fragments in adult degenerate disc and the juvenile scoliotic disc were compared via immunoblot analysis and appeared to have a similar size. We then investigated whether or not chondroadherin fragmentation increases with the severity of disc degeneration. Three different samples with different severities were chosen from the same disc, and chondroadherin fragmentation was found to be more abundant with increasing severity of degeneration. This observation led us to the creation of a neoepitope antibody to the cleavage site observed. We then observed that the cleavage site in adult degenerate discs and juvenile scoliotic discs was identical as confirmed by the neoepitope antibody. Consequently, investigation of the protease capable of cleaving chondroadherin at this site was necessary. In vitro digests of disc tissue demonstrated that ADAMTS-4 and -5; cathepsins K, B, and L; and MMP-3, -7, -12, and -13 were incapable of cleavage of chondroadherin at this site and that HTRA1 was indeed the only protease capable. Furthermore, increased protein levels of the processed form of HTRA1 were demonstrated in degenerate disc tissues via immunoblotting. The results suggest that chondroadherin fragmentation can be used as a biomarker to distinguish the processes of disc degeneration from normal aging. PMID:23673665

  5. Blocking the Function of Inflammatory Cytokines and Mediators by Using IL-10 and TGF-β: A Potential Biological Immunotherapy for Intervertebral Disc Degeneration in a Beagle Model

    PubMed Central

    Li, Wei; Liu, Tianyi; Wu, Liangliang; Chen, Chun; Jia, Zhiwei; Bai, Xuedong; Ruan, Dike

    2014-01-01

    The debilitating effects of lower back pain are a major health issue worldwide. A variety of factors contribute to this, and oftentimes intervertebral disk degeneration (IDD) is an underlying cause of this disorder. Inflammation contributes to IDD, and inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, play key roles in the pathology of IDD. Therefore, the development of treatments that inhibit the expression and/or effects of TNF-α and IL-1β in IDD patients should be a promising therapeutic approach to consider. This study characterized the potential to suppress inflammatory cytokine production in degenerative intervertebral disc (NP) cells by treatment with IL-10 and TGF-β in a canine model of IDD. IDD was induced surgically in six male beagles, and degenerative NP cells were isolated and cultured for in vitro studies on cytokine production. Cultured degenerative NP cells were divided into four experimental treatment groups: untreated control, IL-10-treated, TGF-β-treated, and IL-10- plus TGF-β-treated cells. Cultured normal NP cells served as a control group. TNF-α expression was evaluated by fluorescence activated cell sorting (FACS) analysis and enzyme-linked immunosorbent assay (ELISA); moreover, ELISA and real-time PCR were also performed to evaluate the effect of IL-10 and TGF-β on NP cell cytokine expression in vitro. Our results demonstrated that IL-10 and TGF-β treatment suppressed the expression of IL-1β and TNF-α and inhibited the development of inflammatory responses. These data suggest that IL-10 and TGF-β should be evaluated as therapeutic approaches for the treatment of lower back pain mediated by IDD. PMID:25264742

  6. Biological repair of the degenerated intervertebral disc by the injection of growth factors

    PubMed Central

    2008-01-01

    The homeostasis of intervertebral disc (IVD) tissues is accomplished through a complex and precise coordination of a variety of substances, including cytokines, growth factors, enzymes and enzyme inhibitors. Recent biological therapeutic strategies for disc degeneration have included attempts to up-regulate the production of key matrix proteins or to down-regulate the catabolic events induced by pro-inflammatory cytokines. Several approaches to deliver these therapeutic biologic agents have been proposed and tested in a preclinical setting. One of the most advanced biological therapeutic approaches to regenerate or repair a degenerated disc is the injection of a recombinant growth factor. Abundant evidence for the efficacy of growth factor injection therapy for the treatment of IVD degeneration can be found in preclinical animal studies. Recent data obtained from animal studies on changes in cytokine expression following growth factor injection illustrate the great potential for patients with chronic discogenic low back pain. The first clinical trial for growth factor injection has been initiated and the results of that study may prove the usefulness of growth factor injection for treating the symptoms of patients with degenerative disc diseases. The focus of this review article is the effects of an in vivo injection of growth factors on the biological repair of the degenerated intervertebral disc in animal models. The effects of growth factor injection on the symptoms of patients with low back pain, the therapeutic target of growth factor injection and the limitations of the efficacy of growth factor therapy are also reviewed. Further quantitative studies on the effect of growth factor injection on pain generation and the long term effects on the endplate and cell survival after an injection using large animals are needed. An international academic-industrial consortium addressing these aims, such as was achieved for osteoarthritis (The Osteoarthritis Initiative

  7. Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration

    PubMed Central

    Nasto, Luigi A.; Robinson, Andria R.; Ngo, Kevin; Clauson, Cheryl L.; Dong, Qing; St. Croix, Claudette; Sowa, Gwendolyn; Pola, Enrico; Robbins, Paul D.; Kang, James; Niedernhofer, Laura J.; Wipf, Peter; Vo, Nam V.

    2013-01-01

    Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O2) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O2). Human disc cells grown at 20% O2 showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O2. Importantly, we demonstrated that treatment of accelerated aging Ercc1−/Δmice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1−/Δmice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD. PMID:23389888

  8. Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.

    PubMed

    Oehme, David; Ghosh, Peter; Goldschlager, Tony; Itescu, Silviu; Shimon, Susan; Wu, Jiehua; McDonald, Courtney; Troupis, John M; Rosenfeld, Jeffrey V; Jenkin, Graham

    2016-05-01

    OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly

  9. Axial Creep Loading and Unloaded Recovery of the Human Intervertebral Disc and the Effect of Degeneration

    PubMed Central

    O'Connell, Grace D.; Jacobs, Nathan T.; Sen, Sounok; Vresilovic, Edward J.; Elliott, Dawn M.

    2011-01-01

    The intervertebral disc maintains a balance between externally applied loads and internal osmotic pressure. Fluid flow plays a key role in this process, causing fluctuations in disc hydration and height. The objectives of this study were to quantify and model the axial creep and recovery responses of nondegenerate and degenerate human lumbar discs. Two experiments were performed. First, a slow compressive ramp was applied to 2000 N, unloaded to allow recovery for up to 24 hours, and re-applied. The linear-region stiffness and disc height were within 5% of the initial condition for recovery times greater than 8 hours. In the second experiment, a 1000 N creep load was applied for four hours, unloaded recovery monitored for 24 hours, and the creep load repeated. A viscoelastic model comprised of a “fast” and “slow” exponential response was used to describe the creep and recovery, where the fast response is associated with flow in the nucleus pulposus (NP) and endplate, while the slow response is associated with the annulus fibrosus (AF). The study demonstrated that recovery is 3-4X slower than loading. The fast response was correlated with degeneration, suggesting larger changes in the NP with degeneration compared to the AF. However, the fast response comprised only 10-15% of the total equilibrium displacement, with the AF-dominated slow response comprising 40-70%. Finally, the physiological loads and deformations and their associated long equilibrium times confirm that diurnal loading does not represent “equilibrium” in the disc, but that over time the disc is in steady-state. PMID:21783103

  10. Clinical Impact of Sagittal Spinopelvic Parameters on Disc Degeneration in Young Adults

    PubMed Central

    Oh, Young-Min; Eun, Jong-Pil

    2015-01-01

    Abstract The sagittal balance plays an important role in the determination of shear and compressive forces applied on the anterior (vertebral bodies and intervertebral discs) and posterior (facet joints) elements of the lumbar vertebral column. Many studies have also examined the effect of structural changes in the disc on the biomechanical characteristics of the spinal segment. Nevertheless, the relationship between sagittal balance and the degree of disc degeneration has not been extensively explored. Thus, here we investigated the relationships between various sagittal spinopelvic parameters and the degree of disc degeneration in young adults. A total of 278 young adult male patients were included in this study (age range: 18–24 years old). Multiple sagittal spinopelvic parameters, including pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), sacral inclination (SI), lumbosacral angle (LSA), and sacral table angle (STA), were measured from standing lateral lumbosacral radiographs. The degree of intervertebral disc degeneration was classified using a modified Pfirrmann scale. To assess the pain intensity of each patient, the visual analogue scale (VAS) score for low back pain (LBP) was obtained from all the patients. Finally, the relationships between these spinopelvic parameters and the degree of disc degeneration in young adults were analyzed. Also, we performed multiple logistic regression study. Out of all the spinopelvic parameters measured in this study, a low STA and a low SI were the only significant risk factors that were associated with disc degeneration in young adults. It means that patients with disc degeneration tend to have more severe sacral kyphosis and vertical sacrum. We found that patients with disc degeneration showed a lower SI and lower STA compared with patients without disc degeneration in young adults. Therefore, we suggest that the patients with disc degeneration tend to have more vertical sacrum, more

  11. Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low Back Pain and Disc Degeneration

    PubMed Central

    Zeckser, Jeffrey; Wolff, Michael; Tucker, Jason; Goodwin, Josh

    2016-01-01

    Low back pain with resultant loss of function, decreased productivity, and high economic costs is burdensome for both the individual and the society. Evidence suggests that intervertebral disc pathology is a major contributor to spine-related pain and degeneration. When commonly used conservative therapies fail, traditional percutaneous or surgical options may be beneficial for pain relief but are suboptimal because of their inability to alter disc microenvironment catabolism, restore disc tissue, and/or preserve native spine biomechanics. Percutaneously injected Multipotent Mesenchymal Stem Cell (MSC) therapy has recently gained clinical interest for its potential to revolutionarily treat disc-generated (discogenic) pain and associated disc degeneration. Unlike previous therapies to date, MSCs may uniquely offer the ability to improve discogenic pain and provide more sustained improvement by reducing disc microenvironment catabolism and regenerating disc tissue. Consistent treatment success has the potential to create a paradigm shift with regards to the treatment of discogenic pain and disc degeneration. PMID:26880958

  12. Comparative role of disc degeneration and ligament failure on functional mechanics of the lumbar spine.

    PubMed

    Ellingson, Arin M; Shaw, Miranda N; Giambini, Hugo; An, Kai-Nan

    2016-07-01

    Understanding spinal kinematics is essential for distinguishing between pathological conditions of spine disorders, which ultimately lead to low back pain. It is of high importance to understand how changes in mechanical properties affect the response of the lumbar spine, specifically in an effort to differentiate those associated with disc degeneration from ligamentous changes, allowing for more precise treatment strategies. To do this, the goals of this study were twofold: (1) develop and validate a finite element (FE) model of the lumbar spine and (2) systematically alter the properties of the intervertebral disc and ligaments to define respective roles in functional mechanics. A three-dimensional non-linear FE model of the lumbar spine (L3-sacrum) was developed and validated for pure moment bending. Disc degeneration and sequential ligament failure were modelled. Intersegmental range of motion (ROM) and bending stiffness were measured. The prediction of the FE model to moment loading in all three planes of bending showed very good agreement, where global and intersegmental ROM and bending stiffness of the model fell within one standard deviation of the in vitro results. Degeneration decreased ROM for all directions. Stiffness increased for all directions except axial rotation, where it initially increased then decreased for moderate and severe degeneration, respectively. Incremental ligament failure produced increased ROM and decreased stiffness. This effect was much more pronounced for all directions except lateral bending, which is minimally impacted by ligaments. These results indicate that lateral bending may be more apt to detect the subtle changes associated with degeneration, without being masked by associated changes of surrounding stabilizing structures. PMID:26404463

  13. Association of Abdominal Obesity with Lumbar Disc Degeneration – A Magnetic Resonance Imaging Study

    PubMed Central

    Takatalo, Jani; Karppinen, Jaro; Taimela, Simo; Niinimäki, Jaakko; Laitinen, Jaana; Sequeiros, Roberto Blanco; Samartzis, Dino; Korpelainen, Raija; Näyhä, Simo; Remes, Jouko; Tervonen, Osmo

    2013-01-01

    Purpose To evaluate whether midsagittal (abdominal) obesity in magnetic resonance imaging (MRI), waist circumference (WC) and body fat percentage are associated with lumbar disc degeneration in early adulthood. Methods We obtained the lumbar MRI (1.5-T scanner) of 325 females and 233 males at a mean age of 21 years. Lumbar disc degeneration was evaluated using Pfirrmann classification. We analysed the associations of MRI measures of obesity (abdominal diameter (AD), sagittal diameter (SAD), ventral subcutaneous thickness (VST), and dorsal subcutaneous thickness (DST)), WC and body fat percentage with disc degeneration sum scores using ordinal logistic regression. Results A total of 155 (48%) females and 147 (63%) males had disc degeneration. AD and SAD were associated with a disc degeneration sum score of ≥3 compared to disc degeneration sum score of 0–2 (OR 1.67; 95% confidence interval (CI) 1.20–2.33 and OR 1.40; 95% CI 1.12–1.75, respectively) among males, but we found no association among females. WC was also associated with disc degeneration among males (OR 1.03 per one cm; 95% CI 1.00–1.05), but not among females. Conclusion Measures of abdominal obesity in MRI and waist circumference were associated with disc degeneration among 21-year-old males. PMID:23418543

  14. Investigation of intervertebral disc degeneration using multivariate FTIR spectroscopic imaging.

    PubMed

    Mader, Kerstin T; Peeters, Mirte; Detiger, Suzanne E L; Helder, Marco N; Smit, Theo H; Le Maitre, Christine L; Sammon, Chris

    2016-06-23

    Traditionally tissue samples are analysed using protein or enzyme specific stains on serial sections to build up a picture of the distribution of components contained within them. In this study we investigated the potential of multivariate curve resolution-alternating least squares (MCR-ALS) to deconvolute 2nd derivative spectra of Fourier transform infrared (FTIR) microscopic images measured in transflectance mode of goat and human paraffin embedded intervertebral disc (IVD) tissue sections, to see if this methodology can provide analogous information to that provided by immunohistochemical stains and bioassays but from a single section. MCR-ALS analysis of non-degenerate and enzymatically in vivo degenerated goat IVDs reveals five matrix components displaying distribution maps matching histological stains for collagen, elastin and proteoglycan (PG), as well as immunohistochemical stains for collagen type I and II. Interestingly, two components exhibiting characteristic spectral and distribution profiles of proteoglycans were found, and relative component/tissue maps of these components (labelled PG1 and PG2) showed distinct distributions in non-degenerate versus mildly degenerate goat samples. MCR-ALS analysis of human IVD sections resulted in comparable spectral profiles to those observed in the goat samples, highlighting the inter species transferability of the presented methodology. Multivariate FTIR image analysis of a set of 43 goat IVD sections allowed the extraction of semi-quantitative information from component/tissue gradients taken across the IVD width of collagen type I, collagen type II, PG1 and PG2. Regional component/tissue parameters were calculated and significant correlations were found between histological grades of degeneration and PG parameters (PG1: p = 0.0003, PG2: p < 0.0001); glycosaminoglycan (GAG) content and PGs (PG1: p = 0.0055, PG2: p = 0.0001); and MRI T2* measurements and PGs (PG1: p = 0.0021, PG2: p < 0.0001). Additionally

  15. The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration

    PubMed Central

    Le Maitre, Christine Lyn; Freemont, Anthony J; Hoyland, Judith Alison

    2005-01-01

    In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration. PMID:15987475

  16. Expression and regulation of metalloproteinases and their inhibitors in intervertebral disc aging and degeneration

    PubMed Central

    Vo, Nam V.; Hartman, Robert A.; Yurube, Takashi; Jacobs, Lloydine J.; Sowa, Gwendolyn A.; Kang, James D.

    2013-01-01

    BACKGROUND CONTEXT Destruction of extracellular matrix (ECM) leads to intervertebral disc degeneration (IDD), which underlies many spine-related disorders. Matrix metalloproteinases (MMPs), and disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) are believed to be the major proteolytic enzymes responsible for ECM degradation in the intervertebral disc (IVD). PURPOSE To summarize the current literature on gene expression and regulation of MMPs, ADAMTSs, and tissue inhibitors of metalloproteinases (TIMPs) in IVD aging and IDD. METHODS A comprehensive literature review of gene expression of MMP, ADAMTS, and TIMP in human IDD and reported studies on regulatory factors controlling their expressions and activities in both human and animal model systems. RESULTS Upregulation of specific MMPs (MMP-1, -2, -3, -7, -8, -10, and -13) and ADAMTS (ADAMTS-1, -4, and -15) were reported in human degenerated IVDs. However, it is still unclear from conflicting published studies whether the expression of ADAMTS-5, the predominant aggrecanase, is increased with IDD. Tissue inhibitors of metalloproteinase-3 is downregulated, whereas TIMP-1 is upregulated in human degenerated IVDs relative to nondegenerated IVDs. Numerous studies indicate that the expression levels of MMP and ADAMTS are modulated by a combination of many factors, including mechanical, inflammatory, and oxidative stress, some of which are mediated in part through the p38 mitogen-activated protein kinase pathway. Genetic predisposition also plays an important role in determining gene expression of MMP-1, -2, -3, and -9. CONCLUSIONS Upregulation of MMP and ADAMTS expression and enzymatic activity is implicated in disc ECM destruction, leading to the development of IDD. Future IDD therapeutics depends on identifying specific MMPs and ADAMTSs whose dysregulation result in pathological proteolysis of disc ECM. PMID:23369495

  17. Role of biomechanics on intervertebral disc degeneration and regenerative therapies: What needs repairing in the disc and what are promising biomaterials for its repair?

    PubMed Central

    Iatridis, James C.; Nicoll, Steven B.; Michalek, Arthur J.; Walter, Benjamin A.; Gupta, Michelle S.

    2013-01-01

    Background Context Degeneration and injuries of the intervertebral disc result in large alterations in biomechanical behaviors. Repair strategies using biomaterials can be optimized based on biomechanical and biological requirements. Purpose To review current literature on 1) effects of degeneration, simulated degeneration, and injury on biomechanics of the intervertebral disc with special attention paid to needle puncture injuries which are a pathway for diagnostics and regenerative therapies; and 2) promising biomaterials for disc repair with a focus on how those biomaterials may promote biomechanical repair. Study Design/Setting A narrative review to evaluate the role of biomechanics on disc degeneration and regenerative therapies with a focus on what biomechanical properties need to be repaired and how to evaluate and accomplish such repairs using biomaterials. Model systems for screening of such repair strategies are also briefly described. Methods Papers were selected from two main Pubmed searches using keywords: intervertebral AND biomechanics (1823 articles) and intervertebral AND biomaterials (361 articles). Additional keywords (injury, needle puncture, nucleus pressurization, biomaterials, hydrogel, sealant, tissue engineering) were used to narrow articles to the topics most relevant to this review. Results Degeneration and acute disc injuries have the capacity to influence nucleus pulposus pressurization and annulus fibrosus integrity, which are necessary for effective disc function, and therefore, require repair. Needle injection injuries are of particular clinical relevance with potential to influence disc biomechanics, cellularity, and metabolism, yet these effects are localized or small, and more research is required to evaluate and reduce potential clinical morbidity using such techniques. NP replacement strategies, such as hydrogels, are required to restore NP pressurization or lost volume. AF repair strategies, including crosslinked hydrogels

  18. Growth Factors and Anticatabolic Substances for Prevention and Management of Intervertebral Disc Degeneration

    PubMed Central

    Longo, Umile Giuseppe; Petrillo, Stefano; Franceschetti, Edoardo; Maffulli, Nicola; Denaro, Vincenzo

    2012-01-01

    Intervertebral disc (IVD) degeneration is frequent, appearing from the second decade of life and progressing with age. Conservative management often fails, and patients with IVD degeneration may need surgical intervention. Several treatment strategies have been proposed, although only surgical discectomy and arthrodesis have been proved to be predictably effective. Biological strategies aim to prevent and manage IVD degeneration, improving the function and anabolic and reparative capabilities of the nucleus pulposus and annulus fibrosus cells and inhibiting matrix degradation. At present, clinical applications are still in their infancy. Further studies are required to clarify the role of growth factors and anticatabolic substances for prevention and management of intervertebral disc degeneration. PMID:25098367

  19. [Effects of intervertebral disc degeneration on biomechanics behavior characteristics of L4-L5 under the vertical load].

    PubMed

    Hu, Yingchun; Ou, Yalong; Hu, Yizhi; Yu, Binghao

    2015-02-01

    A geometrical model of L4-L5 lumbar segment was constructed using a three-dimensional graphics software. Four conditions of the degenerated discs, i. e. light degeneration, moderate degeneration, severe degeneration and complete excision degeneration, were simulated with loading situations using finite element method under the condition of appropriate computational accuracy. By applying a vertical load of 378.93 N on L4 vertebral plate, stress nephograms on joint isthmus under four different working conditions were obtained. The results showed that the contacted area of facet joint was influenced by the degree of intervertebral disc degeneration level, which influenced the mises stress on joint isthmus. It was proved that joint isthmus was the important pressure-proof structure of the back of lumbar vertebra, and the stress values and distribution were related to structural stiffness of the back of lumbar vertebra as well as the contact area of facet joint. The conclusion could be the theoretical reference for the analysis of spinal biomechanics and artificial disc replacement as well. PMID:25997266

  20. Effect of calcitonin pretreatment on naturally occurring intervertebral disc degeneration in guinea pig

    PubMed Central

    Jiang, Xiaohua; Tian, Faming; Wang, Wenya; Yan, Jinyin; Liu, Huanjiang; Liu, Binbin; Song, Huiping; Zhang, Yingze; Shen, Yong; Zhang, Liu

    2015-01-01

    Introduction: Our previous study suggested protective effects of calcitonin (CT) on experimental osteoarthritis. The aim of the present study was to provide evidence of whether CT pretreatment could prevent naturally occurring intervertebral disc degeneration in guinea pigs. Methods: Forty-two 3 months old female guinea pigs were randomly assigned into 2 groups as follows: Twenty-four were treated by normal saline as control group and sacrificed at 3, 6, 9 and 12 months of age (6 animals at each time point), the other 18 were received salmon CT (8 ug/kg/day, everyday) treatment at 3 months of age and sacrificed at the age of 6, 9 and 12 months respectively. Van Gieson stain and the histological score were used to identify the histological changes of the lumbar intervertebral discs. The disc height and vertebral body height were measured. Immunohistochemistry measurements for glycosaminoglycan, type II collagen, and matrix metalloprotease (MMP)-1 expressions were performed. Bone quality and microstructural changes in the L3-6 lumbar vertebral bodies were assessed by bone mineral density (BMD), micro-CT analysis and biomechanical testing. Results: Histological analysis indicated significantly higher disc degeneration scores in 9-month-old guinea pigs in comparison with younger animals, and grew higher with increasing age. CT treatment significantly reduced the histological score, and increased the disc height and the ratio to vertebral body height in 12 months old animals, as well as upregulated the glycosaminoglycan, type II collagen and inhibited the MMP-1 expression. Micro-CT analysis showed decreased percent bone volume (BV/TV) and increased trabecular separation (Tb.Sp), structural model index (SMI) in 12 months old animals in comparison with the younger animals. Markedly increased BV/TV and decreased Tb.Sp were observed in CT treated animals when compared with control animals. The biomechanical properties including maximum load, maximum stress, yield stress and

  1. Regional variations in the compressive properties of lumbar vertebral trabeculae. Effects of disc degeneration

    SciTech Connect

    Keller, T.S.; Hansson, T.H.; Abram, A.C.; Spengler, D.M.; Panjabi, M.M. )

    1989-09-01

    The compressive mechanical properties of human lumbar vertebral trabeculae were examined on the basis of anatomic origin, bone density, and intervertebral disc properties. Trabecular bone compressive strength and stiffness increased with increasing bone density, the latter proportional to strength and stiffness to the one-half power. Regional variations within each segment were found, the most prevalent differences occurring in regions of bone overlying the disc nucleus in comparison with bone overlying the disc anulus. For normal discs, the ratio of strength of bone overlying the disc nucleus to bone overlying the disc anulus was 1.25, decreasing to 1.0 for moderately degenerated discs. These results suggest that an interdependency of trabecular bone properties and intervertebral disc properties may exist.

  2. Functional probe for annulus fibrosus-targeted intervertebral disc degeneration imaging

    PubMed Central

    Kim, Hye-Yeong; Mcclincy, Michael; Vo, Nam V.; Sowa, Gwendolyn A.; Kang, James D.

    2013-01-01

    Abstract. Intervertebral disc degeneration (IDD) is closely associated with low back pain. Typically nonsurgical treatment of IDD is the most effective when detected early. As such, establishing reliable imaging methods for the early diagnosis of disc degeneration is critical. The cellular and tissue localization of a facile functional fluorescent probe, HYK52, that labels disc annulus fibrosus is reported. HYK52 was synthesized with high yield and purity via a two-step chemical reaction. Rabbit disc cell studies and ex vivo tissue staining images indicated intracellular localization and intervertebral disc (IVD) tissue binding of HYK52 with negligible cytotoxicity. Moreover, HYK52 is purposefully designed with a functional terminal carboxyl group to allow for coupling with various signaling molecules for multimodal imaging applications. These results suggest that this IVD-targeted probe may have great potential in early diagnosis of IDD. PMID:23839314

  3. Functional probe for annulus fibrosus-targeted intervertebral disc degeneration imaging.

    PubMed

    Kim, Hye-Yeong; Mcclincy, Michael; Vo, Nam V; Sowa, Gwendolyn A; Kang, James D; Bai, Mingfeng

    2013-10-01

    Intervertebral disc degeneration (IDD) is closely associated with low back pain. Typically nonsurgical treatment of IDD is the most effective when detected early. As such, establishing reliable imaging methods for the early diagnosis of disc degeneration is critical. The cellular and tissue localization of a facile functional fluorescent probe, HYK52, that labels disc annulus fibrosus is reported. HYK52 was synthesized with high yield and purity via a two-step chemical reaction. Rabbit disc cell studies and ex vivo tissue staining images indicated intracellular localization and intervertebral disc (IVD) tissue binding of HYK52 with negligible cytotoxicity. Moreover, HYK52 is purposefully designed with a functional terminal carboxyl group to allow for coupling with various signaling molecules for multimodal imaging applications. These results suggest that this IVD-targeted probe may have great potential in early diagnosis of IDD. PMID:23839314

  4. Molecular immunotherapy might shed a light on the treatment strategies for disc degeneration and herniation.

    PubMed

    Sun, Zhen; Liu, Zhi-Heng; Chen, Yu-fei; Zhang, Yong-zhao; Wan, Zhong-yuan; Zhang, Wei-lin; Che, Lu; Liu, Xu; Wang, Hai-Qiang; Luo, Zhuo-Jing

    2013-09-01

    Despite surgical discectomy is one of the most effective treatments for intervertebral disc degeneration and lumbar disc herniation, a number of patients still complain of reserved low back pain, sciatica and numbness post-operatively with decreased life quality. Sciatica in patients with disc herniation is not only due to mechanical compression from herniated nucleus pulposus, but chemical and immunity agents. The intervertebral disc is composed of annulus fibrosus in the wedge and gelatinous nucleus pulposus in the centre with cartilage endplate sandwiched. Similar to other immune privilege organs, human intervertebral disc is one of the biggest avascular structures with FasL expression. Moreover, FasL-Fas and TRAIL death pathways might play roles in the machinery of immune privilege of the disc. We found that down-regulated miR-155 promotes Fas-mediated apoptosis in disc degeneration. Furthermore, once exposed to human immune system, nucleus pulposus can activate multiple specific and non-specific immune responses with cellular and fluid immune cells and molecules involved. Taken together, we hypothesize that a combined molecular immunotherapy with local and systemic immunity regulators might shed a novel light on the treatment strategies for disc degeneration and herniation. PMID:23849654

  5. Population Average T2 MRI Maps Reveal Quantitative Regional Transformations in the Degenerating Rabbit Intervertebral Disc that Vary by Lumbar Level

    PubMed Central

    Martin, John T.; Collins, Christopher M.; Mauck, Robert L.; Ikuta, Kensuke; Elliott, Dawn M.; Zhang, Yeija; Anderson, D. Greg; Vaccaro, Alexander R.; Albert, Todd J.; Arlet, Vincent; Smith, Harvey E.

    2015-01-01

    Magnetic resonance imaging (MRI) with T2-weighting is routinely performed to assess intervertebral disc degeneration. Standard clinical evaluations of MR images are qualitative, however, and do not focus on region-specific alterations in the disc. Utilizing a rabbit needle puncture model, T2 mapping was performed on injured discs to develop a quantitative description of the degenerative process following puncture. To do so, an 18G needle was inserted into four discs per rabbit (L3/L4 to L6/L7) and T2 maps were generated pre- and 4 weeks post-injury. Individual T2 maps were normalized to a disc-specific coordinate system and then averaged for pre- and post-injury population composite T2 maps. We also developed a method to automatically segment the nucleus pulposus by 2-D and 3-D curve fitting routines. Puncture injury produced alterations in MR signal intensity in a region-specific manner mirroring human degeneration. Population average T2 maps provided a quantitative representation of the injury response, and identified deviations of individual degenerate discs from the pre-injury population. We found that the response to standardized injury was modest at lower lumbar levels, likely as a result of increased disc dimensions. These tools will be valuable for the quantitative characterization of disc degeneration in future clinical and pre-clinical studies. PMID:25273831

  6. Emerging technologies for molecular therapy for intervertebral disc degeneration

    PubMed Central

    Bae, Won C.; Masuda, Koichi

    2014-01-01

    Intervertebral discs are biologically regulated by the maintenance of a balance between the anabolic and catabolic activities of disc cells. Therapeutic agents, initially evaluated using in vitro studies on disc cells and explants, have been used as intradiscal injections in preclinical settings to test in vivo efficacy. These include anabolic growth factors and other biostimulatory agents as well as antagonistic agents against matrix-degrading enzymes and cytokines. Additional work is needed to identify suitable patient populations, using methods such as MRI, and to better understand the mechanism of healing. Clinical trials are currently underway for a few of these agents, while many other promising candidates are on the horizon. PMID:21944594

  7. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors

    PubMed Central

    Krock, Emerson; Rosenzweig, Derek H; Chabot-Doré, Anne-Julie; Jarzem, Peter; Weber, Michael H; Ouellet, Jean A; Stone, Laura S; Haglund, Lisbet

    2014-01-01

    Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1β, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo. PMID:24650225

  8. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors.

    PubMed

    Krock, Emerson; Rosenzweig, Derek H; Chabot-Doré, Anne-Julie; Jarzem, Peter; Weber, Michael H; Ouellet, Jean A; Stone, Laura S; Haglund, Lisbet

    2014-06-01

    Intervertebral disc degeneration (IVD) can result in chronic low back pain, a common cause of morbidity and disability. Inflammation has been associated with IVD degeneration, however the relationship between inflammatory factors and chronic low back pain remains unclear. Furthermore, increased levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) are both associated with inflammation and chronic low back pain, but whether degenerating discs release sufficient concentrations of factors that induce nociceptor plasticity remains unclear. Degenerating IVDs from low back pain patients and healthy, painless IVDs from human organ donors were cultured ex vivo. Inflammatory and nociceptive factors released by IVDs into culture media were quantified by enzyme-linked immunosorbent assays and protein arrays. The ability of factors released to induce neurite growth and nociceptive neuropeptide production was investigated. Degenerating discs release increased levels of tumour necrosis factor-α, interleukin-1β, NGF and BDNF. Factors released by degenerating IVDs increased neurite growth and calcitonin gene-related peptide expression, both of which were blocked by anti-NGF treatment. Furthermore, protein arrays found increased levels of 20 inflammatory factors, many of which have nociceptive effects. Our results demonstrate that degenerating and painful human IVDs release increased levels of NGF, inflammatory and nociceptive factors ex vivo that induce neuronal plasticity and may actively diffuse to induce neo-innervation and pain in vivo. PMID:24650225

  9. Clarifying the nomenclature of intervertebral disc degeneration and displacement: from bench to bedside

    PubMed Central

    Wang, Hai-Qiang; Samartzis, Dino

    2014-01-01

    As a significant determinant of low back pain, intervertebral disc degeneration (IDD) has attracted more and more attention of both investigators and physicians. Disc herniation, termed as intervertebral disc displacement, is amongst the most prevalent spinal diseases closely linked with IDD. Due to the same origins and similar pathophysiology, the ambiguity regarding the similarity and difference of IDD and intervertebral disc displacement thus remains. The aim of this study was to clarify the nomenclature of IDD and disc herniation in terms of molecular etiology, pathophysiology, nature history and clinical outcomes. Collectively, IDD is a type of multifaceted, progressive spinal disease with or without clinical symptoms as back pain, characterized by extracellular matrix and the integrity of NP and AF lost, fissures formation. Disc herniation (termed as intervertebral disc displacement) is a type of spinal disease based on IDD or not, with local pain and/or sciatica due to mechanical compression and autoimmune cascades upon the corresponding nerve roots. Clarifying the nomenclature of intervertebral disc degeneration and displacement has important implications both for investigators and for physicians. PMID:24817926

  10. Organ Culture Bioreactors – Platforms to Study Human Intervertebral Disc Degeneration and Regenerative Therapy

    PubMed Central

    Gantenbein, Benjamin; Illien-Jünger, Svenja; Chan, Samantha CW; Walser, Jochen; Haglund, Lisbet; Ferguson, Stephen J; Iatridis, James C; Grad, Sibylle

    2015-01-01

    In recent decades the application of bioreactors has revolutionized the concept of culturing tissues and organs that require mechanical loading. In intervertebral disc (IVD) research, collaborative efforts of biomedical engineering, biology and mechatronics have led to the innovation of new loading devices that can maintain viable IVD organ explants from large animals and human cadavers in precisely defined nutritional and mechanical environments over extended culture periods. Particularly in spine and IVD research, these organ culture models offer appealing alternatives, as large bipedal animal models with naturally occurring IVD degeneration and a genetic background similar to the human condition do not exist. Latest research has demonstrated important concepts including the potential of homing of mesenchymal stem cells to nutritionally or mechanically stressed IVDs, and the regenerative potential of “smart” biomaterials for nucleus pulposus or annulus fibrosus repair. In this review, we summarize the current knowledge about cell therapy, injection of cytokines and short peptides to rescue the degenerating IVD. We further stress that most bioreactor systems simplify the real in vivo conditions providing a useful proof of concept. Limitations are that certain aspects of the immune host response and pain assessments cannot be addressed with ex vivo systems. Coccygeal animal disc models are commonly used because of their availability and similarity to human IVDs. Although in vitro loading environments are not identical to the human in vivo situation, 3D ex vivo organ culture models of large animal coccygeal and human lumbar IVDs should be seen as valid alternatives for screening and feasibility testing to augment existing small animal, large animal, and human clinical trial experiments. PMID:25764196

  11. High mechanical strain of primary intervertebral disc cells promotes secretion of inflammatory factors associated with disc degeneration and pain

    PubMed Central

    2014-01-01

    Introduction Excessive mechanical loading of intervertebral discs (IVDs) is thought to alter matrix properties and influence disc cell metabolism, contributing to degenerative disc disease and development of discogenic pain. However, little is known about how mechanical strain induces these changes. This study investigated the cellular and molecular changes as well as which inflammatory receptors and cytokines were upregulated in human intervertebral disc cells exposed to high mechanical strain (HMS) at low frequency. The impact of these metabolic changes on neuronal differentiation was also explored to determine a role in the development of disc degeneration and discogenic pain. Methods Isolated human annulus fibrosus (AF) and nucleus pulposus (NP) cells were exposed to HMS (20% cyclical stretch at 0.001 Hz) on high-extension silicone rubber dishes coupled to a mechanical stretching apparatus and compared to static control cultures. Gene expression of Toll-like receptors (TLRs), neuronal growth factor (NGF) and tumour necrosis factor α (TNFα) was assessed. Collected conditioned media were analysed for cytokine content and applied to rat pheocromocytoma PC12 cells for neuronal differentiation assessment. Results HMS caused upregulation of TLR2, TLR4, NGF and TNFα gene expression in IVD cells. Medium from HMS cultures contained elevated levels of growth-related oncogene, interleukin 6 (IL-6), IL-8, IL-15, monocyte chemoattractant protein 1 (MCP-1), MCP-3, monokine induced by γ interferon, transforming growth factor β1, TNFα and NGF. Exposure of PC12 cells to HMS-conditioned media resulted in both increased neurite sprouting and cell death. Conclusions HMS culture of IVD cells in vitro drives cytokine and inflammatory responses associated with degenerative disc disease and low-back pain. This study provides evidence for a direct link between cellular strain, secretory factors, neoinnervation and potential degeneration and discogenic pain in vivo. PMID:24457003

  12. Treatment of the degenerated intervertebral disc; closure, repair and regeneration of the annulus fibrosus.

    PubMed

    Sharifi, Shahriar; Bulstra, Sjoerd K; Grijpma, Dirk W; Kuijer, Roel

    2015-10-01

    Degeneration of the intervertebral disc (IVD) and disc herniation are two causes of low back pain. The aetiology of these disorders is unknown, but tissue weakening, which primarily occurs due to inherited genetic factors, ageing, nutritional compromise and loading history, is the basic factor causing disc degeneration. Symptomatic disc herniation mainly causes radicular pain. Current treatments of intervertebral disc degeneration and low back pain are based on alleviating the symptoms and comprise administration of painkillers or surgical methods such as spinal fusion. None of these methods is completely successful. Current research focuses on regeneration of the IVD and particularly on regeneration of the nucleus pulposus. Less attention has been directed to the repair or regeneration of the annulus fibrosus, although this is the key to successful nucleus pulposus, and therewith IVD, repair. This review focuses on the importance of restoring the function of the annulus fibrosus, as well as on the repair, replacement or regeneration of the annulus fibrosus in combination with restoration of the function of the nucleus pulposus, to treat low back pain. PMID:24616324

  13. Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study.

    PubMed

    Fusellier, Marion; Colombier, Pauline; Lesoeur, Julie; Youl, Samy; Madec, Stéphane; Gauthier, Olivier; Hamel, Olivier; Guicheux, Jérôme; Clouet, Johann

    2016-01-01

    Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos' scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos' scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration. PMID:27247937

  14. Longitudinal Comparison of Enzyme- and Laser-Treated Intervertebral Disc by MRI, X-Ray, and Histological Analyses Reveals Discrepancies in the Progression of Disc Degeneration: A Rabbit Study

    PubMed Central

    Colombier, Pauline; Lesoeur, Julie; Youl, Samy; Madec, Stéphane; Gauthier, Olivier; Hamel, Olivier; Guicheux, Jérôme; Clouet, Johann

    2016-01-01

    Regenerative medicine is considered an attractive prospect for the treatment of intervertebral disc (IVD) degeneration. To assess the efficacy of the regenerative approach, animal models of IVD degeneration are needed. Among these animal models, chemonucleolysis based on the enzymatic degradation of the Nucleus Pulposus (NP) is often used, but this technique remains far from the natural physiopathological process of IVD degeneration. Recently, we developed an innovative animal model of IVD degeneration based on the use of a laser beam. In the present study, this laser model was compared with the chemonucleolysis model in a longitudinal study in rabbits. The effects of the treatments were studied by MRI (T2-weighted signal intensity (T2wsi)), radiography (IVD height index), and histology (NP area and Boos' scoring). The results showed that both treatments induced a degeneration of the IVD with a decrease in IVD height and T2wsi as well as NP area and an increase in Boos' scoring. The enzyme treatment leads to a rapid and acute process of IVD degeneration. Conversely, laser radiation induced more progressive and less pronounced degeneration. It can be concluded that laser treatment provides an instrumental in vivo model of slowly evolving IVD degenerative disease that can be of preclinical relevance for assessing new prophylactic biological treatments of disc degeneration. PMID:27247937

  15. Disc Degeneration Assessed by Quantitative T2* (T2 star) Correlated with Functional Lumbar Mechanics

    PubMed Central

    Ellingson, Arin M.; Mehta, Hitesh; Polly, David W.; Ellermann, Jutta; Nuckley, David J.

    2013-01-01

    Study Design Experimental correlation study design to quantify features of disc health, including signal intensity and distinction between the annulus fibrosus (AF) and nucleus pulposus (NP), with T2* magnetic resonance imaging (MRI) and correlate with the functional mechanics in corresponding motion segments. Objective Establish the relationship between disc health assessed by quantitative T2* MRI and functional lumbar mechanics. Summary of Background Data Degeneration leads to altered biochemistry in the disc, affecting the mechanical competence. Clinical routine MRI sequences are not adequate in detecting early changes in degeneration and fails to correlate with pain or improve patient stratification. Quantitative T2* relaxation time mapping probes biochemical features and may offer more sensitivity in assessing disc degeneration. Methods Cadaveric lumbar spines were imaged using quantitative T2* mapping, as well as conventional T2-weighted MRI sequences. Discs were graded by the Pfirrmann scale and features of disc health, including signal intensity (T2* Intensity Area) and distinction between the AF and NP (Transition Zone Slope), were quantified by T2*. Each motion segment was subjected to pure moment bending to determine range of motion (ROM), neutral zone (NZ), and bending stiffness. Results T2* Intensity Area and Transition Zone Slope were significantly correlated with flexion ROM (p=0.015; p=0.002), ratio of NZ/ROM (p=0.010; p=0.028), and stiffness (p=0.044; p=0.026), as well as lateral bending NZ/ROM (p=0.005; p=0.010) and stiffness (p=0.022; p=0.029). T2* Intensity Area was also correlated with LB ROM (p=0.023). Pfirrmann grade was only correlated with lateral bending NZ/ROM (p=0.001) and stiffness (p=0.007). Conclusions T2* mapping is a sensitive quantitative method capable of detecting changes associated with disc degeneration. Features of disc health quantified with T2* predicted altered functional mechanics of the lumbar spine better than

  16. The Effects of Platelet-Rich Plasma on Halting the Progression in Porcine Intervertebral Disc Degeneration.

    PubMed

    Cho, Hongsik; Holt, David C; Smith, Richard; Kim, Song-Ja; Gardocki, Raymond J; Hasty, Karen A

    2016-02-01

    Disc degeneration and the subsequent herniation and/or rupture of the intervertebral disc (IVD) are due to a failure of the extracellular matrix of the annulus to contain the contents of the nucleus. This results from inadequate maintenance of the matrix components as well as the proteolytic activity of matrix metalloproteinases (MMPs) that degrade matrix molecules. Arresting progression of disc degeneration in the annulus holds greater clinical potential at this point than prevention of its onset in the nucleus. Therefore, in this study, we have therapeutic aims that would decrease levels of the cytokines and growth factors that indirectly lead to disc degeneration via stimulating MMP and increase levels of several beneficial growth factors, such as transforming growth factor-β, with the addition of platelet-rich plasma (PRP) that would stimulate cell growth and matrix synthesis. For this study, we attempted to address these imbalances of metabolism by using tumor necrosis factor-α treated annulus fibrosus cells isolated from porcine IVD tissue and incubating the cells in a growth factor rich environment with PRP. These results indicate that the PRP in vitro increased the production of the major matrix components (type II collagen and aggrecan) and decreased the inhibitory collagenase MMP-1. This application will address a therapeutic approach for intervening early in the degenerative process. PMID:26147759

  17. Structured bilaminar co-culture outperforms stem cells and disc cells in a simulated degenerate disc environment

    PubMed Central

    Allon, Aliza A.; Butcher, Kristin; Schneider, Richard A.; Lotz, Jeffrey C.

    2011-01-01

    Study Design This study explores the use of bilaminar coculture pellets of mesenchymal stem cells (MSC) and Nucleus Pulposus cells (NPC) as a cell-based therapy for intervertebral disc regeneration. The pellets were tested under conditions that mimic the degenerative disc. Objective Our goal is to optimize our cell-based therapy in vitro under conditions representative of the eventual diseased tissue. Summary of Background Data Harnessing the potential of stem cells is an important strategy for regenerative medicine. Our approach seeks to direct the behavior of stem cells by mimicking embryonic processes underlying cartilage and intervertebral disc development. Prior experiments have shown that bilaminar co-culture can help differentiate MSC and substantially improve new matrix deposition. Methods We have designed a novel spherical bilaminar cell pellet (BCP) where MSC are enclosed in a shell of NPC. There were three groups: MSC, NPC, and BCP. The pellets were tested under three different culture conditions: in a bioreactor that provides pressure & hypoxia (mimicking normal disc conditions), with inflammatory cytokines (IL-1b and TNF-a), and a bioreactor with inflammation (mimicking painful disc conditions). Results When cultured in the bioreactor, the NPC pellets produced significantly more glycosaminoglycan (GAG)/cell than the other groups: 70-80% more than the BCP and MSC alone. When cultured in an inflammatory environment, the MSC and BCP groups produced 30-34% more GAG/cell than NPC (p<0.05). When the pellets were cultured in a bioreactor with inflammation, the BCP made 25% more GAG/cell than MSC and 57% more than NPC (p<0.05). Conclusion This study shows that BCP outperform controls in a simulated degenerated disc environment. Adapting inductive mechanisms from development to trigger differentiation and restore diseased tissue has many advantages. As opposed to strategies that require growth factor supplements or genetic manipulations, our method is self

  18. A role for TNFα in intervertebral disc degeneration: A non-recoverable catabolic shift

    SciTech Connect

    Purmessur, D.; Walter, B.A.; Roughley, P.J.; Laudier, D.M.; Hecht, A.C.; Iatridis, James

    2013-03-29

    Highlights: ► TNFα induced catabolic changes similar to human intervertebral disc degeneration. ► The metabolic shift induced by TNFα was sustained following removal. ► TNFα induced changes suggestive of cell senescence without affecting cell viability. ► Interventions are required to stimulate anabolism and increase cell proliferation. -- Abstract: This study examines the effect of TNFα on whole bovine intervertebral discs in organ culture and its association with changes characteristic of intervertebral disc degeneration (IDD) in order to inform future treatments to mitigate the chronic inflammatory state commonly found with painful IDD. Pro-inflammatory cytokines such as TNFα contribute to disc pathology and are implicated in the catabolic phenotype associated with painful IDD. Whole bovine discs were cultured to examine cellular (anabolic/catabolic gene expression, cell viability and senescence using β-galactosidase) and structural (histology and aggrecan degradation) changes in response to TNFα treatment. Control or TNFα cultures were assessed at 7 and 21 days; the 21 day group also included a recovery group with 7 days TNFα followed by 14 days in basal media. TNFα induced catabolic and anti-anabolic shifts in the nucleus pulposus (NP) and annulus fibrosus (AF) at 7 days and this persisted until 21 days however cell viability was not affected. Data indicates that TNFα increased aggrecan degradation products and suggests increased β-galactosidase staining at 21 days without any recovery. TNFα treatment of whole bovine discs for 7 days induced changes similar to the degeneration processes that occur in human IDD: aggrecan degradation, increased catabolism, pro-inflammatory cytokines and nerve growth factor expression. TNFα significantly reduced anabolism in cultured IVDs and a possible mechanism may be associated with cell senescence. Results therefore suggest that successful treatments must promote anabolism and cell proliferation in

  19. The imbalance between TIMP3 and matrix-degrading enzymes plays an important role in intervertebral disc degeneration.

    PubMed

    Li, Yan; Li, Kang; Han, Xiuguo; Mao, Chuanyuan; Zhang, Kai; Zhao, Tengfei; Zhao, Jie

    2016-01-15

    It is well-known that one of the most important features of intervertebral disc degeneration (IDD) is the extracellular matrix (ECM) degradation. Collagen and aggrecan are major components of ECM; the degradation of ECM in intervertebral discs (IVDs) is closely related to the activities of collagenase and aggrecanase. TIMP-3 is the most efficient inhibitor of aggrecanase in IVD. However, only few studies focus on the potential relationship between TIMP-3 and IDD. In our study, we found TIMP-3 gene expression was decreased after stimulating with LPS in rat nucleus pulposus (NP) cells. Then we used a lentivirus vector to reconstruct rat NP cells which high expressed TIMP-3 gene (LV-TIMP3). The upregulation of MMPs and ADAMTSs induced by LPS was significantly inhibited in LV-TIMP3 cells. After overexpression of TIMP-3, the aggrecan breakdown caused by LPS was also reduced in both monolayer culture and three-dimension culture model. To further study the relation between TIMP-3 and IDD, we collected human NP tissue samples of different degenerative degrees. Real-time PCR and immunohistochemical staining showed that the expression of TIMP-3 was negatively correlated with the degree of intervertebral disc degeneration, while MMP-1 and ADAMTS-4 were markedly increased in degenerative IVD. Taken together, our results suggest that the imbalance between aggrecanase and TIMP-3 may play an important role in the pathogenesis of IDD and therefore be a potential therapeutic target for treating IDD. PMID:26686417

  20. A Systematic Review of the Safety and Efficacy of Mesenchymal Stem Cells for Disc Degeneration: Insights and Future Directions for Regenerative Therapeutics

    PubMed Central

    Yim, Rita Lok-Hay; Lee, Juliana Tsz-Yan; Bow, Cora H.; Meij, Björn; Leung, Victor; Cheung, Kenneth M.C.; Vavken, Patrick

    2014-01-01

    Intervertebral disc degeneration is associated with low-back pain. Mesenchymal stem cells (MSCs) have been used to “regenerate” the disc. The aim of this study was to perform a systematic review of comparative controlled studies that have assessed the safety and efficacy of using MSCs for disc regeneration. Literature databases were extensively searched. Trial design, subject-type, MSC sources, injection method, disc assessment, outcome intervals, and complication events were assessed. Validity of each study was performed. Twenty-four animal studies were included with 20.8% of the studies reporting randomization of groups. Trials in humans fulfilling inclusion criteria were not noted. The studies represented 862 discs that were injected with MSCs and 1,603 discs as controls. All three types of MSCs (ie, bone marrow, synovial, and adipose tissues) showed successful inhibition of disc degeneration. Bone-marrow-derived MSCs demonstrated superior quality of repair compared with other non-MSC treatments. A 2.7% overall complication rate was noted, whereby complications were noted only in rabbits. Overall, evidence suggested that MSCs increased disc space height in the majority of animal models. This is the first systematic review to assess the safety and efficacy of MSCs for the treatment of disc degeneration. Short-term MSC transplantation is safe and effective; however, additional, larger, and higher-quality studies are needed to assess the long-term safety and efficacy. Inconsistencies in methodological design and outcome parameters prevent any robust conclusions. Human-based clinical trials are needed. Recommendations are further made to improve efficacy, reduce potential complications, and standardize techniques for future studies. PMID:25050446

  1. MSC response to pH levels found in degenerating intervertebral discs

    SciTech Connect

    Wuertz, Karin Godburn, Karolyn; Iatridis, James C.

    2009-02-20

    Painful degenerative disc disease is a major health problem and for successful tissue regeneration, MSCs must endure and thrive in a harsh disc microenvironment that includes matrix acidity as a critical factor. MSCs were isolated from bone marrow of Sprague-Dawley rats from two different age groups (<1 month, n = 6 and 4-5 months, n = 6) and cultured under four different pH conditions representative of the healthy, mildly or severely degenerated intervertebral disc (pH 7.4, 7.1, 6.8, and 6.5) for 5 days. Acidity caused an inhibition of aggrecan, collagen-1, and TIMP-3 expression, as well as a decrease in proliferation and viability and was associated with a change in cell morphology. Ageing had generally minor effects but young MSCs maintained greater mRNA expression levels. As acidic pH levels are typical of increasingly degenerated discs, our findings demonstrate the importance of early interventions and predifferentiation when planning to use MSCs for reparative treatments.

  2. Effects of psoralen on chondrocyte degeneration in lumbar intervertebral disc of rats.

    PubMed

    Yang, Libin; Sun, Xiaohui; Geng, Xiaolin

    2015-03-01

    Discuss the internal mechanism of delaying degeneration of lumber intervertebral disc. The cartilage of lumbar intervertebral disc of SD rats was selected in vitro, then cultured by tissue explant method, and identified by HE staining, toluidine blue staining and immunofluorescence. The optimal concentration of psoralen was screened by cell proliferation assay and RT-PCR method. The cells in third generation with good growth situation is selected and placed in 6-well plate at concentration of 1×10(5)/well and its expression was tested. Compared to concentration of 0, the mRNA expression of Col2al (Collagen Ⅱ) secreted by was up regulated chondrocyte of lumbar intervertebral disc at the concentration of 12.5 and 25μM (P<0.0 or P<0.01). The aggrecan mRNA of psoralen group was higher than blank control group (P<0.01); compared with IL-1β induced group, the mRNA expression of Col2al was significantly increased but the mRNA expression of ADAMTS-5 was significantly decreased in psoralen group (P<0.01). These findings suggest that, psoralen can remit the degeneration of lumbar intervertebral disc induced by IL-1β to some extent, and affect the related factors of IL-1β signaling pathway. PMID:25796142

  3. The Involvement of Protease Nexin-1 (PN1) in the Pathogenesis of Intervertebral Disc (IVD) Degeneration

    PubMed Central

    Wu, Xinghuo; Liu, Wei; Duan, Zhenfeng; Gao, Yong; Li, Shuai; Wang, Kun; Song, Yu; Shao, Zengwu; Yang, Shuhua; Yang, Cao

    2016-01-01

    Protease nexin-1 (PN-1) is a serine protease inhibitor belonging to the serpin superfamily. This study was undertaken to investigate the regulatory role of PN-1 in the pathogenesis of intervertebral disk (IVD) degeneration. Expression of PN-1 was detected in human IVD tissue of varying grades. Expression of both PN-1 mRNA and protein was significantly decreased in degenerated IVD, and the expression levels of PN-1 were correlated with the grade of disc degeneration. Moreover, a decrease in PN-1 expression in primary NP cells was confirmed. On induction by IL-1β, the expression of PN-1 in NP cells was decreased at day 7, 14, and 21, as shown by western blot analysis and immunofluorescence staining. PN-1 administration decreased IL-1β-induced MMPs and ADAMTS production and the loss of Agg and Col II in NP cell cultures through the ERK1/2/NF-kB signaling pathway. The changes in PN-1 expression are involved in the pathogenesis of IVD degeneration. Our findings indicate that PN-1 administration could antagonize IL-1β-induced MMPs and ADAMTS, potentially preventing degeneration of IVD tissue. This study also revealed new insights into the regulation of PN-1 expression via the ERK1/2/NF-kB signaling pathway and the role of PN-1 in the pathogenesis of IVD degeneration. PMID:27460424

  4. Injection of human umbilical tissue–derived cells into the nucleus pulposus alters the course of intervertebral disc degeneration in vivo

    PubMed Central

    Leckie, Steven K.; Sowa, Gwendolyn A.; Bechara, Bernard P.; Hartman, Robert A.; Coelho, Joao Paulo; Witt, William T.; Dong, Qing D.; Bowman, Brent W.; Bell, Kevin M.; Vo, Nam V.; Kramer, Brian C.; Kang, James D.

    2016-01-01

    Background context Patients often present to spine clinic with evidence of intervertebral disc degeneration (IDD). If conservative management fails, a safe and effective injection directly into the disc might be preferable to the risks and morbidity of surgery. Purpose To determine whether injecting human umbilical tissue–derived cells (hUTC) into the nucleus pulposus (NP) might improve the course of IDD. Design Prospective, randomized, blinded placebo–controlled in vivo study. Patient sample Skeletally mature New Zealand white rabbits. Outcome measures Degree of IDD based on magnetic resonance imaging (MRI), biomechanics, and histology. Methods Thirty skeletally mature New Zealand white rabbits were used in a previously validated rabbit annulotomy model for IDD. Discs L2–L3, L3–L4, and L4–L5 were surgically exposed and punctured to induce degeneration and then 3 weeks later the same discs were injected with hUTC with or without a hydrogel carrier. Serial MRIs obtained at 0, 3, 6, and 12 weeks were analyzed for evidence of degeneration qualitatively and quantitatively via NP area and MRI Index. The rabbits were sacrificed at 12 weeks and discs L4–L5 were analyzed histologically. The L3–L4 discs were fixed to a robotic arm and subjected to uniaxial compression, and viscoelastic displacement curves were generated. Results Qualitatively, the MRIs demonstrated no evidence of degeneration in the control group over the course of 12 weeks. The punctured group yielded MRIs with the evidence of disc height loss and darkening, suggestive of degeneration. The three treatment groups (cells alone, carrier alone, or cells+carrier) generated MRIs with less qualitative evidence of degeneration than the punctured group. MRI Index and area for the cell and the cell+carrier groups were significantly distinct from the punctured group at 12 weeks. The carrier group generated MRI data that fell between control and punctured values but failed to reach a statistically

  5. A biochemical/biophysical 3D FE intervertebral disc model.

    PubMed

    Schroeder, Y; Huyghe, J M; van Donkelaar, C C; Ito, K

    2010-10-01

    Present research focuses on different strategies to preserve the degenerated disc. To assure long-term success of novel approaches, favorable mechanical conditions in the disc tissue are essential. To evaluate these, a model is required that can determine internal mechanical conditions which cannot be directly measured as a function of assessable biophysical characteristics. Therefore, the objective is to evaluate if constitutive and material laws acquired on isolated samples of nucleus and annulus tissue can be used directly in a whole-organ 3D FE model to describe intervertebral disc behavior. The 3D osmo-poro-visco-hyper-elastic disc (OVED) model describes disc behavior as a function of annulus and nucleus tissue biochemical composition, organization and specific constituent properties. The description of the 3D collagen network was enhanced to account for smaller fibril structures. Tissue mechanical behavior tests on isolated nucleus and annulus samples were simulated with models incorporating tissue composition to calculate the constituent parameter values. The obtained constitutive laws were incorporated into the whole-organ model. The overall behavior and disc properties of the model were corroborated against in vitro creep experiments of human L4/L5 discs. The OVED model simulated isolated tissue experiments on confined compression and uniaxial tensile test and whole-organ disc behavior. This was possible, provided that secondary fiber structures were accounted for. The fair agreement (radial bulge, axial creep deformation and intradiscal pressure) between model and experiment was obtained using constitutive properties that are the same for annulus and nucleus. Both tissue models differed in the 3D OVED model only by composition. The composition-based modeling presents the advantage of reducing the numbers of material parameters to a minimum and to use tissue composition directly as input. Hence, this approach provides the possibility to describe internal

  6. The Early Stage Adjacent Disc Degeneration after Percutaneous Vertebroplasty and Kyphoplasty in The Treatment of Osteoporotic VCFs

    PubMed Central

    Qian, Jun; Yang, Huilin; Jing, Juehua; Zhao, Hong; Ni, Li; Tian, Dasheng; Wang, Zhengfei

    2012-01-01

    Background The purpose of this paper is to determine the early incidence of disc de- generation adjacent to the vertebral body of osteoporotic fracture treated with percutaneous vertebroplasty or balloon kyphoplasty and whether adjacent disc degeneration is accelerated by this two procedures. Methods 182 patients with painful vertebral compression fractures were treated. A total of 97 patients were enrolled in this prospective study. 97 patients with a mean age of 65.3 years were classified into control group and surgical treatment group of non-random. 35 patients were in contol group and 62 patients who were performed percutaneous vertebroplasty or balloon kyphoplasty in treatment group. X-ray and Magnetic resonance imaging were done at the first and final visit. The grade of disc degeneration above the fractured vertebral was confirmed by evaluation of bony oedema in the fat suppressed sequences and T2-weighted image of magnetic resonance imaging. The height of degenerative disc was measured on X-ray film. Results All patients were followed up two years after the first visit and the follow-up rate was 90.7% (88/97). The incidence of degeneration of adjacent disc above the fractured vertebral was 29.0% (9/31) in control group and 52.6% (30/57) in treatment group. It presented a statistically significant difference between two groups about the incidence of adjacent disc degeneration (P = 0.033). The percentage of adjacent disc height reduction in control group was 13.5% and 17.6% in treatment group. Statistically significant difference of VAS score and ODI was not found between the first evaluation postoperatively and the final follow-up in treatment group (P>0.05). Conclusions Disc degeneration adjacent to the fractured vertebral is accelerated by VP and BK procedures in the early stage, but clinical outcomes has not been weakened even in the presence of accelerated disc degeneration. PMID:23056283

  7. TWEAK/Fn14 signaling: a promising target in intervertebral disc degeneration.

    PubMed

    Liu, Yu-Ping; Yuan, Chong-Ming; Zhang, Shuai-Gong; Hao, Qing-Hai; Wang, Ming-Ming; Zhang, Zhong; Meng, Qian; Li, Ming; Hao, Yue-Dong

    2016-09-01

    Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a potent chemoattractant cytokine with various biological functions, such as stimulation of angiogenesis, induction of proinflammatory cytokines, regulation of cellular proliferation and apoptosis. Therefore, it has also been implicated in several pathological processes, from cancer to inflammatory diseases. Remarkably, TWEAK and its receptors, fibroblast growth factor inducible 14 (Fn14), are also present in intervertebral disc (IVD) tissue, where they play a role in the pathogenesis of IVD degeneration. The interaction of TWEAK with Fn14 is involved in physiological and pathological activities of IVD degeneration patients, which includes apoptosis of endplate chondrocytes, extracellular matrix degradation, reduction in proteoglycan synthesis and so on. The blockade of this interaction results in suppressing over-production of proinflammatory factors and cell death in in vivo or in vitro experiments, suggesting that TWEAK/Fn14 signaling may be therapeutically relevant in IVD degeneration, and the targeting of TWEAK or Fn14 has been proposed as a potential therapeutic approach for autoimmune diseases such as Rheumatoid arthritis (RA). In this article, we discuss the biological features of TWEAK/Fn14 signaling and summarize recent advances in our understanding of the role of TWEAK/Fn14 signaling in the pathogenesis and treatment of IVD degeneration. We think that the blockade of TWEAK/Fn14 signaling may be a promising therapeutic strategy for IVD degeneration in the near future. PMID:26907852

  8. Enhancement of Runx2 expression is potentially linked to β-catenin accumulation in canine intervertebral disc degeneration.

    PubMed

    Iwata, Munetaka; Aikawa, Takeshi; Hakozaki, Takaharu; Arai, Kiyotaka; Ochi, Hiroki; Haro, Hirotaka; Tagawa, Masahiro; Asou, Yoshinori; Hara, Yasushi

    2015-01-01

    Intervertebral disc degeneration (IVDD) greatly affects the quality of life. The nucleus pulposus (NP) of chondrodystrophic dog breeds (CDBs) is similar to the human NP because the cells disappear with age and are replaced by fibrochondrocyte-like cells. Because IVDD develops as early as within the first year of life, we used canines as a model to investigate the in vitro mechanisms underlying IVDD. The mechanism underlying age-related IVDD, however, is poorly understood. Several research groups have suggested that Wnt/β-catenin signaling plays an important role in IVDD. However, the role of Wnt/β-catenin signals in IVD cells is not yet well understood. Here, we demonstrate that Wnt/β-catenin signaling could enhance Runx2 expression in IVDD and lead to IVD calcification. Nucleus pulposus (NP) tissue was obtained from Beagle dogs after evaluation of the degeneration based on magnetic resonance imaging (MRI). Histological analysis showed that lack of Safranin-O staining, calcified area, and matrix metalloproteinase (MMP) 13-positive cells increased with progression of the degeneration. Furthermore, the levels of β-catenin- and Runx2-positive cells also increased. Real-time reverse-transcription polymerase chain reaction analysis showed that the MRI signal intensity and mRNA expression levels of β-catenin and Runx2 are correlated in NP tissues. Moreover, supplementation of LiCl induced β-catenin accumulation and Runx2 expression. In contrast, FH535 inhibited LiCl-induced upregulation. These results suggest that Runx2 transcript and protein expression, potentially in combination with β-catenin accumulation, are enhanced in degenerated and calcified intervertebral discs of CDBs. PMID:24916026

  9. Association between ADAMTS-4 gene polymorphism and lumbar disc degeneration in Chinese Han population.

    PubMed

    Liu, Sen; Wu, Nan; Liu, Jiaqi; Liu, Hao; Su, Xinlin; Liu, Zhenlei; Zuo, Yuzhi; Chen, Weisheng; Liu, Gang; Chen, Yixin; Ming, Yue; Yuan, Tangmi; Li, Xiao; Chen, Jun; Xia, Zenan; Wang, Shengru; Chen, Jia; Liu, Tao; Yang, Xu; Ma, Yufen; Zhang, Jianguo; Shen, Jianxiong; Li, Shugang; Wang, Yipeng; Zhao, Hong; Yu, Keyi; Zhao, Yu; Huang, Shishu; Weng, Xisheng; Qiu, Guixing; Wan, Chao; Zhou, Guangqian; Wu, Zhihong

    2016-05-01

    Low back pain (LBP) is a common health problem and many LBP are caused by lumbar disc degeneration (LDD). ADAMTS-4 (a disintegrin and metalloprotease with thrombospondin motifs-4), also known as aggrecanse-1, plays a core role in degeneration of extracellular matrix in LDD. To investigate the association between ADAMTS-4 genetic polymorphism and LDD, we genotyped SNPs in and around ADAMTS-4. We recruited 482 sporadic cases of LDD and 496 healthy controls from Chinese Han population. Five SNPs were selected and phenotyped by the Sequenom MassARRAY system. Allelic, genotypic, and haplotypic association was performed. Rs4233367 (c.1877 C>T), which located in exon of ADAMTS-4 showed significant association with LDD. The T allele conferred a lower risk of LDD with an OR of 0.69 and TT genotype is at nearly one-fifth of the risk compared to CC genotype. Other tested SNPs didn't show significant difference between the case and control groups. The SNP rs4233367 in the exon of ADAMTS-4 gene may be associated with lumbar disc degeneration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:860-864, 2016. PMID:26495885

  10. Viscoelastic Disc Arthroplasty Provides Superior Back and Leg Pain Relief in Patients with Lumbar Disc Degeneration Compared to Anterior Lumbar Interbody Fusion

    PubMed Central

    Rischke, Burkhard; Smith, Eric

    2015-01-01

    Background Lumbar disc degeneration (LDD) is one of the most frequently diagnosed spinal diseases. The symptoms these disorders cause are anticipated to increase as the population in Western countries ages. Purpose Compare back and leg pain alleviation in patients with LDD and a viscoelastic disc prosthesis documented in the SWISSspine registry versus patients with anterior lumbar interbody fusion documented in the Spine Tango registry. Study Design Prospectively collected clinical and outcome data in two independent spine registries. Outcome Measures were back and leg pain relief on 0 to 10 numerical rating scales. Materials and Methods The analysis included a single surgeon series of 48 patients with viscoelastic total disc replacement (VTDR) from the SWISSspine registry which were compared to 131 patients with anterior lumbar interbody fusion (ALIF) from the Spine Tango registry. Two linear multivariate regression models were built to assess the associations of patient characteristics with back and leg pain relief. The following covariates were included in the models: patient age and sex, disc herniation as additional diagnosis, number of treated segments, level of treated segment, treatment type (VTDR, ALIF), preoperative back and leg pain levels and follow-up interval. Results Both models showed VTDR to be associated with significantly higher back (2.76 points; 95% confidence interval (CI) 1.78 - 3.73; p < 0.001) and leg pain (2.12 points; 95% CI 1.12 to 3.13; p < 0.001) relief than ALIF. Other influential factors for higher back pain relief were female sex compared with male sex (1.03 additional points; 95% CI 0.27 to 1.78; p = 0.008), monosegmental surgery compared with bisegmental surgery (1.02 additional points; 95% CI 0.21 to 1.83; p = 0.014), and higher back pain at baseline (0.87 points additional pain relief per level of preoperative back pain; 95% CI 0.70 to 1.03; p < 0.001). Other influential factors for leg pain relief were monosegmental surgery (0

  11. High Prevalence of Disc Degeneration and Spondylolysis in the Lumbar Spine of Professional Beach Volleyball Players

    PubMed Central

    Külling, Fabrice A.; Florianz, Hannes; Reepschläger, Bastian; Gasser, Johann; Jost, Bernhard; Lajtai, Georg

    2014-01-01

    Background: Beach volleyball is an intensive sport with high impact on the lumbar spine. Low back pain (LBP) is frequent among elite players. Increased prevalence of pathological changes on magnetic resonance imaging (MRI) in the lumbar spine of elite athletes has been reported. Hypothesis: There is an increased prevalence of disc degeneration and spondylolysis in the MRI of the lumbar spine of professional beach volleyball players. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Twenty-nine fully competitive professional male volleyball players (mean age, 28 years) completed outcomes questionnaires and underwent a complete clinical examination and an MRI of their lumbar spine. Results: Whereas 86% of players suffered from LBP during their career, the incidence of LBP in the last 4 weeks was 35%. Pain rated using a visual analog scale (VAS) averaged 3 points (range, 0-8). Twenty-three of 29 players (79%) had at least 1 degenerated disc of Pfirrmann grade ≥3. The most affected spinal levels were L4-5 in 14 (48%) and L5-S1 in 15 players (52%); both levels were involved in 5 players (17%). Six of 29 (21%) players showed a spondylolysis grade 4 according to the Hollenburg classification; there was evidence of spondylolisthesis in 2 players. There was no significant correlation between LBP and MRI abnormalities. Conclusion: In the lumbar spine MRI of professional beach volleyball players, the prevalence of disc degeneration is 79%. Spondylolysis (21%) is up to 3 times higher compared with the normal population. Abnormal MRI findings did not correlate with LBP, thus MRIs have to be interpreted with caution. PMID:26535316

  12. Degeneration of the intervertebral disc with new approaches for treating low back pain.

    PubMed

    Le Maitre, C L; Binch, A L; Thorpe, A A; Hughes, S P

    2015-03-01

    This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities. PMID:25423135

  13. Role of posterior elements in the disc bulging of a degenerated cervical spine

    PubMed Central

    Solitro, Giovanni F.; Siemionow, Kris; Drucker, David; Upadhyay, Ashish; Patel, Priyesh

    2015-01-01

    Background Many studies have been developed to characterize the mechanical behavior of the intervertebral disc specifically for the lumbar spine and there have been limited studies done on the cervical spine with the goal to evaluate the strength of the cervical spine under compression without any information on the bulging of the intervertebral discs. The goal of the current study is to examine the deformation response of the cervical intervertebral disc classified with grade III or greater degeneration and analyze the relationship between axial deformation and anterior and posterior bulge under compression up to 550 N. Methods Each specimen was compressed for 3 cycles to a maximum load of 550N in steps of 50 N. The bulge was measured using Linear Variable Differential Transformers (LVDTs on an intact spinal segment, spinal segment with post laminectomy, and spinal segment post facetectomy. Results The anterior budge for an intact spinal segment shows a change of slope at loads of 262N±66N. For a physiological load of 250N the vertical displacement or spine segment height was reduced by 10.1% for an intact segment and 8.78% for the laminectomy and facetectomy configurations with F = 0.159 (Fcrit = 3.89) with no statistical difference observed. For the post laminectomy there was a decrease of 35% in anterior bulge compared to the intact specimen. Conclusions Our results show that for grade III disc degeneration the cervical segments bulging for both the laminectomy and facetectomy procedures are not significantly different. In post laminectomy the average anterior and posterior bulges are similar to the average anterior and posterior bulge post facetectomy. PMID:26056628

  14. Lumbar spinal stenosis is a highly genetic condition partly mediated by disc degeneration.

    PubMed

    Battié, Michele C; Ortega-Alonso, Alfredo; Niemelainen, Riikka; Gill, Kevin; Levalahti, Esko; Videman, Tapio; Kaprio, Jaakko

    2014-12-01

    Objective. Lumbar spinal stenosis is one of the most commonly diagnosed spinal disorders in older adults. Although the pathophysiology of the clinical syndrome is not well understood, a narrow central canal or intervertebral foramen is an essential or defining feature. The aim of the present study was to estimate the magnitude of genetic versus environmental influences on central lumbar spinal stenosis and to investigate disc degeneration and stature or bone development as possible genetic pathways.Methods. A classic twin study with multivariate analyses considering lumbar level and other covariates was conducted. The study sample comprised 598 male twins (147 monozygotic and 152 dizygotic pairs), 35-70 years of age, from the population-based Finnish Twin Cohort. The primary phenotypes were central lumbar stenosis as assessed qualitatively on magnetic resonance imaging (MRI) and quantitatively measured dural sac cross-sectional area. Additional phenotypes (to examine possible genetic pathways) included disc bulging and standing height, as an indicator of overall skeletal size or development.Results. The heritability estimate (h²) for qualitatively assessed central lumbar spinal stenosis on MRI was 66.9% (95% confidence interval [95% CI] 56.8,74.5). The broad-sense heritability estimate for dural sac cross-sectional area was 81.2% (95% CI 74.5, 86.1),with a similar magnitude of genetic influences across lumbar levels (h²=72.4–75.6). The additive genetic correlation of quantitatively assessed stenosis and disc bulging was extremely high. There was no indication of shared genetic influences between stenosis and stature.Conclusion. Central lumbar spinal stenosis and associated dural sac dimensions are highly genetic, and disc degeneration (bulging) appears to be one pathway through which genes influence spinal stenosis. PMID:25155712

  15. Acid-sensing ion channels in healthy and degenerated human intervertebral disc.

    PubMed

    Cuesta, Antonio; Del Valle, Miguel E; García-Suárez, Olivia; Viña, Eliseo; Cabo, Roberto; Vázquez, Gorka; Cobo, Juan L; Murcia, Antonio; Alvarez-Vega, Marco; García-Cosamalón, José; Vega, José A

    2014-06-01

    Acid-sensing ion channels (ASICs) are a family of H(+)-gated voltage-insensitive ion channels that respond to extracellular acidification by regulating transmembrane Ca(2+) flux. Moreover, ASICs can also be gated by mechanical forces and may function as mechanosensors. The cells of the intervertebral disc (IVD) have an unusual acidic and hyperosmotic microenvironment. Changes in the pH and osmolarity determine the viability of IVD cells and the composition of the extracellular matrix, and both are the basis of IVD degeneration. In this study, the expression of ASICs (ASIC1, ASIC2, ASIC3 and ASIC4) mRNAs and proteins in human healthy and degenerated IVD was evaluated by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot. The distribution of ASIC proteins was determined by immunohistochemistry. The mRNAs for all ASICs were detected in normal human IVD, and significantly increased levels were found in degenerated IVD. Western blots demonstrated the presence of proteins with estimated molecular weights of approximately 68-72 kDa. In both the annulus fibrosus (AF) and nucleus pulposus (NP) of normal IVD, ASIC2 is the most frequently expressed ASIC followed by ASIC3, ASIC1 and ASIC4. In the AF of degenerated IVD, there was a significant increase in the number of ASIC1 and ASIC4 positive cells, whereas in the NP, we found significant increase of expression of ASIC1, ASIC2 and ASIC3. These results describe the occurrence and localization of different ASICs in human healthy IVD, and their increased expression in degenerated IVD, thus suggesting that ASICs may be involved in IVD degeneration. PMID:24432912

  16. Magnetic resonance imaging on disc degeneration changes after implantation of an interspinous spacer and fusion of the adjacent segment

    PubMed Central

    Liu, Xiaokang; Liu, Yingjie; Lian, Xiaofeng; Xu, Jianguang

    2015-01-01

    The aim of the study was to investigate the changes of the lumbar intervertebral disc degeneration by magnetic resonance imaging (MRI) after the implantation of interspinous device and the fusion of the adjacent segment. A total of 62 consecutive patients suffering L5/S1 lumbar disc herniation (LDH) with concomitant disc space narrowing or low-grade instability up to 5 mm translational slip in L5/S1 level were treated with lumbar interbody fusion (LIF) via posterior approach. Thirty-four of these patients (Coflex group) received an additional implantation of the interspinous spacer device (Coflex™) in the level L4/L5, while the rest of 28 patients (fusion group) underwent the fusion surgery alone. Clinical and radiographic examinations were performed at pre- and postoperative visits to compare the clinical outcomes and the changes of the L4/L5 vertebral disc degeneration on MRI in both Coflex and fusion group. Although both Coflex and fusion group showed improvements of the clinical outcomes assessed by the Oswestry Disability Index (ODI) after surgery, patients in Coflex group had more significant amelioration (P < 0.05) compared to fusion group. During follow up, the postoperative disc degeneration changes in Coflex group assessed by the relative signal intensity (RSI) differed from those in fusion group (P < 0.05). The supplemental implantation of Coflex™ after the fusion surgery could delay the disc degeneration of the adjacent segment. PMID:26131210

  17. 2D segmentation of intervertebral discs and its degree of degeneration from T2-weighted magnetic resonance images

    NASA Astrophysics Data System (ADS)

    Castro-Mateos, Isaac; Pozo, José Maria; Lazary, Aron; Frangi, Alejandro F.

    2014-03-01

    Low back pain (LBP) is a disorder suffered by a large population around the world. A key factor causing this illness is Intervertebral Disc (IVD) degeneration, whose early diagnosis could help in preventing this widespread condition. Clinicians base their diagnosis on visual inspection of 2D slices of Magnetic Resonance (MR) images, which is subject to large interobserver variability. In this work, an automatic classification method is presented, which provides the Pfirrmann degree of degeneration from a mid-sagittal MR slice. The proposed method utilizes Active Contour Models, with a new geometrical energy, to achieve an initial segmentation, which is further improved using fuzzy C-means. Then, IVDs are classified according to their degree of degeneration. This classification is attained by employing Adaboost on five specific features: the mean and the variance of the probability map of the nucleus using two different approaches and the eccentricity of the fitting ellipse to the contour of the IVD. The classification method was evaluated using a cohort of 150 intervertebral discs assessed by three experts, resulting in a mean specificity (93%) and sensitivity (83%) similar to the one provided by every expert with respect to the most voted value. The segmentation accuracy was evaluated using the Dice Similarity Index (DSI) and Root Mean Square Error (RMSE) of the point-to-contour distance. The mean DSI ± 2 standard deviation was 91:7% ±5:6%, the mean RMSE was 0:82mm and the 95 percentile was 1:36mm. These results were found accurate when compared to the state-of-the-art.

  18. [MicroRNAs: a type of novel regulative factor for intervertebral disc degeneration].

    PubMed

    Cheng, Wang; Wenjun, Wang; Wei, Yang; Xiaohua, Y U; Yiguo, Yan; Jian, Zhang; Zhisheng, Jiang

    2016-03-25

    Intervertebral disc degeneration (IDD) is one of major causes for intervertebral disc degenerative diseases, and patients with IDD usually suffer from serious low back pain. The current treatments for patients with IDD only relieve the clinical symptom rather than restore biological balance of IDD, leading to inadequate and unsatisfactory results. MicroRNAs (miRNAs) are endogenous, non-coding, single-stranded RNA molecules, which regulate the gene expression at the post-transcription levels. Research evidences support the involvement of miRNAs in many biological processes, such as lipid metabolism, apoptosis, differentiation and organ development. Accumulating evidences indicate that the expressions of miRNAs change significantly in degenerative tissues. In addition, dysregulated miRNAs contribute to multiple pathological process of IDD, including proliferation and apoptosis of nucleus pulposus and extracellular matrix components, inflammatory response and cartilage endplates degeneration. In this review article, we summarize the expression profiles and roles of miRNAs in IDD, which may provide a novel strategy of biological therapy for the disease. PMID:27273991

  19. Best paper NASS 2013: link-N can stimulate proteoglycan synthesis in the degenerated human intervertebral discs.

    PubMed

    Gawri, Rahul; Antoniou, John; Ouellet, Jean; Awwad, Waleed; Steffen, Thomas; Roughley, Peter; Haglund, Lisbet; Mwale, Fackson

    2013-01-01

    Intervertebral disc (IVD) degeneration is the most common cause of back pain. Presently there is no medical treatment, leaving surgery as the only offered option. Here we evaluate the potential of Link-N to promote extracellular matrix regeneration in human IVDs. Human disc cells cultured in alginate and intact human discs were exposed to a combination of Link-N and ³⁵SO₄ in the presence or absence of interleukin (IL)-1, and the effect on proteoglycan synthesis was evaluated. In addition, message levels of aggrecan, matrix metalloproteinase (MMP)-3, MMP-13, a Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS)-4 and ADAMTS-5 were evaluated in alginate cultures. Human disc cells responded in a dose dependent manner with maximal proteoglycan synthesis at 1 µg/mL Link-N. Link-N treatment also induced proteoglycan synthesis in intact human discs, and a prolonged effect was found up to one week after Link-N treatment. Message levels of proteinases were decreased by Link-N in the presence of IL-1. Thus, Link-N can promote proteoglycan synthesis and deplete proteinase expression in adult human discs. Link-N could therefore be a promising candidate for biologically-induced disc repair, and could provide an alternative to surgical intervention for early stage disc degeneration. PMID:24027023

  20. ADAMTS-5 and intervertebral disc degeneration: the results of tissue immunohistochemistry and in vitro cell culture.

    PubMed

    Zhao, Chang-Qing; Zhang, Yue-Hui; Jiang, Sheng-Dan; Li, Hai; Jiang, Lei-Sheng; Dai, Li-Yang

    2011-05-01

    Matrix metalloproteinases (MMPs) are known to be involved in IVD degeneration by hydrolyzing the extracellular matrix (ECM), especially the collagens. The degradation of proteoglycans, which is another main ECM component in the IVD, however, has not been extensively investigated. This study aimed to determine the expression of ADAMTS-5 in human herniated intervertebral disc (IVD) tissues and to investigate whether interleukin-1β (IL-1β)-induced expression of ADAMTS-5 is mediated by nitric oxide (NO). Forty-five herniated IVDs were harvested and immunostained to determine the distribution and type of ADAMTS-5 expressing cells. Rat NP cells maintained in alginate beads were treated with IL-1β, accumulation of NO was detected by Griess reaction, the expression of ADAMTS-5 and inducible nitric oxide synthase (iNOS) was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), the content of proteoglycans in alginate beads was visualized by alcian blue staining, and the effect of aminoguanidine on the changes in alginate beads induced by IL-1β treatment were also examined. Immunohistochemical results from 45 herniated discs showed that ADAMTS-5-positive cells are commonly seen in cell clusters, that the percentage of ADAMTS-5-positive cells was higher in uncontained herniated discs than in contained ones, and that the percentage of ADAMTS-5-positive cells correlated with the age of the patients. IL-1β treatment resulted in increased accumulation of NO, increased expression of ADAMTS-5 and iNOS, whereas the accumulation of proteoglycan in alginate beads decreased. Aminoguanidine significantly reversed the changes in alginate beads induced by IL-1β treatment. We thus suggested that ADAMTS-5 is probably involved in the process of IVD degeneration, and that IL-1β-induced expression of ADAMTS-5 is mediated by NO. PMID:21437951

  1. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

    PubMed Central

    Song, You-Qiang; Karasugi, Tatsuki; Cheung, Kenneth M.C.; Chiba, Kazuhiro; Ho, Daniel W.H.; Miyake, Atsushi; Kao, Patrick Y.P.; Sze, Kit Ling; Yee, Anita; Takahashi, Atsushi; Kawaguchi, Yoshiharu; Mikami, Yasuo; Matsumoto, Morio; Togawa, Daisuke; Kanayama, Masahiro; Shi, Dongquan; Dai, Jin; Jiang, Qing; Wu, Chengai; Tian, Wei; Wang, Na; Leong, John C.Y.; Luk, Keith D.K.; Yip, Shea-ping; Cherny, Stacey S.; Wang, Junwen; Mundlos, Stefan; Kelempisioti, Anthi; Eskola, Pasi J.; Männikkö, Minna; Mäkelä, Pirkka; Karppinen, Jaro; Järvelin, Marjo-Riitta; O’Reilly, Paul F.; Kubo, Michiaki; Kimura, Tomoatsu; Kubo, Toshikazu; Toyama, Yoshiaki; Mizuta, Hiroshi; Cheah, Kathryn S.E.; Tsunoda, Tatsuhiko; Sham, Pak-Chung; Ikegawa, Shiro; Chan, Danny

    2013-01-01

    Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA. PMID:24216480

  2. Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant.

    PubMed

    Song, You-Qiang; Karasugi, Tatsuki; Cheung, Kenneth M C; Chiba, Kazuhiro; Ho, Daniel W H; Miyake, Atsushi; Kao, Patrick Y P; Sze, Kit Ling; Yee, Anita; Takahashi, Atsushi; Kawaguchi, Yoshiharu; Mikami, Yasuo; Matsumoto, Morio; Togawa, Daisuke; Kanayama, Masahiro; Shi, Dongquan; Dai, Jin; Jiang, Qing; Wu, Chengai; Tian, Wei; Wang, Na; Leong, John C Y; Luk, Keith D K; Yip, Shea-ping; Cherny, Stacey S; Wang, Junwen; Mundlos, Stefan; Kelempisioti, Anthi; Eskola, Pasi J; Männikkö, Minna; Mäkelä, Pirkka; Karppinen, Jaro; Järvelin, Marjo-Riitta; O'Reilly, Paul F; Kubo, Michiaki; Kimura, Tomoatsu; Kubo, Toshikazu; Toyama, Yoshiaki; Mizuta, Hiroshi; Cheah, Kathryn S E; Tsunoda, Tatsuhiko; Sham, Pak-Chung; Ikegawa, Shiro; Chan, Danny

    2013-11-01

    Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA. PMID:24216480

  3. Genetic and Functional Studies of the Intervertebral Disc: A Novel Murine Intervertebral Disc Model

    PubMed Central

    Pelle, Dominic W.; Peacock, Jacqueline D.; Schmidt, Courtney L.; Kampfschulte, Kevin; Scholten, Donald J.; Russo, Scott S.; Easton, Kenneth J.; Steensma, Matthew R.

    2014-01-01

    Intervertebral disc (IVD) homeostasis is mediated through a combination of micro-environmental and biomechanical factors, all of which are subject to genetic influences. The aim of this study is to develop and characterize a genetically tractable, ex vivo organ culture model that can be used to further elucidate mechanisms of intervertebral disc disease. Specifically, we demonstrate that IVD disc explants (1) maintain their native phenotype in prolonged culture, (2) are responsive to exogenous stimuli, and (3) that relevant homeostatic regulatory mechanisms can be modulated through ex-vivo genetic recombination. We present a novel technique for isolation of murine IVD explants with demonstration of explant viability (CMFDA/propidium iodide staining), disc anatomy (H&E), maintenance of extracellular matrix (ECM) (Alcian Blue staining), and native expression profile (qRT-PCR) as well as ex vivo genetic recombination (mT/mG reporter mice; AdCre) following 14 days of culture in DMEM media containing 10% fetal bovine serum, 1% L-glutamine, and 1% penicillin/streptomycin. IVD explants maintained their micro-anatomic integrity, ECM proteoglycan content, viability, and gene expression profile consistent with a homeostatic drive in culture. Treatment of genetically engineered explants with cre-expressing adenovirus efficaciously induced ex vivo genetic recombination in a variety of genetically engineered mouse models. Exogenous administration of IL-1ß and TGF-ß3 resulted in predicted catabolic and anabolic responses, respectively. Genetic recombination of TGFBR1fl/fl explants resulted in constitutively active TGF-ß signaling that matched that of exogenously administered TGF-ß3. Our results illustrate the utility of the murine intervertebral disc explant to investigate mechanisms of intervertebral disc degeneration. PMID:25474689

  4. Inter-lamellar shear resistance confers compressive stiffness in the intervertebral disc: An image-based modelling study on the bovine caudal disc.

    PubMed

    Adam, Clayton; Rouch, Philippe; Skalli, Wafa

    2015-12-16

    The intervertebral disc withstands large compressive loads (up to nine times bodyweight in humans) while providing flexibility to the spinal column. At a microstructural level, the outer sheath of the disc (the annulus fibrosus) comprises 12-20 annular layers of alternately crisscrossed collagen fibres embedded in a soft ground matrix. The centre of the disc (the nucleus pulposus) consists of a hydrated gel rich in proteoglycans. The disc is the largest avascular structure in the body and is of much interest biomechanically due to the high societal burden of disc degeneration and back pain. Although the disc has been well characterized at the whole joint scale, it is not clear how the disc tissue microstructure confers its overall mechanical properties. In particular, there have been conflicting reports regarding the level of attachment between adjacent lamellae in the annulus, and the importance of these interfaces to the overall integrity of the disc is unknown. We used a polarized light micrograph of the bovine tail disc in transverse cross-section to develop an image-based finite element model incorporating sliding and separation between layers of the annulus, and subjected the model to axial compressive loading. Validation experiments were also performed on four bovine caudal discs. Interlamellar shear resistance had a strong effect on disc compressive stiffness, with a 40% drop in stiffness when the interface shear resistance was changed from fully bonded to freely sliding. By contrast, interlamellar cohesion had no appreciable effect on overall disc mechanics. We conclude that shear resistance between lamellae confers disc mechanical resistance to compression, and degradation of the interlamellar interface structure may be a precursor to macroscopic disc degeneration. PMID:26549764

  5. Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity

    PubMed Central

    Jia, Haobo; Ma, Jianxiong; Lv, Jianwei; Ma, Xinlong; Xu, Weiguo; Yang, Yang; Tian, Aixian; Wang, Ying; Sun, Lei; Xu, Liyan; Fu, Lin; Zhao, Jie

    2016-01-01

    To investigate the mitigation effect and mechanism of oestrogen and PTH on disc degeneration in rats after ovariectomy, as well as on Wnt/β-catenin pathway activity, thirty 3-month-old rats were ovariectomized and divided into three groups. Ten additional rats were used as controls. Eight weeks later, the rats were administered oestrogen or PTH for 12 weeks, and then discs were collected for tests. Results showed that nucleus pulposus cells in the Sham group were mostly notochord cells, while in the OVX group, cells gradually developed into chondrocyte-like cells. Oestrogen or PTH could partly recover the notochord cell number. After ovariectomy, the endplate roughened and endplate porosity decreased. After oestrogen or PTH treatment, the smoothness and porosity of endplate recovered. Compared with the Sham group, Aggrecan, Col2a and Wnt/β-catenin pathway expression in OVX group decreased, and either oestrogen or PTH treatment improved their expression. The biomechanical properties of intervertebral disc significantly changed after ovariectomy, and oestrogen or PTH treatment partly recovered them. Disc degeneration occurred with low oestrogen, and the underlying mechanisms involve nutrition supply disorders, cell type changes and decreased Wnt/β-catenin pathway activity. Oestrogen and PTH can retard disc degeneration in OVX rats and enhance Wnt/β-catenin pathway activity in nucleus pulposus. PMID:27279629

  6. Oestrogen and parathyroid hormone alleviate lumbar intervertebral disc degeneration in ovariectomized rats and enhance Wnt/β-catenin pathway activity.

    PubMed

    Jia, Haobo; Ma, Jianxiong; Lv, Jianwei; Ma, Xinlong; Xu, Weiguo; Yang, Yang; Tian, Aixian; Wang, Ying; Sun, Lei; Xu, Liyan; Fu, Lin; Zhao, Jie

    2016-01-01

    To investigate the mitigation effect and mechanism of oestrogen and PTH on disc degeneration in rats after ovariectomy, as well as on Wnt/β-catenin pathway activity, thirty 3-month-old rats were ovariectomized and divided into three groups. Ten additional rats were used as controls. Eight weeks later, the rats were administered oestrogen or PTH for 12 weeks, and then discs were collected for tests. Results showed that nucleus pulposus cells in the Sham group were mostly notochord cells, while in the OVX group, cells gradually developed into chondrocyte-like cells. Oestrogen or PTH could partly recover the notochord cell number. After ovariectomy, the endplate roughened and endplate porosity decreased. After oestrogen or PTH treatment, the smoothness and porosity of endplate recovered. Compared with the Sham group, Aggrecan, Col2a and Wnt/β-catenin pathway expression in OVX group decreased, and either oestrogen or PTH treatment improved their expression. The biomechanical properties of intervertebral disc significantly changed after ovariectomy, and oestrogen or PTH treatment partly recovered them. Disc degeneration occurred with low oestrogen, and the underlying mechanisms involve nutrition supply disorders, cell type changes and decreased Wnt/β-catenin pathway activity. Oestrogen and PTH can retard disc degeneration in OVX rats and enhance Wnt/β-catenin pathway activity in nucleus pulposus. PMID:27279629

  7. Understanding nucleus pulposus cell phenotype: A prerequisite for stem cell based therapies to treat intervertebral disc degeneration

    PubMed Central

    Choi, Hyowon; Johnson, Zariel I.; Risbud, Makarand V.

    2015-01-01

    Intervertebral disc (IVD) degeneration and associated low back pain (LBP) remains a major burden to our society without a significant improvement in treatment strategies or patient’s quality of life. While the recent cell-transplantation studies for treatment of degenerative disc disease showed promising results, to better gauge the success and functional outcomes of these therapies, it is crucial to understand if transplanted cells give rise to healthy nucleus pulposus (NP) tissue. NP cell phenotype is unique and is defined by expression of a characteristic set of markers that reflect their specialized physiology and function. This review summarizes phenotypic markers that mirror unique physiology and function of NP cells and their progenitors and should be considered to measure outcomes of cell-based therapies to treat disc degeneration. PMID:25584906

  8. Elevated interleukin-6 expression levels are associated with intervertebral disc degeneration

    PubMed Central

    DENG, XIAO; ZHAO, FENG; KANG, BAOLIN; ZHANG, XIN

    2016-01-01

    The present study aimed to investigate whether serum interleukin-6 (IL-6) expression levels were associated with the onset and progression of intervertebral disc degeneration (IDD). A comprehensive meta-analysis of the scientific literature from numerous electronic databases was performed, in order to obtain published studies associated with the topic of interest. Relevant case-control studies that had previously assessed a correlation between IL-6 expression levels and IDD were identified using predetermined inclusion and exclusion criteria. The STATA version 12.0 software was used for statistical analysis of the extracted data. A total of 112 studies were initially retrieved, with eight studies meeting the inclusion criteria. These contained a total of 392 subjects, of which 263 were patients with IDD and 129 were healthy controls. A meta-analysis of the eight studies demonstrated that serum IL-6 protein expression levels may be associated with IDD, and this was irrespective of IDD subtype (bulging, protrusion, or sequestration). Notably, serum expression levels of the IL-6 protein were upregulated in intervertebral disc (IVD) protrusion tissue, as compared with normal IVD tissue; thus suggesting that IL-6 may have an important role in the pathophysiological process of IDD. PMID:27073460

  9. Prevalence and pattern of radiographic intervertebral disc degeneration in Vietnamese: a population-based study.

    PubMed

    Ho-Pham, Lan T; Lai, Thai Q; Mai, Linh D; Doan, Minh C; Pham, Hoa N; Nguyen, Tuan V

    2015-06-01

    Intervertebral disc degeneration (IDD) is one of the most common skeletal disorders, yet few data are available in Asian populations. We sought to assess the prevalence and pattern of radiographic IDD in a Vietnamese population. This population-based cross-sectional investigation involved 170 men and 488 women aged ≥40 years, who were randomly sampled from the Ho Chi Minh City (Vietnam). Anthropometric data, clinical history and self-reported back and neck pain were ascertained by a questionnaire. Plain radiographs (from the cervical spine, thoracic spine to the lumbar spine) were examined for the presence of disc space narrowing and/or osteophytosis using the Kellgren-Lawrence (KL) grading system. The presence of radiographic IDD was defined if the KL grade was 2 or greater in at least one disc. The prevalence of radiographic IDD was 62.4% (n = 106) in men and 54.7% (n = 267) in women. The most frequently affected site was the lumbar spine with prevalence being 50.6 and 43.2% in men and women, respectively. The prevalence of IDD increased with advancing age: 18.8% among those aged 40-49 years, and increased to 83.4% in those aged ≥60 years. Self-reported neck pain and lower back pain were found in 30 and 44% of individuals, respectively. There was no statistically significant association between self-reported neck pain and cervical spine OA. These data suggest that radiographic IDD is highly prevalent in the Vietnamese population, and that self-reported back pain is not a sensitive indicator of IDD. PMID:25791571

  10. MyD88-dependent Toll-like receptor 4 signal pathway in intervertebral disc degeneration

    PubMed Central

    Qin, Chuqiang; Zhang, Bo; Zhang, Liang; Zhang, Zhi; Wang, Le; Tang, Long; Li, Shuangqing; Yang, Yixi; Yang, Fuguo; Zhang, Ping; Yang, Bo

    2016-01-01

    Lower back pain (LBP) is a common and remitting problem. One of the primary causes of LBP is thought to be degeneration of the intervertebral disc (IVD). The aim of the present study was to investigate the role of the myeloid differentiation primary-response protein 88 (MyD88)-dependent Toll-like receptor 4 (TLR4) signal pathway in the mechanism of IVD degeneration. IVD nucleus pulposus cells isolated and cultured from the lumbar vertebrae of Wistar rats were stimulated by various doses of lipopolysaccharide (LPS; 0.1, 1, 10 and 100 µg/ml) to simulate IVD degeneration. Cells were rinsed and cultured in serum-free Dulbecco's modified Eagle's medium/F12. Reverse transcription-quantitative polymerase chain reaction was used to determine the levels of TLR4, MyD88, tumor necrosis factor α (TNFα), and interleukin-1β (IL-1β) mRNA expression after 1, 3, 6, 9 and 12 h of incubation. Additionally, western blot and enzyme-linked immunosorbent assay analyses were used to determine the levels of TLR4, MyD88, TNFα, and IL-1β protein expression after 24, 48 and 72 h of incubation. The levels of TLR4, MyD88, TNFα and IL-1β mRNA all increased in the cells stimulated by 10 µg/ml LPS at 3, 6 and 9 h (all P<0.001). Furthermore, the levels of TLR4, MyD88, TNFα and IL-1β protein all increased at 24, 48 and 72 h (all P<0.001). Additionally, the mRNA and protein levels of TLR4, MyD88, TNFα and IL-1β increased significantly in the cells stimulated by 1, 10 and 100 µg/ml LPS compared with the control group, and reached a peak in the 10 µg/ml LPS group (all P<0.001). These results suggest that the MyD88-dependent TLR4 signal pathway is a target pathway in IVD degeneration. This pathway is time phase- and dose-dependent, and when activated can lead to the release of inflammatory factors that participate in IVD degeneration. PMID:27446251

  11. Aquaporin 3 protects against lumbar intervertebral disc degeneration via the Wnt/β-catenin pathway.

    PubMed

    Xie, Huanxin; Jing, Yongbin; Xia, Jingjun; Wang, Xintao; You, Changcheng; Yan, Jinglong

    2016-03-01

    Previous studies have demonstrated that the expression of aquaporin 3 (AQP3), a water channel which promotes glycerol permeability and water transport across cell membranes, is reduced in degenerative lumbar intervertebral disc (IVD) tissues. However, the role of AQP3 in the pathogenesis of IVD degeneration has not recieved much scholarly attention. The objective of the present study was to investigate the effect of AQP3 on cell proliferation and extracellular matrix (ECM) degradation in human nucleus pulposus cells (hNPCs) using gain-of-function and loss-of-function experiments, and to determine whether Wnt/β-catenin signaling is involved in the effect of AQP3 on IVD degeneration. hNPCs were transfected with the AQP3-pcDNA3.1 plasmid or AQP3 siRNA to overexpress or suppress AQP3. An MTT assay was performed to determine cell proliferation, and we found that AQP3 promoted hNPC proliferation. The expression of aggrecan, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)4 and ADAMTS5 was detected using western blot analysis, to examine the effect of AQP3 on ECM degradation in hNPCs. The results revealed that AQP3 inhibited ECM degradation in hNPCs. In addition, we found that Wnt/β-catenin signaling was suppressed by AQP3. However, the effect of AQP3 on hNPC proliferation and ECM degradation was reversed by treatment with lithium chloride, a known activator of Wnt/β‑catenin signaling. In conclusion, using in vitro and in vivo tests, we have reported for the first time, to the best of our knowledge, that AQP3 exerts protective effects against IVD degeneration, and these are effected, at least partially, through the inhibition of Wnt/β-catenin signaling. PMID:26820815

  12. Translation of an Engineered Nanofibrous Disc-like Angle Ply Structure for Intervertebral Disc Replacement in a Small Animal Model

    PubMed Central

    Martin, John T.; Milby, Andrew H.; Chiaro, Joseph A.; Kim, Dong Hwa; Hebela, Nader M.; Smith, Lachlan J.; Elliott, Dawn M.; Mauck, Robert L.

    2015-01-01

    Intervertebral disc degeneration has been implicated in the etiology of low back pain; however the current surgical strategies for treating symptomatic disc disease are limited. A variety of materials have been developed to replace disc components, including the nucleus pulposus (NP), the annulus fibrosus (AF), and their combination into disc-like engineered constructs. We have previously shown that layers of electrospun poly(ε-caprolactone) scaffold, mimicking the hierarchical organization of the native AF, have functional parity with native tissue. Likewise, we have combined these structures with cell-seeded hydrogels (as an NP replacement) to form disc-like angle ply structures (DAPS). The objective of this study was to develop a model for the evaluation of DAPS in vivo. Through a series of studies, we developed a surgical approach to replace the rat caudal disc with an acellular DAPS and then stabilize the motion segment by external fixation. We then optimized cell infiltration into DAPS by including sacrificial poly(ethylene oxide) layers interspersed throughout the angle-ply structure. Our findings illustrate that DAPS are stable in the caudal spine, are infiltrated by cells from the peri-implant space, and that infiltration is expedited by providing additional routes for cell migration. These findings establish a new in vivo platform in which to evaluate and optimize the design of functional disc replacements. PMID:24560621

  13. An organ culture system to model early degenerative changes of the intervertebral disc II: profiling global gene expression changes

    PubMed Central

    2013-01-01

    Introduction Despite many advances in our understanding of the molecular basis of disc degeneration, there remains a paucity of preclinical models which can be used to study the biochemical and molecular events that drive disc degeneration, and the effects of potential therapeutic interventions. The goal of this study is to characterize global gene expression changes in a disc organ culture system that mimics early nontraumatic disc degeneration. Methods To mimic a degenerative insult, rat intervertebral discs were cultured in the presence of TNF-α, IL-1β and serum-limiting conditions. Gene expression analysis was performed using a microarray to identify differential gene expression between experimental and control groups. Differential pattern of gene expression was confirmed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or Western blot. Results Treatment resulted in significant changes in expression of more than 1,000 genes affecting many aspects of cell function including cellular movement, the cell cycle, cellular development, and cell death and proliferation. Many of the most highly upregulated and downregulated genes have known functions in disc degeneration and extracellular matrix hemostasis. Construction of gene networks based on known cellular pathways and expression data from our analysis demonstrated that the network associated with cell death, cell cycle regulation and DNA replication and repair was most heavily affected in this model of disc degeneration. Conclusions This rat organ culture model uses cytokine exposure to induce wide gene expression changes with the most affected genes having known reported functions in disc degeneration. We propose that this model is a valuable tool to study the etiology of disc degeneration and evaluate potential therapeutic treatments. PMID:24171898

  14. An In Vivo Model of Reduced Nucleus Pulposus Glycosaminoglycan Content in the Rat Lumbar Intervertebral Disc

    PubMed Central

    Boxberger, John I.; Auerbach, Joshua D.; Sen, Sounok; Elliott, Dawn M.

    2009-01-01

    Study Design An in vivo model resembling early stage disc degeneration in the rat lumbar spine. Objective Simulate the reduced glycosaminoglycan content and altered mechanics observed in intervertebral disc degeneration using a controlled injection of chondroitinase ABC (ChABC). Summary of Background Data Nucleus glycosaminoglycan reduction occurs early during disc degeneration; however, mechanisms through which degeneration progresses from this state are unknown. Animal models simulating this condition are essential for understanding disease progression and for development of therapies aimed at early intervention. Methods ChABC was injected into the nucleus pulposus, and discs were evaluated via micro-CT, mechanical testing, biochemical assays, and histology 4 and 12 weeks after injection. Results At 4 weeks, reductions in nucleus glycosaminoglycan level by 43%, average height by 12%, neutral zone modulus by 40%, and increases in range of motion by 40%, and creep strain by 25% were found. Neutral zone modulus and range of motion were correlated with nucleus glycosaminoglycan. At 12 weeks, recovery of some mechanical function was detected as range of motion and creep returned to control levels; however, this was not attributed to glycosaminoglycan restoration, because mechanics were no longer correlated with glycosaminoglycan. Conclusion An in vivo model simulating physiologic levels of glycosaminoglycan loss was created to aid in understanding the relationships between altered biochemistry, altered mechanics, and altered cellular function in degeneration. PMID:18197098

  15. The Relation Between Sacral Angle and Vertical Angle of Sacral Curvature and Lumbar Disc Degeneration

    PubMed Central

    Ghasemi, Ahmad; Haddadi, Kaveh; Khoshakhlagh, Mohammad; Ganjeh, Hamid Reza

    2016-01-01

    Abstract The purpose of this study is to determine the reliability and validity of a goniometric measurement of the vertical angle of the sacrum and sacral angle (SA), and their relationships to lumbar degeneration. A herniated lumbar disc is one of the most frequent medical issues. Investigators in a number of studies have reported associated risk factors for prevalent disc degeneration. Atypical lumbosacral angles and curvature are thought to contribute to the degradation of the spine by many researchers. This study analyzed 360 patients referred to our clinic from 2013 to 2015 due to low back pain. A cross-sectional case–control study was designed in order to compare the sagittal alignment of the lumbosacral area in 3 groups of patients suffering from LBP. A total 120 patients were in a control group with a normal lumbar magnetic resonance imaging (MRI), 120 patients had lumbar disk herniation (LDH), and 120 patients had spinal stenosis. From the sagittal plan of lumbar MRI, SA and vertical angle of sacral curvature (VASC) were determined and then analyzed. The means of VASC in these groups were: 38.98 (SD: 6.36 ± 0.58), 40.89 (SD: 7.69 ± 0.69), and 40.54 (SD: 7.13 ± 0.92), respectively (P = 0.089). Moreover, studies of SA in 3 groups showed that the means of SA were: 39.30 (SD: 6.69 ± 0.63), 40.52 (SD: 7.47 ± 0.65), and 35.63 (SD: 6.07 ± 0.79), respectively. Relation between SA and spinal stenosis was just statistically significant (P ≤ 0.05). One significant limitation of our study is the lack of standing MRI for increased accuracy of measurement. However, we were reluctant to give patients needless exposure to radiation from conventional X-ray, and instead used MRI scans. We did not find any significant correlation between the VASC and LDH in lumbar MRI. Also, SA is not an independent risk factor for LDH in men and women. We suggested that there are several biomechanical factors involved in LDH. PMID:26871821

  16. Characterization of microRNA expression profiles in patients with intervertebral disc degeneration

    PubMed Central

    ZHAO, BO; YU, QIANG; LI, HAOPENG; GUO, XIONG; HE, XIJING

    2014-01-01

    Intervertebral disc degeneration (IDD) is associated with lower back pain and is a global burden with severe healthcare and socioeconomic consequences. However, the underlying mechanisms of IDD remain largely unelucidated. Accumulating evidence has indicasted that newly defined gene regulators, microRNAs (miRNAs), play a vital role in neurodegenerative, pathophysiological and certain reproductive disorders. To characterize the differential miRNA expression profiles between IDD and spinal cord injury, specimens from 3 patients with IDD and 3 with spinal cord injury were selected for microarray analysis. Total RNA from these 6 specimens was extracted and subjected to global miRNA expression analysis using the Exiqon miRCURY™ LNA Array (v.16.0). The microarray data were then validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, bioinformatics analysis was performed to investigate the dysregulated miRNA target genes and signaling pathways involved. Among the miRNAs analyzed, 25 miRNAs were found to be upregulated and 26 were found to be downregulated in the IDD group compared with the spinal cord injury group. The qRT-PCR results validated the microarray data. Bioinformatics analysis indicated that the signaling pathways most likely to be controlled by these miRNAs were the phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR; ErbB) and Wnt pathways. Our results demonstrated that the miRNA expression in patients with IDD differed significantly from that in patients who sustained injury to the intervertebral disc. Our data indicate that the dysregulated miRNAs control the signaling pathways important for the maintenance of IDD. Further studies on miRNA target gene identification and biological functions may address the specific regulatory mechanisms of miRNAs in IDD, and may provide valuable insight into the diagnosis and treatment of IDD. PMID:24173697

  17. Characterization of microRNA expression profiles in patients with intervertebral disc degeneration.

    PubMed

    Zhao, Bo; Yu, Qiang; Li, Haopeng; Guo, Xiong; He, Xijing

    2014-01-01

    Intervertebral disc degeneration (IDD) is associated with lower back pain and is a global burden with severe healthcare and socioeconomic consequences. However, the underlying mechanisms of IDD remain largely unelucidated. Accumulating evidence has indicasted that newly defined gene regulators, microRNAs (miRNAs), play a vital role in neurodegenerative, pathophysiological and certain reproductive disorders. To characterize the differential miRNA expression profiles between IDD and spinal cord injury, specimens from 3 patients with IDD and 3 with spinal cord injury were selected for microarray analysis. Total RNA from these 6 specimens was extracted and subjected to global miRNA expression analysis using the Exiqon miRCURY™ LNA Array (v.16.0). The microarray data were then validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In addition, bioinformatics analysis was performed to investigate the dysregulated miRNA target genes and signaling pathways involved. Among the miRNAs analyzed, 25 miRNAs were found to be upregulated and 26 were found to be downregulated in the IDD group compared with the spinal cord injury group. The qRT-PCR results validated the microarray data. Bioinformatics analysis indicated that the signaling pathways most likely to be controlled by these miRNAs were the phosphoinositide 3-kinase (PI3K)-Akt, mitogen-activated protein kinase (MAPK), epidermal growth factor receptor (EGFR; ErbB) and Wnt pathways. Our results demonstrated that the miRNA expression in patients with IDD differed significantly from that in patients who sustained injury to the intervertebral disc. Our data indicate that the dysregulated miRNAs control the signaling pathways important for the maintenance of IDD. Further studies on miRNA target gene identification and biological functions may address the specific regulatory mechanisms of miRNAs in IDD, and may provide valuable insight into the diagnosis and treatment of IDD. PMID:24173697

  18. No Acceleration of Intervertebral Disc Degeneration after a Single Injection of Bupivacaine in Young Age Group with Follow-Up of 5 Years

    PubMed Central

    Inoue, Gen; Orita, Sumihisa; Eguchi, Yawara; Ochiai, Nobuyasu; Kishida, Shunji; Kuniyoshi, Kazuki; Nakamura, Junichi; Aoki, Yasuchika; Ishikawa, Tetsuhiro; Miyagi, Masayuki; Kamoda, Hiroto; Suzuki, Miyako; Takaso, Masashi; Toyone, Tomoaki; Kubota, Gou; Sakuma, Yoshihiro; Oikawa, Yasuhiro; Inage, Kazuhide; Sainoh, Takeshi; Takahashi, Kazuhisa

    2013-01-01

    Study Design Prospective study of changes in intervertebral disc degeneration after injection of bupivacaine. Purpose To examine whether injection of bupivacaine into human intervertebral discs accelerates their degeneration. Overview of Literature Bupivacaine is commonly used for therapy and diagnosis of discogenic low back pain. However, several in vitro studies have reported toxic effects of bupivacaine to disc cells. We sought to evaluate whether this finding is clinically relevant. Methods We selected 46 patients with low back pain who showed disc degeneration at only one level (L4-L5 or L5-S1) on magnetic resonance imaging (MRI) (discography group, n=18), discoblock group (injection of bupivacaine, n=18), and a control group, n=10). There were no significant differences in baseline characteristics across the 3 groups. The two experimental groups underwent either discography or anesthetic discoblock, respectively. All three groups were followed up 5 years after the examination. Results At 5 years follow-up, there was no significant difference in the rate of disc degeneration among the 3 groups (p>0.1). Moreover, X-ray images showed that there was no significant difference in disc height, range of motion, or translation between flex and extension position (p>0.1). Conclusions In conclusion, radiologic and MRI findings did not show acceleration of intervertebral disc degeneration at 5 years after a single injection of bupivacaine into human discs. PMID:24066217

  19. Microarray based analysis of gene regulation by microRNA in intervertebral disc degeneration

    PubMed Central

    HU, PENG; FENG, BO; WANG, GUANGLIN; NING, BIN; JIA, TANGHONG

    2015-01-01

    The present study aimed to explore the underlying mechanism of the development of intervertebral disc degeneration (IDD) by bioinformatics based on microarray datasets. GSE 19943 and GSE 34095 datasets downloaded from Gene Expression Omnibus data were used to screen the differentially expressed genes (DEGs) in IDD. The correlation between microRNAs and target genes was investigated using different algorithms. The underlying molecular mechanisms of the target genes were then explored using Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology function enrichment analysis. A total of 9 differentially expressed microRNAs, including 3 down- and 6 upregulated microRNAs and 850 DEGs were identified in tissue from patients with IDD. Two regulation networks of the target genes by microRNAs were constructed, including 33 upregulated microRNA-target gene pairs and 4 downregulated microRNA-target gene pairs. Certain target genes had been demonstrated to be involved in IDD progression via various pathways, including in the cell cycle and pathways in cancer. In addition, two important microRNAs (microRNA-222 and microRNA-589) were identified that were pivotal for the development of IDD, and their target genes, CDKNAB and SMAD4. In conclusion, a comprehensive miRNA-target gene regulatory network was constructed, which was found to be important in IDD progression. PMID:26134418

  20. Noncoding RNAs in human intervertebral disc degeneration: An integrated microarray study

    PubMed Central

    Liu, Xu; Che, Lu; Xie, Yan-Ke; Hu, Qing-Jie; Ma, Chi-Jiao; Pei, Yan-Jun; Wu, Zhi-Gang; Liu, Zhi-Heng; Fan, Li-Ying; Wang, Hai-Qiang

    2015-01-01

    Accumulating evidence indicates that noncoding RNAs play important roles in a multitude of biological processes. The striking findings of miRNAs (microRNAs) and lncRNAs (long noncoding RNAs) as members of noncoding RNAs open up an exciting era in the studies of gene regulation. More recently, the reports of circRNAs (circular RNAs) add fuel to the noncoding RNAs research. Human intervertebral disc degeneration (IDD) is a main cause of low back pain as a disabling spinal disease. We have addressed the expression profiles if miRNAs, lncRNAs and mRNAs in IDD (Wang et al., J Pathology, 2011 and Wan et al., Arthritis Res Ther, 2014). Furthermore, we thoroughly analysed noncoding RNAs, including miRNAs, lncRNAs and circRNAs in IDD using the very same samples. Here we delineate in detail the contents of the aforementioned microarray analyses. Microarray and sample annotation data were deposited in GEO under accession number GSE67567 as SuperSeries. The integrated analyses of these noncoding RNAs will shed a novel light on coding-noncoding regulatory machinery. PMID:26484230

  1. Down-Regulated CK8 Expression in Human Intervertebral Disc Degeneration

    PubMed Central

    Sun, Zhen; Wang, Hai-Qiang; Liu, Zhi-Heng; Chang, Le; Chen, Yu-Fei; Zhang, Yong-Zhao; Zhang, Wei-Lin; Gao, Yang; Wan, Zhong-Yuan; Che, Lu; Liu, Xu; Samartzis, Dino; Luo, Zhuo-Jing

    2013-01-01

    As an intermediate filament protein, cytokeratin 8 (CK8) exerts multiple cellular functions. Moreover, it has been identified as a marker of notochord cells, which play essential roles in human nucleus pulposus (NP). However, the distribution of CK8 positive cells in human NP and their relationship with intervertebral disc degeneration (IDD) have not been clarified until now. Here, we found the percentage of CK8 positive cells in IDD (25.7±4.14%) was significantly lower than that in normal and scoliosis NP (51.9±9.73% and 47.8±5.51%, respectively, p<0.05). Western blotting and qRT-PCR results confirmed the down-regulation of CK8 expression in IDD on both of protein and mRNA levels. Furthermore, approximately 37.4% of cell clusters were CK8 positive in IDD. Taken together, this is the first study to show a down-regulated CK8 expression and the percentage of CK8 positive cell clusters in IDD based upon multiple lines of evidence. Consequently, CK8 positive cells might be considered as a potential option in the development of cellular treatment strategies for NP repair. PMID:23801880

  2. Noncoding RNAs in human intervertebral disc degeneration: An integrated microarray study.

    PubMed

    Liu, Xu; Che, Lu; Xie, Yan-Ke; Hu, Qing-Jie; Ma, Chi-Jiao; Pei, Yan-Jun; Wu, Zhi-Gang; Liu, Zhi-Heng; Fan, Li-Ying; Wang, Hai-Qiang

    2015-09-01

    Accumulating evidence indicates that noncoding RNAs play important roles in a multitude of biological processes. The striking findings of miRNAs (microRNAs) and lncRNAs (long noncoding RNAs) as members of noncoding RNAs open up an exciting era in the studies of gene regulation. More recently, the reports of circRNAs (circular RNAs) add fuel to the noncoding RNAs research. Human intervertebral disc degeneration (IDD) is a main cause of low back pain as a disabling spinal disease. We have addressed the expression profiles if miRNAs, lncRNAs and mRNAs in IDD (Wang et al., J Pathology, 2011 and Wan et al., Arthritis Res Ther, 2014). Furthermore, we thoroughly analysed noncoding RNAs, including miRNAs, lncRNAs and circRNAs in IDD using the very same samples. Here we delineate in detail the contents of the aforementioned microarray analyses. Microarray and sample annotation data were deposited in GEO under accession number GSE67567 as SuperSeries. The integrated analyses of these noncoding RNAs will shed a novel light on coding-noncoding regulatory machinery. PMID:26484230

  3. Microarray based analysis of gene regulation by microRNA in intervertebral disc degeneration.

    PubMed

    Hu, Peng; Feng, Bo; Wang, Guanglin; Ning, Bin; Jia, Tanghong

    2015-10-01

    The present study aimed to explore the underlying mechanism of the development of intervertebral disc degeneration (IDD) by bioinformatics based on microarray datasets. GSE 19943 and GSE 34095 datasets downloaded from Gene Expression Omnibus data were used to screen the differentially expressed genes (DEGs) in IDD. The correlation between microRNAs and target genes was investigated using different algorithms. The underlying molecular mechanisms of the target genes were then explored using Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology function enrichment analysis. A total of 9 differentially expressed microRNAs, including 3 down‑ and 6 upregulated microRNAs and 850 DEGs were identified in tissue from patients with IDD. Two regulation networks of the target genes by microRNAs were constructed, including 33 upregulated microRNA‑target gene pairs and 4 downregulated microRNA‑target gene pairs. Certain target genes had been demonstrated to be involved in IDD progression via various pathways, including in the cell cycle and pathways in cancer. In addition, two important microRNAs (microRNA‑222 and microRNA‑589) were identified that were pivotal for the development of IDD, and their target genes, CDKNAB and SMAD4. In conclusion, a comprehensive miRNA‑target gene regulatory network was constructed, which was found to be important in IDD progression. PMID:26134418

  4. Interleukin 1 Polymorphisms Contribute to Intervertebral Disc Degeneration Risk: A Meta-Analysis

    PubMed Central

    Fu, Changfeng; Xu, Feng; Chen, Yong; Wang, Zhenyu; Liu, Yi

    2016-01-01

    Objective We performed a meta-analysis to assess association between interleukin 1 (IL-1) polymorphisms and the risk of Intervertebral Disc Degeneration (IDD). Background A series of studies have investigated the association between common single nucleotide polymorphisms in IL-1 and IDD risk; however, the overall results are inconclusive. Methods Two independent investigators conducted a systematic search for relevant available studies. Allele frequencies were extracted from each study. The association between the IL-1α (+889C/T) or IL-1β (+3954C/T) polymorphism and IDD risk was measured by odds ratios (OR) with 95% confidence intervals (95% CI). Results Five and six studies, respectively, were ultimately included in the meta-analysis for the IL-1α (+889C/T) and IL-1β (+3954C/T) polymorphism. The combined results showed that the IL-1α (+889C/T) polymorphism was significantly associated with increased susceptibility to IDD, particularly in Caucasians (TT versus CC: OR = 2.95, 95% CI: 1.45, 6.04; Pheterogeneity = 0.82; TT versus CC/CT: OR = 2.29, 95% CI: 1.18, 4.47; Pheterogeneity = 0.20). In contrast, the IL-1β (+3954C/T) polymorphism showed a trend towards increased risk in Caucasians but no association in Asians. Conclusion This meta-analysis suggested that the IL-1α (+889C/T) polymorphism is significantly associated with risk of IDD, especially in Caucasian populations. PMID:27253397

  5. Retinal Cell Degeneration in Animal Models

    PubMed Central

    Niwa, Masayuki; Aoki, Hitomi; Hirata, Akihiro; Tomita, Hiroyuki; Green, Paul G.; Hara, Akira

    2016-01-01

    The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient retinal ischemia-induced). The target regions, pathology and proposed mechanism of each model are described in a comparative fashion. Animal models of retinal cell degeneration provide insight into the underlying mechanisms of the disease, and will facilitate the development of novel effective therapeutic drugs to treat retinal cell damage. PMID:26784179

  6. TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions.

    PubMed

    Zieba, Jennifer; Forlenza, Kimberly Nicole; Khatra, Jagteshwar Singh; Sarukhanov, Anna; Duran, Ivan; Rigueur, Diana; Lyons, Karen M; Cohn, Daniel H; Merrill, Amy E; Krakow, Deborah

    2016-03-01

    Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb-/-mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb-/-mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb-/-mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. PMID:27019229

  7. Extent of Disc Degeneration after Single-Level Cervical Anterior Microforaminotomy Analyzed with Long-Term Radiological Data

    PubMed Central

    Han, Chul

    2014-01-01

    Objective To prove the extents and details of cervical degeneration after anterior microforaminotomy (AMF) with 6-years follow-up. Methods A retrospective study of 24 patients, underwent single-level AMF, was performed. Clinical and radiologic data were analyzed with office charts, questionaires, and picture achieving and communication system images. Results According to Odom's criteria, 91.6% achieved favorable outcome. The mean visual analog scale score was improved from 8.6 to 3, and the mean neck disability index was improved from 27.9 to 7.3 (p<0.01). Eighteen cases (75%) showed disc height (DH) decrease. The disc invasion was correlated with DH decrease (p<0.05). The disc height decrease correlated with static, dynamic changes of shell angle and spur formation (p<0.05). Any radiological parameters did not affect the clinical outcome. Conclusion AMF is an effective technique for treating unilateral cervical radiculopathy. It showed excellent surgical outcomes even in long-term follow-ups. However, a decrease in DH occurred in a considerable number of patients. Disc invasion during surgery may be the trigger of sequential degeneration. PMID:25368761

  8. TGFβ and BMP Dependent Cell Fate Changes Due to Loss of Filamin B Produces Disc Degeneration and Progressive Vertebral Fusions

    PubMed Central

    Zieba, Jennifer; Forlenza, Kimberly Nicole; Khatra, Jagteshwar Singh; Sarukhanov, Anna; Duran, Ivan; Rigueur, Diana; Lyons, Karen M.; Cohn, Daniel H.; Merrill, Amy E.; Krakow, Deborah

    2016-01-01

    Spondylocarpotarsal synostosis (SCT) is an autosomal recessive disorder characterized by progressive vertebral fusions and caused by loss of function mutations in Filamin B (FLNB). FLNB acts as a signaling scaffold by linking the actin cytoskleteon to signal transduction systems, yet the disease mechanisms for SCT remain unclear. Employing a Flnb knockout mouse, we found morphologic and molecular evidence that the intervertebral discs (IVDs) of Flnb–/–mice undergo rapid and progressive degeneration during postnatal development as a result of abnormal cell fate changes in the IVD, particularly the annulus fibrosus (AF). In Flnb–/–mice, the AF cells lose their typical fibroblast-like characteristics and acquire the molecular and phenotypic signature of hypertrophic chondrocytes. This change is characterized by hallmarks of endochondral-like ossification including alterations in collagen matrix, expression of Collagen X, increased apoptosis, and inappropriate ossification of the disc tissue. We show that conversion of the AF cells into chondrocytes is coincident with upregulated TGFβ signaling via Smad2/3 and BMP induced p38 signaling as well as sustained activation of canonical and noncanonical target genes p21 and Ctgf. These findings indicate that FLNB is involved in attenuation of TGFβ/BMP signaling and influences AF cell fate. Furthermore, we demonstrate that the IVD disruptions in Flnb–/–mice resemble aging degenerative discs and reveal new insights into the molecular causes of vertebral fusions and disc degeneration. PMID:27019229

  9. Modeling Jupiter's current disc: Pioneer 10 outbound

    SciTech Connect

    Jones, D.E.; Melville, J.G. II; Blake, M.L.

    1980-07-01

    The magnetic field of the Jovian current disc has been modeled by using Euler functions and the Biot-Savart law applied to a series of concentric, but not necessarily coplanar, current rings. We find that a best fit to the Pioneer 10 outbound perturbation magnetic field data (B/sub total/-B/sub dipole/) is obtained if the current disc is twisted (outer edges increasingly lag behind inner edges with radial distance) and also bent so as to tend toward parallelism with the Jovigraphic equator. The inner and outer radii of the disc appear to be about 7 R/sub J/ and 150 R/sub J/, respectively, although some indication of a changing magnetopause location is apparent in the data. Because of the observed current disc penetrations, the bent disc also requires a deformation in the form of a bump or wrinkle whose axis tends also to exhibit spiraling. The radial dependence of the azimuthal current in the disc is not described by a simple power law, the outer region showing a smaller power law dependence. Modeling of the azimuthal field shows it to be due to a thin radial current sheet, but there is some evidence that this may, in fact, be due in large part to penetration of a tail current sheet as suggested by the Voyager observations.

  10. The Relationship between Disc Degeneration and Morphologic Changes in the Intervertebral Foramen of the Cervical Spine: A Cadaveric MRI and CT Study

    PubMed Central

    Sohn, Hong Moon; Lee, Jun Young

    2004-01-01

    A cadaveric study was performed to investigate the relationship between disc degeneration and morphological changes in the intervertebral foramen of cervical spine, including the effect on the nerve root. Seven fresh frozen human cadavers were dissected from C1 to T1, preserving the ligaments, capsules, intervertebral disc and the neural structures. The specimens were scanned with MRI and then scanned through CT scan in the upright position. Direct mid-sagittal and 45 degree oblique images were obtained to measure the dimension of the intervertebral disc height, foraminal height, width, area and segmental angles. Disc degeneration was inversely correlated with disc height. There was a significant correlation between disc degeneration and foraminal width (p<0.005) and foraminal area (p<0.05), but not with foraminal height. Disc height was correlated with foraminal width but not with height. The segmental angles were decreased more in advanced degenerated discs. There was a correlation between nerve root compression and decreased foraminal width and area (p<0.005). This information and critical dimensions of the intervertebral foramen for nerve root compression should help in the diagnosis of foraminal stenosis of the cervical spine in patients presenting with cervical spondylosis and radiculopathy. PMID:14966350

  11. Metabolic Syndrome Components Are Associated with Intervertebral Disc Degeneration: The Wakayama Spine Study

    PubMed Central

    Teraguchi, Masatoshi; Yoshimura, Noriko; Hashizume, Hiroshi; Muraki, Shigeyuki; Yamada, Hiroshi; Oka, Hiroyuki; Minamide, Akihito; Ishimoto, Yuyu; Nagata, Keiji; Kagotani, Ryohei; Tanaka, Sakae; Kawaguchi, Hiroshi; Nakamura, Kozo; Akune, Toru; Yoshida, Munehito

    2016-01-01

    Objective The objective of the present study was to examine the associations between metabolic syndrome (MS) components, such as overweight (OW), hypertension (HT), dyslipidemia (DL), and impaired glucose tolerance (IGT), and intervertebral disc degeneration (DD). Design The present study included 928 participants (308 men, 620 women) of the 1,011 participants in the Wakayama Spine Study. DD on magnetic resonance imaging was classified according to the Pfirrmann system. OW, HT, DL, and IGT were assessed using the criteria of the Examination Committee of Criteria for MS in Japan. Results Multivariable logistic regression analysis revealed that OW was significantly associated with cervical, thoracic, and lumbar DD (cervical: odds ratio [OR], 1.28; 95% confidence interval [CI], 0.92–1.78; thoracic: OR, 1.75; 95% CI, 1.24–2.51; lumbar: OR, 1.87; 95% CI, 1.06–3.48). HT and IGT were significantly associated with thoracic DD (HT: OR, 1.54; 95% CI, 1.09–2.18; IGT: OR, 1.65; 95% CI, 1.12–2.48). Furthermore, subjects with 1 or more MS components had a higher OR for thoracic DD compared with those without MS components (vs. no component; 1 component: OR, 1.58; 95% CI, 1.03–2.42; 2 components: OR, 2.60; 95% CI, 1.62–4.20; ≥3 components: OR, 2.62; 95% CI, 1.42–5.00). Conclusion MS components were significantly associated with thoracic DD. Furthermore, accumulation of MS components significantly increased the OR for thoracic DD. These findings support the need for further studies of the effects of metabolic abnormality on DD. PMID:26840834

  12. Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects

    PubMed Central

    Williams, Frances M K; Bansal, Aruna T; van Meurs, Joyce B; Bell, Jordana T; Meulenbelt, Ingrid; Suri, Pradeep; Rivadeneira, Fernando; Sambrook, Philip N; Hofman, Albert; Bierma-Zeinstra, Sita; Menni, Cristina; Kloppenburg, Margreet; Slagboom, P Eline; Hunter, David J; MacGregor, Alex J; Uitterlinden, Andre G; Spector, Tim D

    2013-01-01

    Objective Lumbar disc degeneration (LDD) is an important cause of low back pain, which is a common and costly problem. LDD is characterised by disc space narrowing and osteophyte growth at the circumference of the disc. To date, the agnostic search of the genome by genome-wide association (GWA) to identify common variants associated with LDD has not been fruitful. This study is the first GWA meta-analysis of LDD. Methods We have developed a continuous trait based on disc space narrowing and osteophytes growth which is measurable on all forms of imaging (plain radiograph, CT scan and MRI) and performed a meta-analysis of five cohorts of Northern European extraction each having GWA data imputed to HapMap V.2. Results This study of 4600 individuals identified four single nucleotide polymorphisms with p<5×10−8, the threshold set for genome-wide significance. We identified a variant in the PARK2 gene (p=2.8×10−8) associated with LDD. Differential methylation at one CpG island of the PARK2 promoter was observed in a small subset of subjects (β=8.74×10−4, p=0.006). Conclusions LDD accounts for a considerable proportion of low back pain and the pathogenesis of LDD is poorly understood. This work provides evidence of association of the PARK2 gene and suggests that methylation of the PARK2 promoter may influence degeneration of the intervertebral disc. This gene has not previously been considered a candidate in LDD and further functional work is needed on this hitherto unsuspected pathway. PMID:22993228

  13. Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes

    PubMed Central

    Liu, Haitao; Tang, Jie; Du, Yunpeng; Saadane, Aicha; Tonade, Deoye; Samuels, Ivy; Veenstra, Alex; Palczewski, Krzysztof; Kern, Timothy S.

    2016-01-01

    Purpose Loss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence of photoreceptor cells is implicated in vascular degeneration in diabetic retinopathy. To investigate how both the absence and presence of photoreceptors could damage the retinal vasculature, we compared two mouse models of photoreceptor degeneration (opsin−/− and RhoP23H/P23H ) and control C57Bl/5J mice, each with and without diabetes. Methods Retinal thickness, superoxide, expression of inflammatory proteins, ERG and optokinetic responses, leukocyte cytotoxicity, and capillary degeneration were evaluated at 1 to 10 months of age using published methods. Results Retinal photoreceptor cells degenerated completely in the opsin mutants by 2 to 4 months of age, and visual function subsided correspondingly. Retinal capillary degeneration was substantial while photoreceptors were still present, but slowed after the photoreceptors degenerated. Diabetes did not further exacerbate capillary degeneration in these models of photoreceptor degeneration, but did cause capillary degeneration in wild-type animals. Photoreceptor cells, however, did not degenerate in wild-type diabetic mice, presumably because the stress responses in these cells were less than in the opsin mutants. Retinal superoxide and leukocyte damage to retinal endothelium contributed to the degeneration of retinal capillaries in diabetes, and leukocyte-mediated damage was increased in both opsin mutants during photoreceptor cell degeneration. Conclusions Photoreceptor cells affect the integrity of the retinal microvasculature. Deterioration of retinal capillaries in opsin mutants was appreciable while photoreceptor cells were present and stressed, but was less after photoreceptors degenerated. This finding proves relevant to diabetes, where persistent stress in photoreceptors likewise contributes to capillary degeneration. PMID:27548901

  14. A pilot study of the prevalence of lumbar disc degeneration in elite athletes with lower back pain at the Sydney 2000 Olympic Games

    PubMed Central

    Ong, A; Anderson, J; Roche, J

    2003-01-01

    Objectives: To observe the prevalence of lumbar intervertebral disc degeneration in elite athletes as compared with published literature of changes seen in non-athletes—that is, normal population. Methods: The lumbar spines of 31 Olympic athletes who presented to the Olympic Polyclinic with low back pain and/or sciatica were examined using magnetic resonance imaging. Three criteria were looked at: (a) the loss of disc signal intensity; (b) the loss of disc height; (c) the presence of disc displacement. The results were then recorded and correlated with the lumbar levels. Results: The disc signal intensity was progressively reduced the more caudal the disc space. It was most common at the L5/S1 level, and, of the abnormal group, 36% (n = 11) showed the most degenerative change. Disc height reduction was also found to be most common at the L5/S1 level. However, the most common height reduction was only mild. A similar trend of increased prevalence of disc herniation was noted with more caudal levels. At the L5/S1 level, 58% were found to have an element of disc displacement, most of which were disc bulges. Compared with changes seen in the normal population (non-athletes) as described in the literature, disc degeneration defined by the above criteria was found to be significantly more severe in these Olympic athletes. Conclusions: Although the study was limited, the results suggest that elite athletes have a greater prevalence and greater degree of lumbar disc degeneration than the normal population. A more detailed follow up study should be considered to investigate which particular training activities have the most impact on the lumbar spine, and how to modify training methods so as to avoid the long term sequelae of degenerative disc disease of the lumbar spine. PMID:12782554

  15. Role of microRNA-210 in human intervertebral disc degeneration

    PubMed Central

    ZHANG, DA-YING; WANG, ZHI-JIAN; YU, YAN-BO; ZHANG, YONG; ZHANG, XUE-XUE

    2016-01-01

    The present study aimed to investigate the role of microRNA (miR)-210 in the development of intervertebral disc degeneration (IDD). Human nucleus pulposus (NP) samples were collected from patients with scoliosis and IDD (n=12 each) as the scoliosis control and IDD groups, respectively. The expression levels of miR-210 were detected using reverse-transcription quantitative polymerase chain reaction. In vitro overexpression and knockdown of miR-210 in human NP cells were achieved by transfection of NP cells with lentiviral pre-miR-210 and antagomiR-210, respectively. The protein expression levels of homeobox A9 (HOXA9) were then detected in NP cells with modulated miR-210 using western blot analysis. Flow cytometry with allophycocyanin-Annexin V/7 and 7-aminoactinomycin D staining was also used to detect the proportion of NP cells with modulated miR-210 undergoing apoptosis. The current study revealed that the miR-210 expression was decreased in patients with IDD compared with that of the scoliosis control group (P<0.05). Furthermore, the upregulation of miR-210 with pre-miR-210 led to the repression of HOXA9. The HOXA9 level was significantly lower in these cells compared with that of NP cells treated with a corresponding negative sequence (P<0.05). Knockdown of miR-210 with antagomiR-210 resulted in upregulation of HOXA9 in NP cells, determined as the level of HOXA9 was significantly higher than that of NP cells treated with a negative sequence (P<0.05). The proportion of apoptotic NP cells also significantly decreased following treatment with pre-miR-210 compared with the scoliosis control group (12.1±1.43 vs. 23.8±1.22%, respectively; P<0.05). In conclusion, downregulation of miR-210 may promote Fas-mediated apoptosis in human IDD by regulating the expression of HOXA9. This indicates that miR-210 may be closely associated with the development of IDD and may act as a novel target in IDD treatment. PMID:27284319

  16. Stem Cell Therapies for Intervertebral Disc Degeneration: Immune Privilege Reinforcement by Fas/FasL Regulating Machinery.

    PubMed

    Ma, Chi-Jiao; Liu, Xu; Che, Lu; Liu, Zhi-Heng; Samartzis, Dino; Wang, Hai-Qiang

    2015-01-01

    As a main contributing factor to low back pain, intervertebral disc degeneration (IDD) is the fundamental basis for various debilitating spinal diseases. The pros and cons of current treatment modalities necessitate biological treatment strategies targeting for reversing or altering the degeneration process in terms of molecules or genes. The advances in stem cell research facilitate the studies aiming for possible clinical application of stem cell therapies for IDD. Human NP cells are versatile with cell morphology full of variety, capable of synthesizing extracellular matrix components, engulfing substances by autophagy and phagocytosis, mitochondrial vacuolization indicating dysfunction, expressing Fas and FasL as significant omens of immune privileged sites. Human discs belong to immune privilege organs with functional FasL expression, which can interact with invasive immune cells by Fas-FasL regulatory machinery. IDD is characterized by decreased expression level of FasL with dysfunctional FasL, which in turn unbalances the interaction between NP cells and immune cells. Certain modulation factors might play a role in the process, such as miR-155. Accumulating evidence indicates that Fas-FasL network expresses in a variety of stem cells. Given the expression of functional FasL and insensitive Fas in stem cells (we term as FasL privilege), transplantation of stem cells into the disc may regenerate the degenerative disc by not only differentiating into NP-like cells, increasing extracellular matrix, but also reinforce immune privilege via interaction with immune cells by Fas-FasL network. PMID:25381758

  17. An in vitro investigation into the role of bone marrow‑derived mesenchymal stem cells in the control of disc degeneration.

    PubMed

    Hu, Jinquan; Deng, Guoying; Tian, Ye; Pu, Yingyan; Cao, Peng; Yuan, Wen

    2015-10-01

    Excessive apoptosis and high expression levels of interleukin‑1β (IL‑1β) in disc cells have been reported to serve important roles in intervertebral disc degeneration (IVDD). Previous studies investigating mesenchymal stem cells (MSCs) have indicated potential for their use in the treatment of IVDD. However, the therapeutic potential and anti‑apoptotic ability of MSCs remains to be fully elucidated. The present study aimed to establish an in vitro model for bone marrow‑derived MSC (BMSC) therapy by investigating the anti‑apoptotic effects, in addition to the migration of BMSCs to nucleus pulposus (NP) cells stimulated by IL‑1β. A co-culture system of BMSCs and NP cells was founded. Following inflammatory stimulation, the NP cells exhibited increased indexes for inflammation‑induced degeneration. The degenerative and apoptotic indexes were significantly reduced when NP cells were co‑cultured with BMSCs. Compared with the indirect co-culture group, the direct co-culture group exhibited an improved capacity for anti-apoptosis. In addition, IL‑1β‑stimulated NP cells attracted and mediated the migration of BMSCs. Mitochondrial transfer from BMSCs to NP cells by tunneling nanotubes was also observed. In conclusion, the anti‑apoptosis and the migration, in addition to mitochondrial transfer associated with BMSC treatments in IVDD, were investigated in vitro in the present study. The interaction between stimulated NP cells and BMSCs is likely involved in to simulating the in vivo process of stem cell‑mediated repair. PMID:26239757

  18. Anterior Herniation of Partially Calcified and Degenerated Cervical Disc Causing Dysphagia.

    PubMed

    Ozdol, Cagatay; Turk, Cezmi Cagri; Yildirim, Ali Erdem; Dalgic, Ali

    2015-08-01

    We report a rare case of anterior cervical disc herniation associated with dysphagia. A 32-year-old man presented with complaints of dysphagia and concomitant pain in the right arm resistant to conservative therapy. On physical examination with respect to the muscle strength, the right shoulder abduction and flexion of the forearm were 3/5. Lateral X-ray revealed calcified osteophytes at the anterior C4-5 level. Magnetic resonance imaging showed soft disc herniation involving the right C6 root at the C5-6 level and anterior herniation of the C4-5 cervical disc. Anterior discectomies for C4-5 and C5-6 levels stabilized and ameliorated the dysphagia and pain. Cervical disc herniation usually presents with radicular findings. However, dysphagia may be an uncommon presentation. Anterior cervical disc herniation should be considered in a patient presenting with dysphagia. PMID:26240723

  19. Regenerative Potential of TGFβ3 + Dex and Notochordal Cell Conditioned Media on Degenerated Human Intervertebral Disc Cells

    PubMed Central

    Abbott, Rosalyn Delia; Purmessur, Devina; Monsey, Robert Daniel; Iatridis, James Christopher

    2011-01-01

    Injection of soluble cell signaling factors into degenerated intervertebral discs (IVDs) offers a minimally invasive treatment that could limit the processes of degeneration by stimulating native matrix repair. This study evaluated the regenerative capacity of degenerated nucleus pulposus (NP) cells obtained from patients undergoing anterior interbody fusions by measuring metabolic activity, DNA content, glycosaminoglycan (GAG) content, and cellular phenotype using qRT-PCR profiling with a custom array of 42 genes. NP cells were cultured in alginate for 7 days with 4 treatment groups: transforming growth factor beta 3 (TGFβ3) + dexamethasone (Dex), soluble factors released from notochordal cells (NCs) cultured in alginate (NCA), soluble factors released from NCs in their native tissue environment (NCT), and basal media. TGFβ3 + Dex stimulated degenerated human NP cells to proliferate and exhibit an anti-catabolic gene expression profile (with a decrease in ADAMTS5 and MMP1 compared to basal, and an increase in SOX9, decrease in ADAMTS5, MMP1, collagen I and collagen III compared to day 0), while NCA stimulated the greatest GAG per cell. We conclude that degenerated human NP cells exhibit regenerative potential, and that an optimal treatment will likely require treatments, such as TGFβ3 + Dex, which were able to increase cell metabolism and reduce catabolism, as well as treatments with factors found in NC conditioned medium, that were able to produce high amounts of GAG per cell. Additional studies to optimize NC culture conditions are required to determine if NC conditioned medium can be made with the capacity to enhance NP cell proliferation and metabolism. PMID:21866573

  20. A prospective randomised study on the long-term effect of lumbar fusion on adjacent disc degeneration.

    PubMed

    Ekman, Per; Möller, Hans; Shalabi, Adel; Yu, Yiang Xiao; Hedlund, Rune

    2009-08-01

    The existence and importance of an accelerated adjacent segment disc degeneration (ASD) after lumbar fusion have previously not been demonstrated by RCTs. The objectives of this study were, to determine whether lumbar fusion in the long term accelerates degenerative changes in the adjacent disc and whether this affects the outcome, by using a prospective randomised design. A total of 111 patients, aged 18-55, with isthmic spondylolisthesis were randomised to exercise (EX, n = 34) or posterolateral fusion (PLF, n = 77), with (n = 37) or without pedicle screw instrumentation (n = 40). The minimum 10 years FU rate was 72%, with a mean FU time of 12.6 years (range 10-17 years). Three radiographic methods of ASD quantification were used, i.e. two digital radiographic measurement methods and the semi quantitative UCLA grading scale. One digital measurement method showed a mean disc height reduction by 2% in the EX group and by 15% in the PLF group (p = 0.0016), and the other showed 0.5 mm more disc height reduction in the PLF compared to the Ex group (ns). The UCLA grading scale showed normal discs in 100% of patients in the EX group, compared to 62% in the PLF group (p = 0.026). There were no significant differences between instrumented and non-instrumented patients. In patients with laminectomy we found a significantly higher incidence of ASD compared to non laminectomised patients (22/47 vs. 2/16 respectively, p = 0.015). In the longitudinal analysis, the posterior and anterior disc heights were significantly reduced in the PLF group, whereas in the EX group only the posterior disc height was significantly reduced. Except for global outcome, which was significantly better for patients without ASD, the clinical outcome was not statistically different in patients with and without ASD. In conclusion, the long-term RCT shows that fusion accelerates degenerative changes at the adjacent level compared with natural history. The study suggests that not only fusion, but also

  1. Matrix stiffness promotes cartilage endplate chondrocyte calcification in disc degeneration via miR-20a targeting ANKH expression

    PubMed Central

    Liu, Ming-Han; Sun, Chao; Yao, Yuan; Fan, Xin; Liu, Huan; Cui, You-Hong; Bian, Xiu-Wu; Huang, Bo; Zhou, Yue

    2016-01-01

    The mechanical environment is crucial for intervertebral disc degeneration (IDD). However, the mechanisms underlying the regulation of cartilage endplate (CEP) calcification by altered matrix stiffness remain unclear. In this study, we found that matrix stiffness of CEP was positively correlated with the degree of IDD, and stiff matrix, which mimicked the severe degeneration of CEP, promoted inorganic phosphate-induced calcification in CEP chondrocytes. Co-expression analysis of the miRNA and mRNA profiles showed that increasing stiffness resulted in up-regulation of miR-20a and down-regulation of decreased ankylosis protein homolog (ANKH) during inorganic phosphate-induced calcification in CEP chondrocytes. Through a dual luciferase reporter assay, we confirmed that miR-20a directly targets 3′-untranslated regions of ANKH. The inhibition of miR-20a attenuated the calcium deposition and calcification-related gene expression, whereas the overexpression of miR-20a enhanced calcification in CEP chondrocytes on stiff matrix. The rescue of ANKH expression restored the decreased pyrophosphate efflux and inhibited calcification. In clinical samples, the levels of ANKH expression were inversely associated with the degeneration degree of CEP. Thus, our findings demonstrate that the miR-20a/ANKH axis mediates the stiff matrix- promoted CEP calcification, suggesting that miR-20a and ANKH are potential targets in restraining the progression of IDD. PMID:27142968

  2. Calcification in the ovine intervertebral disc: a model of hydroxyapatite deposition disease

    PubMed Central

    Burkhardt, D.; Taylor, T. K. F.; Dillon, C. T.; Read, R.; Cake, M.; Little, C. B.

    2009-01-01

    The study design included a multidisciplinary examination of the mineral phase of ovine intervertebral disc calcifications. The objective of the study was to investigate the mineral phase and its mechanisms of formation/association with degeneration in a naturally occurring animal model of disc calcification. The aetiology of dystrophic disc calcification in adult humans is unknown, but occurs as a well-described clinical disorder with hydroxyapatite as the single mineral phase. Comparable but age-related pathology in the sheep could serve as a model for the human disorder. Lumbar intervertebral discs (n = 134) of adult sheep of age 6 years (n = 4), 8 years (n = 12) and 11 years (n = 2) were evaluated using radiography, morphology, scanning and transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray powder diffraction, histology, immunohistology and proteoglycan analysis. Half of the 6-year, 84% of the 8-year and 86% of the 11-year-old discs had calcific deposits. These were not well delineated by plain radiography. They were either: (a) punctate deposits in the outer annulus, (b) diffuse deposits in the transitional zone or inner annulus fibrosus with occasional deposits in the nucleus, or (c) large deposits in the transitional zone extending variably into the nucleus. Their maximal incidence was in the lower lumbar discs (L4/5–L6/7) with no calcification seen in the lumbosacral or lower thoracic discs. All deposits were hydroxyapatite with large crystallite sizes (800–1,300 Å) compared to cortical bone (300–600 Å). No type X-collagen, osteopontin or osteonectin were detected in calcific deposits, although positive staining for bone sialoprotein was evident. Calcified discs had less proteoglycan of smaller hydrodynamic size than non-calcified discs. Disc calcification in ageing sheep is due to hydroxyapatite deposition. The variable, but large, crystal size and lack of protein markers indicate that this does not occur by

  3. Human Annulus Fibrosus Material Properties from Biaxial Testing and Constitutive Modeling are Altered with Degeneration

    PubMed Central

    O’Connell, Grace D.; Sen, Sounok; Elliott, Dawn M.

    2012-01-01

    The annulus fibrosus (AF) of the intervertebral disc undergoes large and multidirectional stresses and strains. Uniaxial tensile tests are limited for measuring AF material properties, because freely contracting edges can prevent fiber stretch and are not representative of in situ boundary conditions. The objectives of this study were to measure human AF biaxial tensile mechanics and to apply and validate a constitutive model to determine material properties. Biaxial tensile tests were performed on samples oriented along the circumferential-axial and the radial-axial directions. Data were fit to a structurally-motivated anisotropic hyperelastic model composed of isotropic extrafibrillar matrix, nonlinear fibers, and fiber-matrix interactions (FMI) normal to the fibers. The validated model was used to simulate shear and uniaxial tensile behavior, to investigate AF structure-function, and to quantify the effect of degeneration. The biaxial stress-strain response was described well by the model (R2>0.9). The model showed that the parameters for fiber nonlinearity and the normal FMI correlated with degeneration, resulting in an elongated toe region and lower stiffness with degeneration. The model simulations in shear and uniaxial tension successfully matched previously published circumferential direction Young’s modulus, provided an explanation for the low values in previously published axial direction Young’s modulus, and was able to simulate shear mechanics. The normal FMI were important contributors to stress and changed with degeneration, therefore, their microstructural and compositional source should be investigated. Finally, the biaxial mechanical data and constitutive model can be incorporated into a disc finite element model to provide improved quantification of disc mechanics. PMID:21748426

  4. Lumbar intervertebral disc degeneration associated with axial and radiating low back pain in ageing SPARC-null mice.

    PubMed

    Millecamps, Magali; Tajerian, Maral; Naso, Lina; Sage, E Helene; Stone, Laura S

    2012-06-01

    Chronic low back pain (LBP) is a complex, multifactorial disorder with unclear underlying mechanisms. In humans and rodents, decreased expression of secreted protein acidic rich in cysteine (SPARC) is associated with intervertebral disc (IVD) degeneration and signs of LBP. The current study investigates the hypothesis that IVD degeneration is a risk factor for chronic LBP. SPARC-null and age-matched control mice ranging from 6 to 78 weeks of age were evaluated in this study. X-ray and histologic analysis revealed reduced IVD height, increased wedging, and signs of degeneration (bulging and herniation). Cutaneous sensitivity to cold, heat, and mechanical stimuli were used as measures of referred (low back and tail) and radiating pain (hind paw). Region specificity was assessed by measuring icilin- and capsaicin-evoked behaviour after subcutaneous injection into the hind paw or upper lip. Axial discomfort was measured by the tail suspension and grip force assays. Motor impairment was determined by the accelerating rotarod. Physical function was evaluated by voluntary activity after axial strain or during ambulation with forced lateral flexion. SPARC-null mice developed (1) region-specific, age-dependent hypersensitivity to cold, icilin, and capsaicin (hind paw only), (2) axial discomfort, (3) motor impairment, and (4) reduced physical function. Morphine (6 mg/kg, i.p.) reduced cutaneous sensitivity and alleviated axial discomfort in SPARC-null mice. Ageing SPARC-null mice mirror many aspects of the complex and challenging nature of LBP in humans and incorporate both anatomic and functional components of the disease. The current study supports the hypothesis that IVD degeneration is a risk factor for chronic LBP. PMID:22414871

  5. Pineal gland calcification, lumbar intervertebral disc degeneration and abdominal aorta calcifying atherosclerosis correlate in low back pain subjects: A cross-sectional observational CT study.

    PubMed

    Turgut, Ahmet Tuncay; Sönmez, Iclal; Cakıt, Burcu Duyur; Koşar, Pınar; Koşar, Uğur

    2008-06-01

    The goal of this cross-sectional observational study was to assess the possible impact of pineal gland calcification upon the intervertebral disc degeneration and abdominal aorta atherosclerosis in subjects with low back pain, and to investigate the course of these processes with aging. The study was carried out on 81 (66 women and 15 men) subjects: younger than 45 years (group X, n=22), 45-65 years of age (group Y, n=45), and older than 65 years (group Z, n=14). In addition to clinical data, computed tomography (CT) scan of the brain as well as X-ray and CT examination of the lumbar spine were recorded in this study. The degree of disc degeneration and calcification rates of aortic wall and pineal gland were independently determined by two radiologists. Both ratio of calcified pineal gland and density of pineal calcification increased progressively with aging. Also, both the degree of aortic wall calcification and disc degeneration score increased with advancing age. On CT scan, a positive correlation between degree of aortic wall calcification and disc degeneration score was found (r=0.306, p<0.01). Importantly, there was a positive association between calcification of the pineal gland and degenerative disc disease in X-ray or CT study (r=0.378 and r=0.295, p<0.005 and p<0.01, respectively), as well as between abdominal aorta atherosclerosis and pineal calcification (r=0.634, p<0.001). Our findings suggest that there is a significant interaction between pineal gland calcification and lumbar intervertebral disc degeneration and also abdominal aorta atherosclerosis. However, further studies with a larger subject cohorts are needed. PMID:18215511

  6. Effects of Single Injection of Local Anesthetic Agents on Intervertebral Disc Degeneration: Ex Vivo and Long-Term In Vivo Experimental Study

    PubMed Central

    Iwasaki, Koji; Sudo, Hideki; Yamada, Katsuhisa; Higashi, Hideaki; Ohnishi, Takashi; Tsujimoto, Takeru; Iwasaki, Norimasa

    2014-01-01

    Background Analgesic discography (discoblock) can be used to diagnose or treat discogenic low back pain by injecting a small amount of local anesthetics. However, recent in vitro studies have revealed cytotoxic effects of local anesthetics on intervertebral disc (IVD) cells. Here we aimed to investigate the deteriorative effects of lidocaine and bupivacaine on rabbit IVDs using an organotypic culture model and an in vivo long-term follow-up model. Methods For the organotypic culture model, rabbit IVDs were harvested and cultured for 3 or 7 days after intradiscal injection of local anesthetics (1% lidocaine or 0.5% bupivacaine). Nucleus pulposus (NP) cell death was measured using confocal microscopy. Histological and TUNEL assays were performed. For in vivo study, each local anesthetic was injected into rabbit lumbar IVDs under a fluoroscope. Six or 12 months after the injection, each IVD was prepared for magnetic resonance imaging (MRI) and histological analysis. Results In the organotypic culture model, both anesthetic agents induced time-dependent NP cell death; when compared with injected saline solution, significant effects were detected within 7 days. Compared with the saline group, TUNEL-positive NP cells were significantly increased in the bupivacaine group. In the in vivo study, MRI analysis did not show any significant difference. Histological analysis revealed that IVD degeneration occurred to a significantly level in the saline- and local anesthetics-injected groups compared with the untreated control or puncture-only groups. However, there was no significant difference between the saline and anesthetic agents groups. Conclusions/Significance In the in vivo model using healthy IVDs, there was no strong evidence to suggest that discoblock with local anesthetics has the potential of inducing IVD degeneration other than the initial mechanical damage of the pressurized injection. Further studies should be performed to investigate the deteriorative effects of

  7. Atomic Absorption Spectrometry Analysis of Trace Elements in Degenerated Intervertebral Disc Tissue

    PubMed Central

    Kubaszewski, Łukasz; Zioła-Frankowska, Anetta; Frankowski, Marcin; Nowakowski, Andrzej; Czabak-Garbacz, Róża; Kaczmarczyk, Jacek; Gasik, Robert

    2014-01-01

    Background Few studies have investigated trace elements (TE) in human intervertebral disc (IVD) tissue. Trace element presence can have diverse meanings: essential TE show the metabolic modalities of the tissue, while environmentally-related TE indicate pollution and tissue-specific absorption and accumulation. IVD is a highly specific compartment with impaired communication with adjacent bone. Analysis of TE in IVD provides new insights regarding tissue metabolism and IVD communication with other tissues. Material/Methods Thirty intervertebral discs were acquired from 22 patients during surgical treatment for degenerative disease. Atomic absorption spectrometry was used to evaluate the concentrations of Al, Cd, Pb, Cu, Ni, Mo, Mg, and Zn. Results Al, Pb, Cu, Mg, and Zn were detected in all samples. Pb was significantly positively correlated with age, and Ni concentration was weakly correlated with population count in the patient’s place of residence. Only Cu was observed in higher concentrations in IVD compared to in other tissues. Significant positive correlations were observed between the following pairs: Mg/Zn, Mg/Al, Mg/Pb, Zn/Al, Zn/Pb, and Al/Pb. Negative correlations were observed between Mg/Cd, Zn/Cd, Mg/Mo, and Mo/Pb. Conclusions This study is one of few to profile the elements in intervertebral discs in patients with degenerative changes. We report significant differences between trace element concentrations in intervertebral discs compared to in other tissues. Knowledge of the TE accumulation pattern is vital for better understanding intervertebral disc nutrition and metabolism. PMID:25366266

  8. A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

    PubMed Central

    Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

    2014-01-01

    SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

  9. MicroRNA-10b promotes nucleus pulposus cell proliferation through RhoC-Akt pathway by targeting HOXD10 in intervetebral disc degeneration.

    PubMed

    Yu, Xin; Li, Zheng; Shen, Jianxiong; Wu, William K K; Liang, Jinqian; Weng, Xisheng; Qiu, Guixing

    2013-01-01

    Aberrant proliferation of nucleus pulposus cell is implicated in the pathogenesis of intervertebral disc degeneration. Recent findings revealed that microRNAs, a class of small noncoding RNAs, could regulate cell proliferation in many pathological conditions. Here, we showed that miR-10b was dramatically upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues isolated from patients with idiopathic scoliosis. Moreover, miR-10b levels were associated with disc degeneration grade and downregulation of HOXD10. In cultured nucleus pulposus cells, miR-10b overexpression stimulated cell proliferation with concomitant translational inhibition of HOXD10 whereas restored expression of HOXD10 reversed the mitogenic effect of miR-10b. MiR-10b-mediated downregulation of HOXD10 led to increased RhoC expression and Akt phosphorylation. Either knockdown of RhoC or inhibition of Akt abolished the effect of miR-10b on nucleus pulposus cell proliferation. Taken together, aberrant miR-10b upregulation in intervertebral disc degeneration could contribute to abnormal nucleus pulposus cell proliferation through derepressing the RhoC-Akt pathway by targeting HOXD10. Our study also underscores the potential of miR-10b and the RhoC-Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24376640

  10. MicroRNA-10b Promotes Nucleus Pulposus Cell Proliferation through RhoC-Akt Pathway by Targeting HOXD10 in Intervetebral Disc Degeneration

    PubMed Central

    Shen, Jianxiong; Wu, William K. K.; Liang, Jinqian; Weng, Xisheng; Qiu, Guixing

    2013-01-01

    Aberrant proliferation of nucleus pulposus cell is implicated in the pathogenesis of intervertebral disc degeneration. Recent findings revealed that microRNAs, a class of small noncoding RNAs, could regulate cell proliferation in many pathological conditions. Here, we showed that miR-10b was dramatically upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues isolated from patients with idiopathic scoliosis. Moreover, miR-10b levels were associated with disc degeneration grade and downregulation of HOXD10. In cultured nucleus pulposus cells, miR-10b overexpression stimulated cell proliferation with concomitant translational inhibition of HOXD10 whereas restored expression of HOXD10 reversed the mitogenic effect of miR-10b. MiR-10b-mediated downregulation of HOXD10 led to increased RhoC expression and Akt phosphorylation. Either knockdown of RhoC or inhibition of Akt abolished the effect of miR-10b on nucleus pulposus cell proliferation. Taken together, aberrant miR-10b upregulation in intervertebral disc degeneration could contribute to abnormal nucleus pulposus cell proliferation through derepressing the RhoC-Akt pathway by targeting HOXD10. Our study also underscores the potential of miR-10b and the RhoC-Akt pathway as novel therapeutic targets in intervertebral disc degeneration. PMID:24376640

  11. Heme oxygenase-1 attenuates IL-1β induced alteration of anabolic and catabolic activities in intervertebral disc degeneration

    PubMed Central

    Hu, Bo; Shi, Changgui; Xu, Chen; Cao, Peng; Tian, Ye; Zhang, Ying; Deng, Lianfu; Chen, Huajiang; Yuan, Wen

    2016-01-01

    Intervertebral disc degeneration (IDD) is characterized by disordered extracellular matrix (ECM) metabolism, implicating subdued anabolism and enhanced catabolic activities in the nucleus pulposus (NP) of discs. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) are considered to be potent mediators of ECM breakdown. Hemeoxygenase-1 (HO-1) has been reported to participate in cellular anti-inflammatory processes. The purpose of this study was to investigate HO-1 modulation of ECM metabolism in human NP cells under IL-1β stimulation. Our results revealed that expression of HO-1 decreased considerably during IDD progression. Induction of HO-1 by cobalt protoporphyrin IX attenuated the inhibition of sulfate glycosaminoglycan and collagen type II (COL-II) synthesis and ameliorated the reduced expressions of aggrecan, COL-II, SOX-6 and SOX-9 mediated by IL-1β. Induction of HO-1 also reversed the effect of IL-1β on expression of the catabolic markers matrix metalloproteinases-1, 3, 9 and 13. This was combined with inhibition of the activation of mitogen-activated protein kinase signaling. These findings suggest that HO-1 might play a pivotal role in IDD, and that manipulating HO-1 expression might mitigate the impairment of ECM metabolism in NP, thus potentially offering a novel therapeutic approach to the treatment of IDD. PMID:26877238

  12. Animal models of age related macular degeneration

    PubMed Central

    Pennesi, Mark E.; Neuringer, Martha; Courtney, Robert J.

    2013-01-01

    Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations. PMID:22705444

  13. Expression levels of IL-17 and TNF-α in degenerated lumbar intervertebral discs and their correlation

    PubMed Central

    LIU, XIAO-GANG; HOU, HONG-WEI; LIU, YI-LIN

    2016-01-01

    The present study aimed to investigate the expression and roles of interleukin (IL)-17 and tumor necrosis factor (TNF)-α in intervertebral disc degeneration (IDD) and to identify the association between the effects of IL-17 and TNF-α in IDD. This may increase understanding of the pathogenic mechanism underlying IDD, and aid the development of alternative therapies. The experimental group consisted of 40 samples of nucleus pulposus tissue obtained from the intervertebral discs (IVDs) of patients with IDD by surgical intervention, and was further divided into an annulus fibrosus disrupted group, comprising 18 patients in which the external annulus was ruptured, and an annulus fibrosus intact group comprising 22 patients. The control group consisted of 20 samples of nucleus pulposus tissue from the IVDs of patients with traumatic lumbar disc fractures. The mRNA and protein expression levels of IL-17 and TNF-α in the 50 tissue samples were detected by semi-quantitative reverse transcription polymerase chain reaction and immunohistochemical staining, respectively, and the results were statistically analyzed. The IL-17 and TNF-α protein and mRNA expression levels in the annulus fibrosus disrupted and annulus fibrosus intact groups were both higher compared with those in the control group. In addition, the expression levels of IL-17 and TNF-α in the annulus fibrosus disrupted group were significantly higher compared with those in the annulus fibrosus intact group (P<0.01). A positive correlation was identified between the mRNA and protein expression levels of IL-17 and TNF-α in the experimental group (r=0.957, P<0.01). IL-17 and TNF-α may therefore be involved in the progression of human IDD, and may have synergistic effects in the development of IDD. PMID:27284317

  14. The Effects of TWEAK, Fn14, and TGF-β1 on Degeneration of Human Intervertebral Disc

    PubMed Central

    Huh, Hoon; Kim, Jung-Hee; Kong, Min-Ho; Song, Kwan-Young; Choi, Gun

    2010-01-01

    Objective The purpose of this study is to explain the effect and reciprocal action among tumor necrosis factor (TNF) like weak inducer of apoptosis (TWEAK), fibroblast growth factor-inducible 14 (Fn14), and transforming growth factor-β1 (TGF-β1) on degeneration of human intervertebral disc (IVD). Methods Human intervertebral disc tissues and cells were cultured with Dulbecco's Modified Eagle's Medium/Nutrient F-12 Ham (DMEM/F-12) media in 37℃, 5% CO2 incubator. When IVD tissues were cultured with TWEAK, Fn14 that is an antagonistic receptor for TWEAK and TGF-β1, the level of sulfated glycosaminoglycan (sGAG) was estimated by dimethyl methyleneblue (DMMB) assay and sex determining region Y (SRY)-box 9 (Sox9) and versican messenger ribonucleic acid (mRNA) levels were estimated by reverse transcriptase polymerase chain reaction (RT-PCR). Results When human IVD tissue was cultured for nine days, the sGAG content was elevated in proportion to culture duration. The sGAG was decreased significantly by TWEAK 100 ng/mL, however, Fn14 500 ng/mL did not change the sGAG production of IVD tissue. The Fn14 increased versican and Sox9 mRNA levels decreased with TWEAK in IVD tissue TGF-β1 20 ng/mL elevated the sGAG concentration 40% more than control. The sGAG amount decreased with TWEAK was increased with Fn14 or TGF-β1 but the result was insignificant statistically. TGF-β1 increased the Sox9 mRNA expression to 180% compared to control group in IVD tissue. Sox9 and versican mRNA levels decreased by TWEAK were increased with TGF-β1 in primary cultured IVD cells, however, Fn14 did not show increasing effect on Sox9 and versican. Conclusion This study suggests that TWEAK would act a role in intervertebral disc degeneration through decreasing sGAG and the mRNA level of versican and Sox9. PMID:20157375

  15. A quadrupolar complete model of the hot disc

    NASA Astrophysics Data System (ADS)

    Jannot, Yves; Acem, Zoubir

    2007-05-01

    The hot disc method is a transient plane source method used for the estimation of the thermal conductivity and diffusivity of solid materials. A complete model based on the thermal quadrupoles formalism has been developed to represent the hot disc temperature variation. This model takes into account both the thermal contact resistance between the solid to be characterized and the hot disc and the thermal inertia of the hot disc. It makes it possible to realize the parameters estimation on all the recorded temperature measurements. This model is used to highlight the estimation uncertainty due to approximations in the heat transfer model.

  16. Mechanical properties of human lumbar spine motion segments. Influence of age, sex, disc level, and degeneration.

    PubMed

    Nachemson, A L; Schultz, A B; Berkson, M H

    1979-01-01

    The influences of age, sex, disc level, and degree of degenration on the mechanical behavior of 42 fresh cadaver lumbar motion segments are reported. The motions and intradiscal pressure changes that result from the application of flexion, extension, lateral bending, and torsional moments; compression; and anterior, posterior, and lateral shears are described. The authors find that the mean behaviors of the different segment classes sometimes differ, but these differences are seldom pronounced. Scatter in the behavior of individual motion segments is pronounced, and very often overshadows any class differences. PMID:432710

  17. Interleukin-1 receptor antagonist delivered directly and by gene therapy inhibits matrix degradation in the intact degenerate human intervertebral disc: an in situ zymographic and gene therapy study

    PubMed Central

    Le Maitre, Christine L; Hoyland, Judith A; Freemont, Anthony J

    2007-01-01

    Data implicate IL-1 in the altered matrix biology that characterizes human intervertebral disc (IVD) degeneration. In the current study we investigated the enzymic mechanism by which IL-1 induces matrix degradation in degeneration of the human IVD, and whether the IL-1 inhibitor IL-1 receptor antagonist (IL-1Ra) will inhibit degradation. A combination of in situ zymography (ISZ) and immunohistochemistry was used to examine the effects of IL-1 and IL-1Ra on matrix degradation and metal-dependent protease (MDP) expression in explants of non-degenerate and degenerate human IVDs. ISZ employed three substrates (gelatin, collagen, casein) and different challenges (IL-1β, IL-1Ra and enzyme inhibitors). Immunohistochemistry was undertaken for MDPs. In addition, IL-1Ra was introduced into degenerate IVD explants using genetically engineered constructs. The novel findings from this study are: IL-1Ra delivered directly onto explants of degenerate IVDs eliminates matrix degradation as assessed by multi-substrate ISZ; there is a direct relationship between matrix degradation assessed by ISZ and MDP expression defined by immunohistochemistry; single injections of IVD cells engineered to over-express IL-1Ra significantly inhibit MDP expression for two weeks. Our findings show that IL-1 is a key cytokine driving matrix degradation in the degenerate IVD. Furthermore, IL-1Ra delivered directly or by gene therapy inhibits IVD matrix degradation. IL-1Ra could be used therapeutically to inhibit degeneration of the IVD. PMID:17760968

  18. A Degenerative/Proinflammatory Intervertebral Disc Organ Culture: An Ex Vivo Model for Anti-inflammatory Drug and Cell Therapy.

    PubMed

    Teixeira, Graciosa Q; Boldt, Antje; Nagl, Ines; Pereira, Catarina Leite; Benz, Karin; Wilke, Hans-Joachim; Ignatius, Anita; Barbosa, Mário A; Gonçalves, Raquel M; Neidlinger-Wilke, Cornelia

    2016-01-01

    Resolution of intervertebral disc (IVD) degeneration-associated inflammation is a prerequisite for tissue regeneration and could possibly be achieved by strategies ranging from pharmacological to cell-based therapies. In this study, a proinflammatory disc organ culture model was established. Bovine caudal disc punches were needle punctured and additionally stimulated with lipopolysaccharide (10 μg/mL) or interleukin-1β (IL-1β, 10-100 ng/mL) for 48 h. Two intradiscal therapeutic approaches were tested: (i) a nonsteroidal anti-inflammatory drug, diclofenac (Df) and (ii) human mesenchymal stem/stromal cells (MSCs) embedded in an albumin/hyaluronan hydrogel. IL-1β-treated disc organ cultures showed a statistically significant upregulation of proinflammatory markers (IL-6, IL-8, prostaglandin E2 [PGE2]) and metalloproteases (MMP1, MMP3) expression, while extracellular matrix (ECM) proteins (collagen II, aggrecan) were significantly downregulated. The injection of the anti-inflammatory drug, Df, was able to reduce the levels of proinflammatory cytokines and MMPs and surprisingly increase ECM protein levels. These results point the intradiscal application of anti-inflammatory drugs as promising therapeutics for disc degeneration. In parallel, the immunomodulatory role of MSCs on this model was also evaluated. Although a slight downregulation of IL-6 and IL-8 expression could be found, the variability among the five donors tested was high, suggesting that the beneficial effect of these cells on disc degeneration needs to be further evaluated. The proinflammatory/degenerative IVD organ culture model established can be considered a suitable approach for testing novel therapeutic drugs, thus reducing the number of animals in in vivo experimentation. Moreover, this model can be used to address the cellular and molecular mechanisms that regulate inflammation in the IVD and their implications in tissue degeneration. PMID:26565141

  19. Narrowing of lumbar spinal canal predicts chronic low back pain more accurately than intervertebral disc degeneration: a magnetic resonance imaging study in young Finnish male conscripts.

    PubMed

    Visuri, Tuomo; Ulaska, Jaana; Eskelin, Marja; Pulkkinen, Pekka

    2005-11-01

    The objective of this magnetic resonance imaging study was to evaluate the role of degenerative changes, developmental spinal stenosis, and compression of spinal nerve roots in chronic low back (CLBP) and radicular pain in Finnish conscripts. The degree of degeneration, protrusion, and herniation of the intervertebral discs and stenosis of the nerve root canals was evaluated, and the midsagittal diameter and cross-sectional area of the lumbar vertebrae canal were measured in 108 conscripts with CLBP and 90 asymptomatic controls. The midsagittal diameters at L1-L4 levels were significantly smaller in the patients with CLBP than in the controls. Moreover, degeneration of the L4/5 disc and protrusion or herniation of the L5/S1 disc and stenosis of the nerve root canals at level L5/S1 were more frequent among the CLBP patients. Multifactorial analysis of the magnetic resonance imaging findings provided a total explanatory rate of only 33%. Narrowing of the vertebral canal in the anteroposterior direction was more likely to produce CLBP and radiating pain than intervertebral disc degeneration or narrowing of the intervertebral nerve root canals. PMID:16450819

  20. Development of a Large Animal Long-Term Intervertebral Disc Organ Culture Model That Includes the Bony Vertebrae for Ex Vivo Studies.

    PubMed

    Grant, Michael; Epure, Laura M; Salem, Omar; AlGarni, Nizar; Ciobanu, Ovidiu; Alaqeel, Motaz; Antoniou, John; Mwale, Fackson

    2016-07-01

    Intervertebral disc (IVD) degeneration is a common cause of low back pain. Testing potential therapeutics in the regeneration of the disc requires the use of model systems. Although several animal models have been developed to investigate IVD degeneration, they are technically challenging to prepare, expensive, present with limitations when performing biomechanical studies on the disc, and are impractical in large-scale screening of novel anabolic and scaffolding agents. An IVD organ culture system offers an inexpensive alternative. In the current paradigm, the bony endplates are removed to allow for nutrient diffusion and maintenance of disc cell viability. Although this is an excellent system for testing biologics, it results in concave cartilage endplates and, as such, requires special platens for loading purposes in a bioreactor as flat ones can overload the annular disc region leading to improper loading. Furthermore, the absence of bone makes it unsuitable for applying complex cyclic loading, a topic of interest in the study of chronic progressive degeneration, as multiaxial loading is more representative of daily forces encountered by the IVD. We have developed and validated a novel long-term IVD organ culture model that retains vertebral bone and is easy to prepare. Our model is ideal for testing potential drugs and alternate-based therapies, in addition to investigating the long-term effects of loading paradigms on disc degeneration and repair. PMID:27216856

  1. Gender difference in genetic association between IL1A variant and early lumbar disc degeneration: a three-year follow-up

    PubMed Central

    Eskola, Pasi J; Kjaer, Per; Sorensen, Joan S; Okuloff, Annaleena; Wedderkopp, Niels; Daavittila, Iita; Ala-Kokko, Leena; Männikkö, Minna; Karppinen, Jaro

    2012-01-01

    Objective The purpose of the present study was to analyze the associations between specific genetic markers and early disc degeneration (DD) or early disc degeneration progression (DDP) defined by magnetic resonance imaging (MRI). Methods We selected eleven of the most promising single nucleotide polymorphisms (SNP) and compared the distributions of these genetic markers between groups defined by MRI in a Danish adolescent population (N=166) over a three-year follow-up period. Results We observed a ten-fold higher annual incidence of endplate changes than previously reported in adults. The gender difference in IL1A rs1800587 association with DD remained significant and another association with DDP emerged in follow-up assessment. Among girls, the rs1800587 T-allele was associated both with DD (OR 2.82 [95% CI 1.29-6.16]) and with DDP (OR 2.45 [95% CI 1.03-5.82]). Among boys, the IL6 rs1800795 genotype G/C was protective in both DD (OR 0.26 [95% CI 0.09-0.72]) and DDP (OR 0.32 [95% CI 0.12-0.88]) with the IL6 rs1800797 genotype G/A was associated with a decreased likelihood of DD (OR 0.27 [95% CI 0.10-0.77]). Gender-genotype interactions were significant for polymorphisms in both IL1A and IL6. Correction for multiple testing weakened the associations for IL6 polymorphisms. Conclusion We conclude that gender specific effects in lumbar disc degeneration and its progression are possible. However, further evaluations in larger populations are needed. Our results provide some support to the hypothesis that early disc degeneration is an especially important phase in the cascade of degenerative disc disease. PMID:23050050

  2. The role of TGF-β1/Smad2/3 pathway in platelet-rich plasma in retarding intervertebral disc degeneration.

    PubMed

    Yang, Huilin; Yuan, Chenxi; Wu, Chunshen; Qian, Jiale; Shi, Qing; Li, Xuefeng; Zhu, Xuesong; Zou, Jun

    2016-08-01

    Recent studies have suggested that platelet-rich plasma (PRP) injections are an effective way to retard intervertebral disc degeneration, but the mechanism of action is unclear. Activated platelets release some growth factors, such as transforming growth factor-β1 (TGF-β1), which positively modulate the extracellular matrix of nucleus pulposus cells. The purpose of this study was to explore the mechanism underlying the PRP-mediated inhibition of intervertebral disc degeneration. In an in vitro study, we found that the proliferation of nucleus pulposus cells was greatly enhanced with 2.5% PRP treatment. The TGF-β1 concentration was much higher after PRP treatment. PRP administration effectively increased the collagen II, aggrecan and sox-9 mRNA levels and decreased collagen X levels. However, Western blotting demonstrated that specifically inhibiting TGF-β1 signalling could significantly prevent nucleus pulpous cellular expression of Smad2/3 and matrix protein. In a rabbit study, magnetic resonance imaging revealed significant recovery signal intensity in the intervertebral discs of the PRP injection group compared with the very low signal intensity in the control groups. Histologically, the PRP plus inhibitor injection group had significantly lower expression levels of Smad2/3 and collagen II than the PRP group. These results demonstrated that a high TGF-β1 content in the platelets retarded disc degeneration in vitro and in vivo. Inhibiting the TGF-β1/Smad2/3 pathway could prevent this recovery by inactivating Smad2/3 and down-regulating the extracellular matrix. Therefore, the TGF-β1/Smad2/3 pathway might play a critical role in the ability of PRP to retard intervertebral disc degeneration. PMID:27061332

  3. Pharmacological enhancement of disc diffusion and differentiation of healthy, ageing and degenerated discs : Results from in-vivo serial post-contrast MRI studies in 365 human lumbar discs.

    PubMed

    Rajasekaran, S; Venkatadass, K; Naresh Babu, J; Ganesh, K; Shetty, Ajoy P

    2008-05-01

    Degenerative disc disease (DDD) is still a poorly understood phenomenon because of the lack of availability of precise definition of healthy, ageing and degenerated discs. Decreased nutrition is the final common pathway for DDD and the status of the endplate (EP) plays a crucial role in controlling the extent of diffusion, which is the only source of nutrition. The vascular channels in the subchondral plate have muscarinic receptors but the possibility of enhancing diffusion pharmacologically by dilation of these vessels has not been probed. Although it is well accepted that EP damage will affect diffusion and thereby nutrition, there is no described method to quantify the extent of EP damage. Precise definitions with an objective method of differentiating healthy, ageing and degenerated discs on the basis of anatomical integrity of the disc and physiological basis of altered nutrition will be useful. This information is an urgent necessity for better understanding of DDD and also strategizing prevention and treatment. Seven hundred and thirty endplates of 365 lumbar discs from 73 individuals (26 healthy volunteers and 47 patients) with age ranging from 10-64 years were evaluated by pre-contrast and 10 min, 2, 4, 6 and 12 h post contrast MRI after IV injection of 0.3 mmol/kg of Gadodiamide. End plates were classified according to the extent of damage into six grades and an incremental score was given for each category. A total endplate score (TEPS) was derived by adding the EP score of the two endplates for each concerned disc. The base line value (SI(base)) and the signal intensity at particular time periods were used to derive the enhancement percentage for each time period (Enhancement (%) = SI(tp) - SI(base)/SI(base) x 100). The enhancement percentage for each time period, the time for peak enhancement (T-max) and the time intensity curve (TIC) over 12 h were used to study and compare the diffusion characteristics. The differences in pattern of diffusion were

  4. Correlation of serum trace elements and melatonin levels to radiological, biochemical, and histological assessment of degeneration in patients with intervertebral disc herniation.

    PubMed

    Turgut, Mehmet; Yenisey, Cigdem; Akyüz, Orhan; Ozsunar, Yelda; Erkus, Muhan; Biçakçi, Tuncay

    2006-02-01

    The aim of our study was to assess the blood concentrations of some trace elements and melatonin (MLT) in patients with intervertebral disc herniation (IDH) and to investigate the interaction of histological and biochemical degeneration findings with aging. The present study was carried out on 13 subjects (8 women and 5 men) diagnosed with IDH. They were divided into three groups according to their ages. Nighttime serum MLT, zinc (Zn), and magnesium (Mg) levels were determined in all patients. In addition, computed tomography (CT) scan of the brain and magnetic resonance imaging examination of the lumbar spine were obtained in this study. The Zn level and Zn/Mg ratio showed a decline in patients with IDH with aging, whereas the serum Mg level and tissue hydroxyproline content increased. A positive correlation between serum Zn and MLT concentrations was found (r=0.104, p=0.734). In addition, there was a positive correlation between serum Zn level and Zn/Mg ratio (r=0.835 and p<0.01), and a negative correlation between serum Mg level and Zn/Mg ratio (r=-0.571, p<0.05). On CT study, both volume percentage of calcified pineal gland and density of calcification were found to increase progressively with advancing age. The results of semiquantitative evaluation of disc tissues of patients with IDH for histological degeneration findings showed that 66.7% of discs treated had slight degeneration in younger age group, but 75.0% and 100% of discs had moderate or marked degeneration in older age groups. Our data indicated that there is a close relationship between MLT and Zn or Mg levels in the serum samples of patients with IDH, and the levels of these elements might be affected by the presence of degeneration process and serum MLT level, or vice versa. PMID:16444002

  5. Aging affects response to cyclic tensile stretch: paradigm for intervertebral disc degeneration.

    PubMed

    Cho, Hongsik; Seth, Aman; Warmbold, Jenna; Robertson, James T; Hasty, Karen A

    2011-01-01

    Much evidence supports a fundamental role for mechanical forces in modulating differentiation, homeostasis, and remodelling of musculoskeletal cells. Little is known, however, regarding mechanobiology and gene expression of intervertebral disc (IVD) cells from older individuals. To characterise the effect of mechanical stimulation on cells from older discs, an in vitro study of IVD cells harvested from different aged pigs was conducted to measure extracellular matrix (ECM) gene expression in response to cyclic tensile stress (CTS). Gene expression of annulus fibrosus (AF) cells from IVDs of mature and older pigs was quantified for the predominant ECM genes; type I collagen, type II collagen and aggrecan, and matrix metalloproteinase 1 (MMP-1), a collagenase that degrades fibrillar collagens. AF cells cultured on flexible-bottom plates were stretched 10 % at 0.5 Hz frequency. After 24 h, gene expression was assayed using reverse transcriptase polymerase chain reaction (RT-PCR). Basal mRNA levels without stretching for type II collagen and aggrecan were lower in older annular cells whereas MMP-1 levels were higher compared to mature cells. Following CTS, an adaptive response was elicited in annular cells from both age groups. ECM protein genes were upregulated, whereas MMP-1 was downregulated. The magnitude of response was significantly greater in older cells as compared to mature cells. These data suggest that the cells from the AF of older animals manifest lower basal levels of mRNA for type II collagen and aggrecan and higher levels of MMP-1 possibly due to decreased tensile stress experienced in vivo and is not the result of reduced capacity for response. PMID:21932191

  6. Treatment of Symptomatic Lumbar Disc Degeneration with the VariLift-L Interbody Fusion System: Retrospective Review of 470 Cases

    PubMed Central

    Neely, Warren F.; Fichtel, Frank; del Monaco, Diana Cardenas

    2016-01-01

    Background Many first generation stand-alone fusion cages required endplate decortication and surgical impaction during the procedure resulting in segmental subsidence, implant migration and loss of lordosis postoperatively. The primary objective of this study was to evaluate radiographically, in a large series of patients, whether engineering and design modifications incorporated in a specific stand-alone, expandable interbody fusion device (VariLift®-L) adequately addressed previously recognized deficiencies of stand-alone interbody cages. Methods In this retrospective chart review of 470 patients (642 treated levels), we evaluated radiographic evidence of fusion, subsidence and migration following a one- or two-level PLIF procedure utilizing this stand-alone expandable interbody fusion device. A secondary objective was to corroborate the low morbidity and symptomatic improvements achieved with previous interbody cage devices used to treat symptomatic disc degeneration. Results The average postoperative followup was 3.9 ± 1.8 years and a solid fusion rate of 94% was achieved among patients with ≥ 9 months of radiographic followup. Subsidence > 3 mm was noted at 10 levels with no cases of device migration. Composite back pain severity scores improved from 8.5 ± 1.5 preoperatively to 0.8 ± 1.5 at final followup (p<0.001) and 94% of patients met or exceeded the minimal clinical important difference of 3.8 points. Eighteen patients required reoperation following the index procedure; 16 of these patients were treated for adjacent segment disease. Conclusions (LOE) The VariLift-L device has excellent clinical and technical performance characteristics, providing adequate stabilization of the anterior column without the need for supplemental posterior instrumentation. Level of Evidence IV. IRB Approval: Expedited Federal Register Categories 5& 7: Methodist IRB 3/30/2011; Informed Consent statement: retrospective data collection, patients signed consent forms

  7. Age-related accumulation of pentosidine in aggrecan and collagen from normal and degenerate human intervertebral discs

    PubMed Central

    Sivan, Sarit Sara; Tsitron, Eve; Wachtel, Ellen; Roughley, Peter; Sakkee, Nico; van der Ham, Frits; Degroot, Jeroen; Maroudas, Alice

    2006-01-01

    During aging and degeneration, many changes occur in the structure and composition of human cartilaginous tissues, which include the accumulation of the AGE (advanced glycation end-product), pentosidine, in long-lived proteins. In the present study, we investigated the accumulation of pentosidine in constituents of the human IVD (intervertebral disc), i.e. collagen, aggrecan-derived PG (proteoglycan) (A1) and its fractions (A1D1–A1D6) in health and pathology. We found that, after maturity, pentosidine accumulates with age. Over the age range studied, a linear 6-fold increase was observed in pentosidine accumulation for A1 and collagen with respective rates of 0.12 and 0.66 nmol·(g of protein)−1·year−1. Using previously reported protein turnover rate constants (kT) obtained from measurements of the D-isomer of aspartic residue in collagen and aggrecan of human IVD, we could calculate the pentosidine formation rate constants (kF) for these constituents [Sivan, Tsitron, Wachtel, Roughley, Sakkee, van der Ham, DeGroot, Roberts and Maroudas (2006) J. Biol. Chem. 281, 13009–13014; Tsitron (2006) MSc Thesis, Technion-Israel Institute of Technology, Haifa, Israel]. In spite of the comparable formation rate constants obtained for A1D1 and collagen [1.81±0.25 compared with 3.71±0.26 μmol of pentosidine·(mol of lysine)−1·year−1 respectively], the higher pentosidine accumulation in collagen is consistent with its slower turnover (0.005 year−1 compared with 0.134 year−1 for A1D1). Pentosidine accumulation increased with decreasing buoyant density and decreasing turnover of the proteins from the most glycosaminoglycan-rich PG components (A1D1) to the least (A1D6), with respective kF values of 1.81±0.25 and 3.18±0.37 μmol of pentosidine·(mol of lysine)−1·year−1. We concluded that protein turnover is an important determinant of pentosidine accumulation in aggrecan and collagen of human IVD, as was found for articular cartilage. Correlation of

  8. The Relation Between Sacral Angle and Vertical Angle of Sacral Curvature and Lumbar Disc Degeneration: A Case-Control Study.

    PubMed

    Ghasemi, Ahmad; Haddadi, Kaveh; Khoshakhlagh, Mohammad; Ganjeh, Hamid Reza

    2016-02-01

    The purpose of this study is to determine the reliability and validity of a goniometric measurement of the vertical angle of the sacrum and sacral angle (SA), and their relationships to lumbar degeneration.A herniated lumbar disc is one of the most frequent medical issues. Investigators in a number of studies have reported associated risk factors for prevalent disc degeneration. Atypical lumbosacral angles and curvature are thought to contribute to the degradation of the spine by many researchers. This study analyzed 360 patients referred to our clinic from 2013 to 2015 due to low back pain. A cross-sectional case-control study was designed in order to compare the sagittal alignment of the lumbosacral area in 3 groups of patients suffering from LBP. A total 120 patients were in a control group with a normal lumbar magnetic resonance imaging (MRI), 120 patients had lumbar disk herniation (LDH), and 120 patients had spinal stenosis. From the sagittal plan of lumbar MRI, SA and vertical angle of sacral curvature (VASC) were determined and then analyzed.The means of VASC in these groups were: 38.98 (SD: 6.36 ± 0.58), 40.89 (SD: 7.69 ± 0.69), and 40.54 (SD: 7.13 ± 0.92), respectively (P = 0.089). Moreover, studies of SA in 3 groups showed that the means of SA were: 39.30 (SD: 6.69 ± 0.63), 40.52 (SD: 7.47 ± 0.65), and 35.63 (SD: 6.07 ± 0.79), respectively. Relation between SA and spinal stenosis was just statistically significant (P ≤ 0.05).One significant limitation of our study is the lack of standing MRI for increased accuracy of measurement. However, we were reluctant to give patients needless exposure to radiation from conventional X-ray, and instead used MRI scans. We did not find any significant correlation between the VASC and LDH in lumbar MRI. Also, SA is not an independent risk factor for LDH in men and women. We suggested that there are several biomechanical factors involved in LDH. PMID:26871821

  9. Injectable microcarriers as human mesenchymal stem cell support and their application for cartilage and degenerated intervertebral disc repair.

    PubMed

    Bertolo, A; Häfner, S; Taddei, A R; Baur, M; Pötzel, T; Steffen, F; Stoyanov, J

    2015-01-01

    Degeneration of the intervertebral disc (IVD) is a progressive and chronic process, and the high incidence of discogenic disorders calls for new therapeutic approaches, such as cell-based therapies using three dimensional cultures and mesenchymal stem cells (MSC), which can differentiate to chondrogenic- and IVD-lineages. Here, we investigated the growth and differentiation of human MSC culture on biodegradable collagen scaffolds in order to obtain an injectable suspension. Commercially available wound dressings were downsized to dimensions between 100 and 1500 μm and seeded with freshly isolated or early passages MSC. Proliferation rate and chondrogenic differentiation potential was tested at oxygenation levels of 2%, 5%, 10% and 21% in static and dynamic cultures. Evaluation methods included cell viability test, disc marker genes expression (aggrecan, collagen type I and type II), histological detection of proteoglycans and immunohistochemical analysis. On microcarriers, freshly isolated MSC had lower proliferation rate and chondrogenic differentiation potential compared with early passages MSC. Proliferation of MSC was significantly increased 1.7-fold at 5% oxygen level and in combination with dynamic culture was further increased to 2.3-fold, with respect to normoxia. Chondrogenesis was positively affected by 2% and 5% hypoxia, as shown by increased transcription levels and protein expression of collagen type II and proteoglycan accumulation in static cultures, while it was inhibited in dynamic cultures. Collagen type I and aggrecan expression were not affected by hypoxia. In conclusion, collagen based microcarriers are a suitable support for in vitro MSC growth and chondrogenesis especially when cultured at 5% oxygen level. PMID:25579755

  10. Role of growth differentiation factor-5 and bone morphogenetic protein type II receptor in the development of lumbar intervertebral disc degeneration

    PubMed Central

    Li, Yi-Fan; Tang, Xian-Zhong; Liang, Chao-Ge; Hui, Yao-Ming; Ji, Yun-Han; Xu, Wei; Qiu, WenJun; Cheng, Li-Ming

    2015-01-01

    The present study was designed to evaluate the role of growth differentiation factor-5 (GDF-5) and bone morphogenetic protein type II receptor (BMPR-II) in the development of lumbar intervertebral disc degeneration (IDD). A total of 24 patients with lumbar IDD (experiment group) and 6 patients with lumbar vertebral fracture (control group) were enrolled in the study. Tissue samples of IVD from the experiment group and control group were obtained during lumbar fusion operation, respectively. Fixation and decalcification of IVD tissue were performed, and then HE staining was carried out to observe the morphological changes of the lumbar IVD tissues. The expression of GDF-5 and BMPRII in human lumbar IVD was detected by immunohistochemical staining. HE staining results showed that non- and minimal degeneration was found in 11 cases (score range, 0-3), moderate degeneration in 12 cases (score range, 4-8), and severe degeneration in 7 cases (score range, 9-12). According to the immunohistochemical results, the positive expression rates of GDF-5 and BMPRII in NP were higher than those in AF of the non- and minimal degeneration group, moderate degeneration group and severe degeneration group (all P < 0.05). However, no significant difference in GDF-5 or BMPRII positive expression was observed among the normal, non- and minimal, moderate and severe degeneration groups in neither NP area nor AF area (all P > 0.05). In conclusion, our results showed that GDF-5 and BMPRII expressed both in normal and degenerated IVD tissues, and GDF-5 might have an inhibition effect on degenerated lumbar IVD, suggesting that gene therapy may be a useful approach in producing physiological effects during early- and late-phase of lumbar IDD. PMID:25755766

  11. Modelling and observations of molecules in discs around young stars

    NASA Astrophysics Data System (ADS)

    Ilee, John David

    2013-04-01

    This thesis contains a study of molecules within circumstellar discs around young stars. Firstly, the chemistry of a disc around a young, Class 0 protostar is modelled. Such discs are thought to be massive, and thus experience gravitational instabilities, which produce spiral density waves. These affect the chemistry in three ways; by desorbing molecules from dust grains, by providing extra energy for new reactions to take place, and by mixing the internal structure of the disc to provide a rich chemistry near the midplane. Secondly, high resolution near-infrared spectra of 20 massive young stellar objects are presented. The objects display CO first overtone bandhead emission, which is excited in the conditions expected within circumstellar discs. The emission is modelled using a simple analytic model of a Keplerian disc, and good fits are found to all spectra. On average, the discs correspond to being geometrically thin, spread across a wide range of inclinations. The discs are located within the dust sublimation radius, providing strong evidence that the CO emission originates in small gaseous discs, supporting the scenario in which massive stars form via disc accretion. Finally, medium resolution near-infrared spectra of 5 Herbig Ae/Be stars are presented. The spectra cover both CO bandhead and Br gamma emission. Accretion rates are derived from the measuring the Br gamma emission and through modelling the CO emission, however these accretion rates are found to be inconsistent. High resolution archival data of one of the targets is presented, and it is shown that this CO disc model is unable to fit the high resolution data. Therefore, it is concluded that to properly fit CO spectra, high resolution data are needed, and that previously published information determined from low resolution spectra should be treated with caution.

  12. Low level light therapy modulates inflammatory mediators secreted by human annulus fibrosus cells during intervertebral disc degeneration in vitro.

    PubMed

    Hwang, Min Ho; Shin, Jae Hee; Kim, Kyoung Soo; Yoo, Chang Min; Jo, Ga Eun; Kim, Joo Han; Choi, Hyuk

    2015-01-01

    Intervertebral disc degeneration (IVD) is one of the important causes of low back pain and is associated with inflammation induced by interaction between macrophages and the human annulus fibrosus (AF) cells. Low-level light therapy (LLLT) has been widely known to regulate inflammatory reaction. However, the effect of LLLT on macrophage-mediated inflammation in the AF cells has not been studied till date. The aim of this study is to mimic the inflammatory microenvironment and to investigate the anti-inflammatory effect of LLLT at a range of wavelengths (405, 532 and 650 nm) on the AF treated with macrophage-like THP-1 cells conditioned medium (MCM) containing proinflammatory cytokines and chemokines (interleukin-1beta, tumor necrosis factor-alpha, interleukin-6 and 8). We observed that AF cells exposed to MCM secrete significantly higher concentrations of IL-6, IL-8, IL-1β and TNF-α. LLLT markedly inhibited secretion of IL-6 at 405 nm in a time-dependent manner. Level of IL-8 was significantly decreased at all wavelengths in a time-dependent manner. We showed that MCM can induce the inflammatory microenvironment in AF cells and LLLT selectively suppressed IL-6 and 8 levels. The results indicate that LLLT is a potential method of IVD treatment and provide insights into further investigation of its anti-inflammation effect on IVD. PMID:25557915

  13. Degenerated intervertebral disc prolapse and its association of collagen I alpha 1 Spl gene polymorphism: A preliminary case control study of Indian population

    PubMed Central

    Anjankar, Shailendra D; Poornima, Subhadra; Raju, Subodh; Jaleel, MA; Bhiladvala, Dilnavaz; Hasan, Qurratulain

    2015-01-01

    Background: Degenerated disc disease (DDD) is a common disorder responsible for increased morbidity in a productive age group. Its etiology is multifactorial and genetic factors have been predominantly implicated. Disc prolapse results due to tear in the annulus, which is a fibrous structure composed largely of type I collagen. Functional polymorphism at the Sp1 site of the collagen I alpha 1 (COL1A1) gene has shown a positive association with DDD in Dutch and Greek populations. The purpose of this study was to assess COL1A1 Sp1 gene polymorphism in the Indian population. Materials and Methods: Fifty clinically and radiologically proven patients with disc prolapse requiring surgery were included as cases and 50 healthy, age-matched volunteers served as controls. After isolating DNA from their blood sample, genotyping for COL1A1 polymorphism (rs1800012) was performed and identified as GG, GT, and TT. Results: The mean age and body mass index in cases and controls were similar. 76% of the patients were males. The most common site of disc degeneration was L4–L5 (36%), followed by L5–S1 (34%). Homozygous–GG, heterozygous GT, and homozygous TT genotypes were seen in 38 (76%), 10 (20%) and 2 (4%) cases respectively, controls had similar percentage of genotypes as well. The alleles in cases and the control group showed no significant difference (P = 0.6744) and followed the Hardy–Weinberg Equilibrium in the study population. Conclusion: The COL1A1 (rs1800012) is in Hardy–Weinberg equilibrium in the present subset of Indian population. But taken as a single factor, it was not found to be associated with DDD in this preliminary study. Disc degeneration is multifactorial and also anticipated to be a result of multiple genes involvement and gene-gene interaction. PMID:26806964

  14. Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: Novel HIF-1-mediated regulation of aquaporins in NP cells.

    PubMed

    Johnson, Zariel I; Gogate, Shilpa S; Day, Rebecca; Binch, Abbie; Markova, Dessislava Z; Chiverton, Neil; Cole, Ashley; Conner, Matt; Shapiro, Irving M; Le Maitre, Christine L; Risbud, Makarand V

    2015-05-20

    Objectives of this study were to investigate whether AQP1 and AQP5 expression is altered during intervertebral disc degeneration and if hypoxia and HIF-1 regulate their expression in NP cells. AQP expression was measured in human tissues from different degenerative grades; regulation by hypoxia and HIF-1 was studied using promoter analysis and gain- and loss-of-function experiments. We show that both AQPs are expressed in the disc and that mRNA and protein levels decline with human disease severity. Bioinformatic analyses of AQP promoters showed multiple evolutionarily conserved HREs. Surprisingly, hypoxia failed to induce promoter activity or expression of either AQP. While genomic chromatin immunoprecipitation showed limited binding of HIF-1α to conserved HREs, their mutation did not suppress promoter activities. Stable HIF-1α suppression significantly decreased mRNA and protein levels of both AQPs, but HIF-1α failed to induce AQP levels following accumulation. Together, our results demonstrate that AQP1 and AQP5 expression is sensitive to human disc degeneration and that HIF-1α uniquely maintains basal expression of both AQPs in NP cells, independent of oxemic tension and HIF-1 binding to promoter HREs. Diminished HIF-1 activity during degeneration may suppress AQP levels in NP cells, compromising their ability to respond to extracellular osmolarity changes. PMID:25844601

  15. Aquaporin 1 and 5 expression decreases during human intervertebral disc degeneration: novel HIF-1-mediated regulation of aquaporins in NP cells

    PubMed Central

    Day, Rebecca; Binch, Abbie; Markova, Dessislava Z.; Chiverton, Neil; Cole, Ashley; Conner, Matt; Shapiro, Irving M.; Le Maitre, Christine L.; Risbud, Makarand V.

    2015-01-01

    Objectives of this study were to investigate whether AQP1 and AQP5 expression is altered during intervertebral disc degeneration and if hypoxia and HIF-1 regulate their expression in NP cells. AQP expression was measured in human tissues from different degenerative grades; regulation by hypoxia and HIF-1 was studied using promoter analysis and gain- and loss-of-function experiments. We show that both AQPs are expressed in the disc and that mRNA and protein levels decline with human disease severity. Bioinformatic analyses of AQP promoters showed multiple evolutionarily conserved HREs. Surprisingly, hypoxia failed to induce promoter activity or expression of either AQP. While genomic chromatin immunoprecipitation showed limited binding of HIF-1α to conserved HREs, their mutation did not suppress promoter activities. Stable HIF-1α suppression significantly decreased mRNA and protein levels of both AQPs, but HIF-1α failed to induce AQP levels following accumulation. Together, our results demonstrate that AQP1 and AQP5 expression is sensitive to human disc degeneration and that HIF-1α uniquely maintains basal expression of both AQPs in NP cells, independent of oxemic tension and HIF-1 binding to promoter HREs. Diminished HIF-1 activity during degeneration may suppress AQP levels in NP cells, compromising their ability to respond to extracellular osmolarity changes. PMID:25844601

  16. Modeling of rotating disc contactor (RDC) column

    NASA Astrophysics Data System (ADS)

    Ismail, Wan Nurul Aiffah; Zakaria, Siti Aisyah; Noor, Nor Fashihah Mohd; Sulong, Ibrahim; Arshad, Khairil Anuar

    2014-12-01

    Liquid-liquid extraction is one of the most important separation processes. Different kinds of liquid-liquid extractor such as Rotating Disc Contactor (RDC) Column being used in industries. The study of liquid-liquid extraction in an RDC column has become a very important subject to be discussed not just among chemical engineers but mathematician as well. In this research, the modeling of small diameter RDC column using the chemical system involving cumene/isobutryric asid/water are analyzed by the method of Artificial Neural Network (ANN). In the previous research, we begin the process of analyzed the data using methods of design of the experiments (DOE) to identify which factor and their interaction factor are significant and to determine the percentage of contribution of the variance for each factor. From the result obtained, we continue the research by discussed the development and validation of an artificial neural network model in estimating the concentration of continuous and concentration of dispersed outlet for an RDC column. It is expected that an efficient and reliable model will be formed to predict RDC column performance as an alternative to speed up the simulation process.

  17. Body mass index is associated with lumbar disc degeneration in young Finnish males: subsample of Northern Finland birth cohort study 1986

    PubMed Central

    2013-01-01

    Background The role of environmental factors in lumbar intervertebral disc degeneration (DD) in young adults is largely unknown. Therefore, we investigated whether body mass index (BMI), smoking, and physical activity are associated with lumbar DD among young adults. Methods The Oulu Back Study (OBS) is a subpopulation of the 1986 Northern Finland Birth Cohort (NFBC 1986) and it originally included 2,969 children. The OBS subjects received a postal questionnaire, and those who responded (N = 1,987) were invited to the physical examination. The participants (N = 874) were invited to lumbar MRI study. A total of 558 young adults (325 females and 233 males) underwent MRI that used a 1.5-T scanner at the mean age of 21. Each lumbar intervertebral disc was graded as normal (0), mildly (1), moderately (2), or severely (3) degenerated. We calculated a sum score of the lumbar DD, and analyzed the associations between environmental risk factors (smoking, physical activity and weight-related factors assessed at 16 and 19 years) and DD using ordinal logistic regression, the results being expressed as cumulative odds ratios (COR). All analyses were stratified by gender. Results Of the 558 subjects, 256 (46%) had no DD, 117 (21%) had sum score of one, 93 (17%) sum score of two, and 92 (17%) sum score of three or higher. In the multivariate ordinal logistic regression model, BMI at 16 years (highest vs. lowest quartile) was associated with DD sum score among males (COR 2.35; 95% CI 1.19-4.65) but not among females (COR 1.29; 95% CI 0.72-2.32). Smoking of at least four pack-years was associated with DD among males, but not among females (COR 2.41; 95% CI 0.99-5.86 and 1.59; 95% 0.67-3.76, respectively). Self-reported physical activity was not associated with DD. Conclusions High BMI at 16 years was associated with lumbar DD at 21 years among young males but not among females. High pack-years of smoking showed a comparable association in males, while physical activity had

  18. Gas Modelling in the Disc of HD 163296

    NASA Technical Reports Server (NTRS)

    Tilling, I.; Woitke, P.; Meeus, G.; Mora, A.; Montesinos, B.; Riviere-Marichalar, P.; Eiroa, C.; Thi, W. -F.; Isella, A.; Roberge, A.; Martin-Zaidi, C.; Kamp, I.; Pinte, C.; Sandell, G.; Vacca, W. D.; Menard, F.; Mendigutia, I.; Duchene, G.; Dent, W. R. F.; Aresu, G.; Meijerink, R.; Spaans, M.

    2011-01-01

    We present detailed model fits to observations of the disc around the Herbig Ae star HD 163296. This well-studied object has an age of approx. 4Myr, with evidence of a circumstellar disc extending out to approx. 540AU. We use the radiation thermo-chemical disc code ProDiMo to model the gas and dust in the circumstellar disc of HD 163296, and attempt to determine the disc properties by fitting to observational line and continuum data. These include new Herschel/PACS observations obtained as part of the open-time key program GASPS (Gas in Protoplanetary Systems), consisting of a detection of the [Oi] 63 m line and upper limits for several other far infrared lines. We complement this with continuum data and ground-based observations of the CO-12 3-2, 2-1 and CO-13 J=1-0 line transitions, as well as the H2 S(1) transition. We explore the effects of stellar ultraviolet variability and dust settling on the line emission, and on the derived disc properties. Our fitting efforts lead to derived gas/dust ratios in the range 9-100, depending on the assumptions made. We note that the line fluxes are sensitive in general to the degree of dust settling in the disc, with an increase in line flux for settled models. This is most pronounced in lines which are formed in the warm gas in the inner disc, but the low excitation molecular lines are also affected. This has serious implications for attempts to derive the disc gas mass from line observations. We derive fractional PAH abundances between 0.007 and 0.04 relative to ISM levels. Using a stellar and UV excess input spectrum based on a detailed analysis of observations, we find that the all observations are consistent with the previously assumed disc geometry

  19. OPG rs2073617 polymorphism is associated with upregulated OPG protein expression and an increased risk of intervertebral disc degeneration

    PubMed Central

    Xue, Jing-Bo; Zhan, Xin-Li; Wang, Wen-Jun; Yan, Yi-Guo; Liu, Chong

    2016-01-01

    The present study aimed to investigate the associations between three distinct osteoprotegerin (OPG) gene polymorphisms and the risk of intervertebral disc degeneration (IDD). A total of 200 IDD patients and 200 healthy controls were recruited from the Department of Spine Surgery at the First Affiliated Hospital of the University of South China (Hengyang, China) between January 2013 and May 2014. The allele, genotype and haplotype frequency distributions of three OPG polymorphisms in the study and control populations were analyzed by polymerase chain reaction prior to restriction fragment length polymorphism or high resolution melting assays. In addition, serum OPG levels were measured via an ELISA. The genotype and allele frequencies of the OPG rs2073617 polymorphisms were significantly higher in the IDD patients, as compared with the control group (P<0.05). Furthermore, carriers of the C allele exhibited a higher risk of IDD, as compared with carriers of the T allele (P<0.001). Conversely, the genotype and allele frequencies of the two other gene polymorphisms, rs2073618 and rs3102735, showed no significant differences between the patients and controls (P>0.05). The serum OPG levels were significantly higher in IDD patients with TT, TC and CC genotypes at the OPG rs2073617 polymorphism, as compared with the control group (P<0.05). Logistic-regression analysis suggested that high serum levels of OPG were positively correlated with IDD risk, whereas the T-C-A, T-G-A and T-G-G haplotypes were negatively correlated with IDD risk (P<0.05). Furthermore, the G-T-G haplotype was associated with protection against IDD (P=0.008), whereas the G-C-G haplotype was associated with an elevated susceptibility to IDD (P=0.007). The results of the present study suggested that OPG rs2073617 polymorphisms and upregulated serum levels of OPG were associated with an increased risk of IDD, whereas the T-C-A, T-G-A and T-G-G haplotypes were protective factors for IDD. The results of the

  20. The Effect of Gamma Irradiation on the Biological Properties of Intervertebral Disc Allografts: In Vitro and In Vivo Studies in a Beagle Model

    PubMed Central

    Ding, Yu; Ruan, Dike; Luk, Keith D. K.; He, Qing; Wang, Chaofeng

    2014-01-01

    Study Design An animal experiment about intervertebral disc allograft. Objective To explore the feasibility to decellularize disc allografts treated by 6°Co Gamma Irradiation, and simultaneously, to assess the possibility to make use of the decellularized natural disc scaffold for disc degeneration biotherapy. Summary of Background Data Studies of both animal and human disc allograft transplantation indicated that the disc allograft may serve as a scaffold to undertake the physiological responsibility of the segment. Methods Experiment in vitro: 48 discs of beagles were harvested and divided randomly into four groups including a control group and three irradiated groups. Immediate cell viability and biomechanical properties of the discs were checked and comparisons were made among these groups. Experiment in vivo: 24 beagles accepted single-level allografted disc treated with different doses of gamma irradiation. Plain X-rays and MRIs were taken before and after surgery. Then, the spinal columns were harvested en bloc from the sacrificed beagles and were examined morphologically. Results There were significant differences of both the annulus fibrosus and nucleus pulposus immediate cell viabilities among the various groups. There were no obvious differences of the biomechanical properties among the four groups. The disc height and range of motion decreased significantly in all groups as time went on. The observed indexes in irradiated groups were much smaller than those in the control group, but the indexes in 18-kGy group were larger than those in 25-kGy and 50-kGy groups. Both MRI and macroscopic findings showed that the segmental degeneration in the control and 18-kGy group was less severe than that in 25-kGy and 50-kGy groups. Conclusion Gamma Irradiation can decellularize disc allograft successfully to provide natural scaffold for the study of degenerative disc disease therapy, and also can be used as an effective method to produce adjustable animal models

  1. In vitro assessment of biomaterial-induced remodeling of subchondral and cancellous bone for the early intervention of joint degeneration with focus on the spinal disc

    NASA Astrophysics Data System (ADS)

    McCanless, Jonathan D.

    Osteoarthritis-associated pain of the spinal disc, knee, and hip derives from degeneration of cartilagenous tissues in these joints. Traditional therapies have focused on these cartilage (and disc specific nucleus pulposus) changes as a means of treatment through tissue grafting, regenerative synthetic implants, non-regenerative space filling implants, arthroplasty, and arthrodesis. Although such approaches may seem apparent upon initial consideration of joint degeneration, tissue pathology has shown changes in the underlying bone and vascular bed precede the onset of cartilaginous changes. It is hypothesized that these changes precedent joint degeneration and as such may provide a route for early prevention. The current work proposes an injectable biomaterial-based therapy within these subchondral and cancellous bone regions as a means of preventing or reversing osteoarthritis. Two human concentrated platelet releasate-containing alginate hydrogel/beta-tricalcium phosphate composites have been developed for this potential biomaterial application. The undertaking of assessing these materials through bench-, in vitro, and ex vivo work is described herein. These studies showed the capability of the biomaterials to initiate a wound healing response in monocytes, angiogenic and differentiation behavior in immature endothelial cells, and early osteochondral differentiation in mesenchymal stem cells. These cellular activities are associated with fracture healing and endochondral bone formation, demonstrating the potential of the biomaterials to induce osseous and vascular tissue remodeling underlying osteoarthritic joints as a novel therapy for a disease with rapidly growing healthcare costs.

  2. Development of Animal Models of Local Retinal Degeneration

    PubMed Central

    Lorach, Henri; Kung, Jennifer; Beier, Corinne; Mandel, Yossi; Dalal, Roopa; Huie, Philip; Wang, Jenny; Lee, Seungjun; Sher, Alexander; Jones, Bryan William; Palanker, Daniel

    2015-01-01

    Purpose Development of nongenetic animal models of local retinal degeneration is essential for studies of retinal pathologies, such as chronic retinal detachment or age-related macular degeneration. We present two different methods to induce a highly localized retinal degeneration with precise onset time, that can be applied to a broad range of species in laboratory use. Methods A 30-μm thin polymer sheet was implanted subretinally in wild-type (WT) rats. The effects of chronic retinal separation from the RPE were studied using histology and immunohistochemistry. Another approach is applicable to species with avascular retina, such as rabbits, where the photoreceptors and RPE were thermally ablated over large areas, using a high power scanning laser. Results Photoreceptors above the subretinal implant in rats degenerated over time, with 80% of the outer nuclear layer disappearing within a month, and the rest by 3 months. Similar loss was obtained by selective photocoagulation with a scanning laser. Cells in the inner nuclear layer and ganglion cell layer were preserved in both cases. However, there were signs of rewiring and decrease in the size of the bipolar cell terminals in the damaged areas. Conclusions Both methods induce highly reproducible degeneration of photoreceptors over a defined area, with complete preservation of the inner retinal neurons during the 3-month follow-up. They provide a reliable platform for studies of local retinal degeneration and development of therapeutic strategies in a wide variety of species. PMID:26207299

  3. The use of genetic algorithms to model protoplanetary discs

    NASA Astrophysics Data System (ADS)

    Hetem, Annibal; Gregorio-Hetem, Jane

    2007-12-01

    The protoplanetary discs of T Tauri and Herbig Ae/Be stars have previously been studied using geometric disc models to fit their spectral energy distribution (SED). The simulations provide a means to reproduce the signatures of various circumstellar structures, which are related to different levels of infrared excess. With the aim of improving our previous model, which assumed a simple flat-disc configuration, we adopt here a reprocessing flared-disc model that assumes hydrostatic, radiative equilibrium. We have developed a method to optimize the parameter estimation based on genetic algorithms (GAs). This paper describes the implementation of the new code, which has been applied to Herbig stars from the Pico dos Dias Survey catalogue, in order to illustrate the quality of the fitting for a variety of SED shapes. The star AB Aur was used as a test of the GA parameter estimation, and demonstrates that the new code reproduces successfully a canonical example of the flared-disc model. The GA method gives a good quality of fit, but the range of input parameters must be chosen with caution, as unrealistic disc parameters can be derived. It is confirmed that the flared-disc model fits the flattened SEDs typical of Herbig stars; however, embedded objects (increasing SED slope) and debris discs (steeply decreasing SED slope) are not well fitted with this configuration. Even considering the limitation of the derived parameters, the automatic process of SED fitting provides an interesting tool for the statistical analysis of the circumstellar luminosity of large samples of young stars.

  4. Potential Role of lncRNAs in Contributing to Pathogenesis of Intervertebral Disc Degeneration Based on Microarray Data

    PubMed Central

    Chen, Yu; Ni, Haijian; Zhao, Yingchuan; Chen, Kai; Li, Ming; Li, Cheng; Zhu, Xiaodong; Fu, Qiang

    2015-01-01

    Background Our study intended to identify potential long non-coding RNAs (lncRNAs) and genes, and to elucidate the underlying mechanisms of intervertebral disc degeneration (IDD). Material/Methods The microarray of GSE56081 was downloaded from the Gene Expression Omnibus database, including 5 human control nucleus pulposus tissues and 5 degenerative nucleus pulposus tissues, which was on the basis of GPL15314 platform. Identification of differentially expressed lncRNAs and mRNAs were performed between the 2 groups. Then, gene ontology (GO) and pathway enrichment analyses were performed to analyze the biological functions and pathways for the differentially expressed mRNAs. Simultaneously, lncRNA-mRNA weighted coexpression network was constructed using the WGCNA package, followed by GO and KEGG pathway enrichment analyses for the genes in the modules. Finally, the protein-protein interaction (PPI) network was visualized. Results A total of 135 significantly up- and 170 down-regulated lncRNAs and 2133 significantly up- and 1098 down-regulated mRNAs were identified. Additionally, UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1), with the highest connectivity degree in PPI network, was remarkably enriched in the pathway of metabolism of proteins. Eight lncRNAs – LINC00917, CTD-2246P4.1, CTC-523E23.5, RP4-639J15.1, RP11-363G2.4, AC005082.12, MIR132, and RP11-38F22.1 – were observed in the modules of lncRNA-mRNA weighted coexpression network. Moreover, SPHK1 in the green-yellow module was significantly enriched in positive regulation of cell migration. Conclusions LncRNAs LINC00917, CTD-2246P4.1, CTC-523E23.5, RP4-639J15.1, RP11-363G2.4, AC005082.12, MIR132, and RP11-38F22.1 were differentially expressed and might play important roles in the development of IDD. Key genes, such as UBA52 and SPHK1, may be pivotal biomarkers for IDD. PMID:26556537

  5. Stellar and gaseous disc structures in cosmological galaxy equilibrium models

    NASA Astrophysics Data System (ADS)

    Rathaus, Ben; Sternberg, Amiel

    2016-05-01

    We present `radially resolved equilibrium models' for the growth of stellar and gaseous discs in cosmologically accreting massive haloes. Our focus is on objects that evolve to redshifts z ˜ 2. We solve the time-dependent equations that govern the radially dependent star formation rates, inflows and outflows from and to the inter- and circumgalactic medium, and inward radial gas flows within the discs. The stellar and gaseous discs reach equilibrium configurations on dynamical time-scales much shorter than variations in the cosmological dark matter halo growth and baryonic accretions rates. We show analytically that mass and global angular momentum conservation naturally give rise to exponential gas and stellar discs over many radial length-scales. As expected, the gaseous discs are more extended as set by the condition Toomre Q < 1 for star formation. The discs rapidly become baryon dominated. For massive, 5 × 1012 M⊙ haloes at redshift z = 2, we reproduced the typical observed star formation rates of ˜100 M⊙ yr-1, stellar masses ˜9 × 1010 M⊙, gas contents ˜1011 M⊙, half-mass sizes of 4.5 and 5.8 kpc for the stars and gas, and characteristic surface densities of 500 and 400 M⊙ pc-2 for the stars and gas.

  6. Polarimetric Models of Circumstellar Discs Including Aggregate Dust Grains

    NASA Astrophysics Data System (ADS)

    Mohan, Mahesh

    The work conducted in this thesis examines the nature of circumstellar discs by investigating irradiance and polarization of scattered light. Two circumstellar discs are investigated. Firstly, H-band high contrast imaging data on the transitional disc of the Herbig Ae/Be star HD169142 are presented. The images were obtained through the polarimetric differential imaging (PDI) technique on the Very Large Telescope (VLT) using the adaptive optics system NACO. Our observations use longer exposure times, allowing us to examine the edges of the disc. Analysis of the observations shows distinct signs of polarization due to circumstellar material, but due to excessive saturation and adaptive optics errors further information on the disc could not be inferred. The HD169142 disc is then modelled using the 3D radiative transfer code Hyperion. Initial models were constructed using a two disc structure, however recent PDI has shown the existence of an annular gap. In addition to this the annular gap is found not to be devoid of dust. This then led to the construction of a four-component disc structure. Estimates of the mass of dust in the gap (2.10E-6 Msun) are made as well as for the planet (1.53E-5 Msun (0.016 Mjupiter)) suspected to be responsible for causing the gap. The predicted polarization was also estimated for the disc, peaking at ~14 percent. The use of realistic dust grains (ballistic aggregate particles) in Monte Carlo code is also examined. The fortran code DDSCAT is used to calculate the scattering properties for aggregates which are used to replace the spherical grain models used by the radiative transfer code Hyperion. Currently, Hyperion uses four independent elements to define the scattering matrix, therefore the use of rotational averaging and a 50/50 percent population of grains and their enantiomers were explored to reduce the number of contributing scattering elements from DDSCAT. A python script was created to extract the scattering data from the DDSCAT

  7. Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies

    PubMed Central

    2013-01-01

    Introduction Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration. Methods Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age. Results Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice

  8. Quantitative T2 Magnetic Resonance Imaging Compared to Morphological Grading of the Early Cervical Intervertebral Disc Degeneration: An Evaluation Approach in Asymptomatic Young Adults

    PubMed Central

    Han, Zhihua; Shao, Lixin; Xie, Yan; Wu, Jianhong; Zhang, Yan; Xin, Hongkui; Ren, Aijun; Guo, Yong; Wang, Deli; He, Qing; Ruan, Dike

    2014-01-01

    Objective The objective of this study was to evaluate the efficacy of quantitative T2 magnetic resonance imaging (MRI) for quantifying early cervical intervertebral disc (IVD) degeneration in asymptomatic young adults by correlating the T2 value with Pfirrmann grade, sex, and anatomic level. Methods Seventy asymptomatic young subjects (34 men and 36 women; mean age, 22.80±2.11 yr; range, 18–25 years) underwent 3.0-T MRI to obtain morphological data (one T1-fast spin echo (FSE) and three-plane T2-FSE, used to assign a Pfirrmann grade (I–V)) and for T2 mapping (multi-echo spin echo). T2 values in the nucleus pulposus (NP, n = 350) and anulus fibrosus (AF, n = 700) were obtained. Differences in T2 values between sexes and anatomic level were evaluated, and linear correlation analysis of T2 values versus degenerative grade was conducted. Findings Cervical IVDs of healthy young adults were commonly determined to be at Pfirrmann grades I and II. T2 values of NPs were significantly higher than those of AF at all anatomic levels (P<0.000). The NP, anterior AF and posterior AF values did not differ significantly between genders at the same anatomic level (P>0.05). T2 values decreased linearly with degenerative grade. Linear correlation analysis revealed a strong negative association between the Pfirrmann grade and the T2 values of the NP (P = 0.000) but not the T2 values of the AF (P = 0.854). However, non-degenerated discs (Pfirrmann grades I and II) showed a wide range of T2 relaxation time. T2 values according to disc degeneration level classification were as follows: grade I (>62.03 ms), grade II (54.60–62.03 ms), grade III (<54.60 ms). Conclusions T2 quantitation provides a more sensitive and robust approach for detecting and characterizing the early stage of cervical IVD degeneration and to create a reliable quantitative in healthy young adults. PMID:24498384

  9. Comparison of vertebral and intervertebral disc lesions in aging humans and rhesus monkeys

    PubMed Central

    Bailey, Jeannie F.; Fields, Aaron J.; Liebenberg, Ellen; Mattison, Julie A.; Lotz, Jeffrey C.; Kramer, Patricia A.

    2014-01-01

    Objective To compare gross and histologic patterns of age-related degeneration within the intervertebral disc and adjacent vertebra between rhesus monkeys and humans. Materials and methods We examined age-related patterns of disc degeneration from mid-sagittal sections of the intervertebral disc and adjacent vertebral bodies among six rhesus monkey thoracolumbar and seven human lumbar spines. Gross morphology and histopathology were assessed via the Thompson grading scheme and other degenerative features of the disc and adjacent bone. Results Thompson grades ranged from 3 through 5 for rhesus monkey discs (T9-L1) and 2 through 5 for the human discs (T12-S1). In both rhesus monkey and human discs, presence of distinct lesions were positively associated with Thompson grade of the overall segment. Degenerative patterns differed for radial tears, which were more prevalent with advanced disc degeneration in humans only. Additionally, compared to the more uniform anteroposterior disc degeneration patterns of humans, rhesus monkeys showed more severe osteophytosis and degeneration on the anterior border of the vertebral column. Conclusions Rhesus monkey spines evaluated in the present study appear to develop age-related patterns of disc degeneration similar to humans. One exception is the absence of an association between radial tears and disc degeneration, which could reflect species-specific differences in posture and spinal curvature. Considering rhesus monkeys demonstrate similar patterns of disc degeneration, and age at a faster rate than humans, these findings suggest longitudinal studies of rhesus monkeys may be a valuable model for better understanding the progression of human age-related spinal osteoarthritis and disc degeneration. PMID:24821664

  10. On degenerate models of cosmic inflation

    SciTech Connect

    Gwyn, Rhiannon; Palma, Gonzalo A.; Sakellariadou, Mairi; Sypsas, Spyros E-mail: gpalmaquilod@ing.uchile.cl E-mail: s.sypsas@apctp.org

    2014-10-01

    In this article we discuss the role of current and future CMB measurements in pinning down the model of inflation responsible for the generation of primordial curvature perturbations. By considering a parameterization of the effective field theory of inflation with a modified dispersion relation arising from heavy fields, we derive the dependence of cosmological observables on the scale of heavy physics Λ{sub UV}. Specifically, we show how the f{sub NL} non-linearity parameters are related to the phase velocity of curvature perturbations at horizon exit, which is parameterized by Λ{sub UV}. BICEP2 and PLANCK findings are shown to be consistent with a value Λ{sub UV} ∼ Λ{sub GUT}. However, we find a degeneracy in the parameter space of inflationary models that can only be resolved with a detailed knowledge of the shape of the non-Gaussian bispectrum.

  11. From birth to death of protoplanetary discs: modelling their formation, evolution and dispersal

    NASA Astrophysics Data System (ADS)

    Kimura, Shigeo S.; Kunitomo, Masanobu; Takahashi, Sanemichi Z.

    2016-09-01

    The formation, evolution and dispersal processes of protoplanetary discs are investigated and the disc lifetime is estimated. The gravitational collapse of a pre-stellar core forms both a central star and a protoplanetary disc. The central star grows by accretion from the disc and irradiation by the central star heats up the disc and generates a thermal wind, which results in the disc's dispersal. Using the one-dimensional diffusion equation, we calculate the evolution of protoplanetary discs numerically. To calculate the disc evolution from formation to dispersal, we add source and sink terms that represent gas accretion from pre-stellar cores and photoevaporation, respectively. We find that the disc lifetimes of typical pre-stellar cores are around 2-4 million years (Myr). A pre-stellar core with high angular momentum forms a larger disc with a long lifetime, while a disc around an X-ray-luminous star has a short lifetime. Integrating disc lifetimes under various masses and angular velocities of pre-stellar cores and X-ray luminosities of young stellar objects, we obtain the disc fraction at a given stellar age and mean lifetime of the disc. Our model indicates that the mean lifetime of a protoplanetary disc is 3.7 Myr, which is consistent with the observational estimate from young stellar clusters. We also find that the dispersion of X-ray luminosity is needed to reproduce the observed disc fraction.

  12. Regulation of insulin-like growth factor 1 receptor signaling by microRNA-4458 in the development of lumbar disc degeneration

    PubMed Central

    Liu, Zuo-Qing; Fu, Wen-Qin; Zhao, Shan; Zhao, Xin

    2016-01-01

    A potential role of Insulin-like growth factor 1 (IGF1) receptor/phosphatidylinositol-3 kinase (PI3k)/Akt signaling in the initiation and progression of Lumbar disc degeneration (LDD) has been recently reported. However, the regulation of IGF1 receptor (IGF1R) at post-transcriptional levels in the development of LDD remains unknown. Here, we studied the effects of microRNA-4458 on the expression of IGF1R. We examined the IGF1R levels and microRNA-4458 (miR-4458) levels in the resected LDD discs, compared with the traumatized, non-LDD discs. We analyzed the binding of miR-4458 to the 3’-UTR of IGF1R mRNA and its effects on IGF1R translation by bioinformatics analysis and by luciferase-reporter assay, respectively. We modified miR-4458 levels in a human nucleus pulposus SV40 cell line (HNPSV), and examined the effects of miR-4458 on the expression of IGF1R and Akt, as well as their phosphorylation. We found that the levels of miR-4458 were significantly higher and the levels of IGF1R were significantly lower in LDD discs, compared with the control non-LDD discs. The levels of IGF1R inversely correlated with the levels of miR-4458 in LDD discs. Moreover, miR-4458 was found to bind to the 3’-UTR of IGF1R mRNA to prevent its translation. In miR-4458-modified HNPSV cells, we found that miR-4458 decreased both total IGF1R and phosphorylated IGF1R, resulting in deceases in phosphorylated Akt. Thus, these data suggest that miR-4458 may suppress PI3k/Akt signaling pathway through 3’-UTR-inhibtion of IGF1R mRNA to promote development of LDD. PMID:27347338

  13. Disc Volume Reduction with Percutaneous Nucleoplasty in an Animal Model

    PubMed Central

    Kasch, Richard; Mensel, Birger; Schmidt, Florian; Ruetten, Sebastian; Barz, Thomas; Froehlich, Susanne; Seipel, Rebecca; Merk, Harry R.; Kayser, Ralph

    2012-01-01

    Study Design We assessed volume following nucleoplasty disc decompression in lower lumbar spines from cadaveric pigs using 7.1Tesla magnetic resonance imaging (MRI). Purpose To investigate coblation-induced volume reductions as a possible mechanism underlying nucleoplasty. Methods We assessed volume following nucleoplastic disc decompression in pig spines using 7.1-Tesla MRI. Volumetry was performed in lumbar discs of 21 postmortem pigs. A preoperative image data set was obtained, volume was determined, and either disc decompression or placebo therapy was performed in a randomized manner. Group 1 (nucleoplasty group) was treated according to the usual nucleoplasty protocol with coblation current applied to 6 channels for 10 seconds each in an application field of 360°; in group 2 (placebo group) the same procedure was performed but without coblation current. After the procedure, a second data set was generated and volumes calculated and matched with the preoperative measurements in a blinded manner. To analyze the effectiveness of nucleoplasty, volumes between treatment and placebo groups were compared. Results The average preoperative nucleus volume was 0.994 ml (SD: 0.298 ml). In the nucleoplasty group (n = 21) volume was reduced by an average of 0.087 ml (SD: 0.110 ml) or 7.14%. In the placebo group (n = 21) volume was increased by an average of 0.075 ml (SD: 0.075 ml) or 8.94%. The average nucleoplasty-induced volume reduction was 0.162 ml (SD: 0.124 ml) or 16.08%. Volume reduction in lumbar discs was significant in favor of the nucleoplasty group (p<0.0001). Conclusions Our study demonstrates that nucleoplasty has a volume-reducing effect on the lumbar nucleus pulposus in an animal model. Furthermore, we show the volume reduction to be a coblation effect of nucleoplasty in porcine discs. PMID:23209677

  14. Substructuring and poroelastic modelling of the intervertebral disc.

    PubMed

    Swider, P; Pédrono, A; Ambard, D; Accadbled, F; Sales de Gauzy, J

    2010-05-01

    We proposed a substructure technique to predict the time-dependant response of biological tissue within the framework of a finite element resolution. Theoretical considerations in poroelasticity preceded the calculation of the sub-structured poroelastic matrix. The transient response was obtained using an exponential fitting method. We computed the creep response of an MRI 3D reconstructed L(5)-S(1) intervertebral disc of a scoliotic spine. The FE model was reduced from 10,000 degrees of freedom for the full 3D disc to only 40 degrees of freedom for the sub-structured model defined by 10 nodes attached to junction nodes located on both lower and upper surfaces of the disc. Comparisons of displacement fields were made between the full poroelastic FE model and the sub-structured model in three different loading conditions: compression, offset compression and torsion. Discrepancies in displacement were lower than 10% for the first time steps when time-dependant events were significant. The substructuring technique provided an exact solution in quasi-static behavior after pressure relaxation. Couplings between vertical and transversal displacements predicted by the reference FE model were well stored by the sub-structured model despite the drastic reduction of degrees of freedom. Finally, we demonstrated that substructuring was very efficient to reduce the size of numerical models while respecting the time-dependant behavior of the structure. This result highlighted the potential interest of substructure techniques in large-scale models of musculoskeletal structures. PMID:20170917

  15. Degeneration of the Y chromosome in evolutionary aging models

    NASA Astrophysics Data System (ADS)

    Lobo, M. P.; Onody, R. N.

    2005-06-01

    The Y chromosomes are genetically degenerated and do not recombine with their matching partners X. Recombination of XX pairs is pointed out as the key factor for the Y chromosome degeneration. However, there is an additional evolutionary force driving sex-chromosomes evolution. Here we show this mechanism by means of two different evolutionary models, in which sex chromosomes with non-recombining XX and XY pairs of chromosomes is considered. Our results show three curious effects. First, we observed that even when both XX and XY pairs of chromosomes do not recombine, the Y chromosomes still degenerate. Second, the accumulation of mutations on Y chromosomes followed a completely different pattern then those accumulated on X chromosomes. And third, the models may differ with respect to sexual proportion. These findings suggest that a more primeval mechanism rules the evolution of Y chromosomes due exclusively to the sex-chromosomes asymmetry itself, i.e., the fact that Y chromosomes never experience female bodies. Over aeons, natural selection favored X chromosomes spontaneously, even if at the very beginning of evolution, both XX and XY pairs of chromosomes did not recombine.

  16. Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration.

    PubMed

    Karan, G; Lillo, C; Yang, Z; Cameron, D J; Locke, K G; Zhao, Y; Thirumalaichary, S; Li, C; Birch, D G; Vollmer-Snarr, H R; Williams, D S; Zhang, K

    2005-03-15

    Macular degeneration is a heterogeneous group of disorders characterized by photoreceptor degeneration and atrophy of the retinal pigment epithelium (RPE) in the central retina. An autosomal dominant form of Stargardt macular degeneration (STGD) is caused by mutations in ELOVL4, which is predicted to encode an enzyme involved in the elongation of long-chain fatty acids. We generated transgenic mice expressing a mutant form of human ELOVL4 that causes STGD. In these mice, we show that accumulation by the RPE of undigested phagosomes and lipofuscin, including the fluorophore, 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetraenyl]-1-(2-hyydroxyethyl)-4-[4-methyl-6-(2,6,6,-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E-hexatrienyl]-pyridinium (A2E) is followed by RPE atrophy. Subsequently, photoreceptor degeneration occurs in the central retina in a pattern closely resembling that of human STGD and age-related macular degeneration. The ELOVL4 transgenic mice thus provide a good model for both STGD and dry age-related macular degeneration, and represent a valuable tool for studies on therapeutic intervention in these forms of blindness. PMID:15749821

  17. Simple and accurate modelling of the gravitational potential produced by thick and thin exponential discs

    NASA Astrophysics Data System (ADS)

    Smith, R.; Flynn, C.; Candlish, G. N.; Fellhauer, M.; Gibson, B. K.

    2015-04-01

    We present accurate models of the gravitational potential produced by a radially exponential disc mass distribution. The models are produced by combining three separate Miyamoto-Nagai discs. Such models have been used previously to model the disc of the Milky Way, but here we extend this framework to allow its application to discs of any mass, scalelength, and a wide range of thickness from infinitely thin to near spherical (ellipticities from 0 to 0.9). The models have the advantage of simplicity of implementation, and we expect faster run speeds over a double exponential disc treatment. The potentials are fully analytical, and differentiable at all points. The mass distribution of our models deviates from the radial mass distribution of a pure exponential disc by <0.4 per cent out to 4 disc scalelengths, and <1.9 per cent out to 10 disc scalelengths. We tabulate fitting parameters which facilitate construction of exponential discs for any scalelength, and a wide range of disc thickness (a user-friendly, web-based interface is also available). Our recipe is well suited for numerical modelling of the tidal effects of a giant disc galaxy on star clusters or dwarf galaxies. We consider three worked examples; the Milky Way thin and thick disc, and a discy dwarf galaxy.

  18. Effects of TGF-β1 and IL-1β on expression of ADAMTS enzymes and TIMP-3 in human intervertebral disc degeneration

    PubMed Central

    WANG, SHI-LONG; YU, YONG-LIN; TANG, CHAO-LIANG; LV, FEI-ZHOU

    2013-01-01

    The aim of this study was to investigate the effects of transforming growth factor-β1 (TGF-β1) and interleukin-1β (IL-1β) on the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes and their inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP-3), in human intervertebral disc (IVD) degeneration. Cells from patients with IVD degeneration were cultured with Dulbecco’s modified Eagle’s medium with Ham’s F12 nutrient mixture (DMEM/F12) medium at 37°C in a 5% CO2 incubator. Cell proliferation was measured by cell counting kit-8 assays with varying concentrations of TGF-β1 and IL-1β in a time-response experiment. The mRNA and protein expression levels of ADAMTS-4, ADAMTS-5 and TIMP-3 were detected with qPCR and western blot analysis, respectively. The present study demonstrated that TGF-β1 promoted nucleus pulposus (NP) cell proliferation, decreased the expression of ADAMTS-4 and -5 and increased the expression of TIMP-3. By contrast, the IL-1β treatment inhibited NP cell proliferation and significantly increased the expression of ADAMTS-4 and -5. However, IL-1β appeared to have no marked effect on the expression of TIMP-3. This study suggests that TGF-β1 and IL-1β are involved in the synthesis and degradation of the extracellular matrix and may act as potential therapeutic targets for the prevention or reversal of IVD degeneration. PMID:24250727

  19. Factors regulating viable cell density in the intervertebral disc: blood supply in relation to disc height

    PubMed Central

    Boubriak, Olga A; Watson, Natasha; Sivan, Sarit S; Stubbens, Naomi; Urban, Jill P G

    2013-01-01

    The intervertebral disc is an avascular tissue, maintained by a small population of cells that obtain nutrients mainly by diffusion from capillaries at the disc–vertebral body interface. Loss of this nutrient supply is thought to lead to disc degeneration, but how nutrient supply influences viable cell density is unclear. We investigated two factors that influence nutrient delivery to disc cells and hence cell viability: disc height and blood supply. We used bovine caudal discs as our model as these show a gradation in disc height. We found that although disc height varied twofold from the largest to the smallest disc studied, it had no significant effect on cell density, unlike the situation found in articular cartilage. The density of blood vessels supplying the discs was markedly greater for the largest disc than the smallest disc, as was the density of pores allowing capillary penetration through the bony endplate. Results indicate that changes in blood vessels in the vertebral bodies supplying the disc, as well as changes in endplate architecture appear to influence density of cells in intervertebral discs. PMID:23311982

  20. Velocity-density twin transforms in the thin disc model

    NASA Astrophysics Data System (ADS)

    Bratek, Łukasz; Sikora, Szymon; Jałocha, Joanna; Kutschera, Marek

    2015-08-01

    Ring mass density and the corresponding circular velocity in thin disc model are known to be integral transforms of one another. But it may be less familiar that the transforms can be reduced to one-fold integrals with identical weight functions. It may be of practical value that the integral for the surface density does not involve the velocity derivative, unlike the equivalent and widely known Toomre's formula.

  1. From Disc Wind Models to Observations of TTauri Microjets

    NASA Astrophysics Data System (ADS)

    Ferreira, Jonathan; Casse, Fabien; Garcia, Paulo; Darren, O'brien; Sylvie, Cabrit; Catherine, Dougados; Pesenti, Nicolas; Luc, Binette

    Two decades after their discovery jets from accreting young stars still represent a major challenge for theorists. Several theoretical scenarii have been proposed but only models involving large scale magnetic fields have proved capable of producing self-collimated jets. However the launching region remains unknown: is it the star the surrounding accretion disc or their interaction zone? Progresses in high angular resolution offer now the opportunity to test the various proposed models. I will first review the results on magnetized disc winds based on the only MHD model describing self-consistently these accretion-ejection structures. Then I will show how the thermal and ionization states of the outflowing matter can be consistently computed once the dominant heating source has been chosen (ambipolar diffusion alfven wave damping or some local mechanical heating). A set of observational predictions (emission maps line fluxes/ratios and line profiles) for selected optical forbidden lines can then be calculated. As an illustration I will compare these predictions with new sub-arcsecond spectroimaging observations of the DG Tau and RW Aur jets and discuss the constraints they set on disc winds in TTauri stars.

  2. Collisional modelling of the AU Microscopii debris disc

    NASA Astrophysics Data System (ADS)

    Schüppler, Ch.; Löhne, T.; Krivov, A. V.; Ertel, S.; Marshall, J. P.; Wolf, S.; Wyatt, M. C.; Augereau, J.-C.; Metchev, S. A.

    2015-09-01

    AU Microscopii's debris disc is one of the most famous and best-studied debris discs and one of only two resolved debris discs around M stars. We perform in-depth collisional modelling of the AU Mic disc including stellar radiative and corpuscular forces (stellar winds), aiming at a comprehensive understanding of the dust production and the dust and planetesimal dynamics in the system. Our models are compared to a suite of observational data for thermal and scattered light emission, ranging from the ALMA radial surface brightness profile at 1.3 mm to spatially resolved polarisation measurements in the visible. Most of the data are shown to be reproduced with dust production in a belt of planetesimals with an outer edge at around 40 au and subsequent inward transport of dust by stellar winds. A low dynamical excitation of the planetesimals with eccentricities up to 0.03 is preferred. The radial width of the planetesimal belt cannot be constrained tightly. Belts that are 5 au and 17 au wide, as well as a broad 44 au-wide belt, are consistent with observations. All models show surface density profiles that increase with distance from the star up to ≈40 au, as inferred from observations. The best model is achieved by assuming a stellar mass loss rate that exceeds the solar one by a factor of 50. The models reproduce the spectral energy distribution and the shape of the ALMA radial profile well, but deviate from the scattered light observations more strongly. The observations show a bluer disc colour and a lower degree of polarisation for projected distances <40 au than predicted by the models. These deviations may be reduced by taking irregularly shaped dust grains which have scattering properties different from the Mie spheres used in this work. From tests with a handful of selected dust materials, we favour mixtures of silicate, carbon, and ice of moderate porosity. We also address the origin of the unresolved central excess emission detected by ALMA and show that

  3. A model for the disc Lyman alpha emission of Uranus

    SciTech Connect

    Jaffel, L.B.; Vidal-Madjar, A. ); Prange, R.; Emerich, C. ); McConnell, J.C. )

    1991-06-01

    A new efficient radiative transfer algorithm for inhomogeneous atmospheres has been used to simulate the limb to limb Lyman {alpha} reflectivities observed with the Voyager ultraviolet spectrometer during the flyby of Uranus. It was shown that complete frequency redistribution should be adequate to describe the disc emissions. The model atmosphere used was derived using a combination of Voyager measurements and modeling. Atomic H densities calculated had sources derivable directly from solar FUV and EUV fluxes. To fit the observations, four contributions are evaluated: (1) the resonance scattering of solar Lyman {alpha} radiation, (2) Rayleigh-Raman scattering of solar Lyman {alpha} radiation, (3) the resonance scattering of interplanetary Lyman {alpha} radiation, and (4) a possible internal source of unknown origin. From comparison with the observations, and provided that the published Voyager calibrations are correct, it is shown that only atmospheres with low eddy diffusion coefficients (K{sub H}{le}100 cm{sup 2} s{sup {minus}1}) and an internal source could simulate both the shape and the strength of the measured disc emission. The main results are then that the direct solar Lyman {alpha} scattering contribution (type 1 plus type 2) is of the order of 760 R, the scattering of interplanetary Lyman {alpha} contributes about 320 R, and a small additional internal source providing about 100-500 R is needed to match the measurements. Further, the analysis of the disc intensities suggests that there is no strong variation of K with latitude.

  4. Mouse Models of Stargardt 3 Dominant Macular Degeneration.

    PubMed

    Barabas, Peter; Gorusupudi, Aruna; Bernstein, Paul S; Krizaj, David

    2016-01-01

    Stargardt type 3 macular degeneration is dependent on a dominant defect in a single gene, ELOVL4 (elongase of very long chain fatty acids 4). The encoded enzyme, ELOVL4, is required for the synthesis of very long chain polyunsaturated fatty acids (VLC-PUFAs), a rare class of > C24 lipids. In vitro expression studies suggest that mutated ELOVL4(STGD3) proteins fold improperly, resulting in ER stress and formation of cytosolic aggresomes of wild type and mutant ELOVL4. Although a number of mouse models have been developed to determine whether photoreceptor cell loss in STGD3 results from depletion of VLC-PUFAs, aggresome-dependent cell stress or a combination of these two factors, none of these models adequately recapitulates the disease phenotype in humans. Thus, the precise molecular mechanism by which ELOVL4 mutation causes photoreceptor degeneration in mice and in human patients remains to be characterized. This mini review compares and evaluates current STGD3 mouse models and determines what conclusions can be drawn from past work. PMID:26427404

  5. Differential regulation of matrix degrading enzymes in a TNFalpha-induced model of nucleus pulposus tissue degeneration.

    PubMed

    Séguin, Cheryle A; Bojarski, Marla; Pilliar, Robert M; Roughley, Peter J; Kandel, Rita A

    2006-09-01

    Intervertebral disc degeneration occurs commonly and is linked to persistent back pain and the development of disc herniation. The mechanisms responsible for tissue catabolism have not yet been fully elucidated. Previously we characterized an in vitro model of TNFalpha-induced nucleus pulposus degeneration, which demonstrates decreased expression of matrix macromolecules, increased expression of matrix degrading enzymes, and the activation of aggrecanase-mediated proteoglycan degradation [Seguin, C.A., Pilliar, R.M., Roughley, P.J., and Kandel, R.A. 2005. Tumor necrosis factor-alpha modulates matrix production and catabolism in nucleus pulposus tissue. Spine 30: 1940-1948]. This study explores the intracellular pathways activated during TNFalpha-induced matrix degradation. We demonstrate that in nucleus pulposus cells, the p38 and JNK pathways regulate induction of MMP-1 and -3; p38, JNK, and NF-kappaB regulate the induction of MMP-13; and ERK regulates the up-regulation of MT1-MMP mRNA in response to TNFalpha. Induction of ADAMTS-4 and -5 mRNA occurred downstream of NF-kappaB activation. Depletion of tissue proteoglycans was mediated by ERK and NF-kappaB-dependent "aggrecanase" activity, suggesting MT1-MMP and ADAMTS-4 and -5 as effectors of TNFalpha-induced tissue catabolism. PMID:16934445

  6. Study of debris discs with a new generation model

    NASA Astrophysics Data System (ADS)

    Kral, Quentin

    2014-10-01

    The present work was dedicated to the development and use of a new generation numerical code, able to model in a self-consistent way debris discs' evolution. These dust discs, optically thin, sometimes very old, are present around at least 30% of stars. Numerous observations with Herschel, the VLT, the LBTI, ALMA and soon the EELT or the JWST give images that are always more accurate of these objects, for which, the visible structures that are observed are astonishingly different from each other; leaving often a mystery to be solved. Various models attempt to reveal the link between the observed structures, the system spectra, its photometry and the interactions with the close-environment. Indeed, the presence of planets, through its resonances or gravitational perturbations, can induce the production of structures in these discs (warp, brightness asymmetry, dust clump, ...). Likewise, the presence of gas, of a stellar companion or a massive collision could explain a part of observed asymmetries. Nonetheless, robust models have to be developed, that are able to take into account the complexity of the physics associated with these discs, especially the interactions between the collisions and dynamics, in order to give the closest outputs to observations.Firstly, our team developed a model named DyCoSS able to partially couple the collisions and dynamics. However, because of numerous limitations of this model, we decided to develop a totally new, stand alone code, called LIDT-DD : the first self-consistent model fully coupling the collisions and dynamics and taking into account the evolution of dust in debris discs. Moreover, the code has been coupled to GRaTer, a radiative transfer code, able to treat the dynamics of grains according to their size, composition, stellar type, ... Once the model, trying to be as generic as possible, was implemented, we carried out a huge number of tests to validate it.In a second part, we analysed massive collisions in debris discs

  7. Dysregulated miR-98 Contributes to Extracellular Matrix Degradation by Targeting IL-6/STAT3 Signaling Pathway in Human Intervertebral Disc Degeneration.

    PubMed

    Ji, Ming-Liang; Lu, Jun; Shi, Pei-Liang; Zhang, Xue-Jun; Wang, Shan-Zheng; Chang, Qing; Chen, Hui; Wang, Chen

    2016-04-01

    Intervertebral disc degeneration (IDD) is associated with dysregulated expression of microRNAs (miRNAs). However, the precise molecular mechanisms underlying this disorder remain unclear. Therefore, we tested the hypothesis that miRNAs modulate IDD through effects on the IL-6/STAT3 signaling pathway, a potential regulator of IDD. The miRNA expression profile was determined in nucleus pulposus (NP) tissues from patients with IDD and controls, employing miRNA microarray and quantitative real-time PCR (RT-qPCR). Biological functions of differential expression miRNAs were further investigated using immunofluorescent staining. Luciferase reporter assays and Western blotting were performed to determine miRNA targets. We identified 41 miRNAs that were differentially expressed in patients compared with controls. Following RT-qPCR confirmation, miR-98 was significantly downregulated in degenerative NP tissues. Moreover, its level was inversely correlated with grade of disc degeneration. Through gain-of-function and loss-of-function studies, miR-98 was shown to significantly promote type II collagen expression in NP cells. Interleukin-6 (IL-6) was identified as a target of miR-98. Knockdown of IL-6 induced effects on NP cells similar to those induced by miR-98. In contrast, IL-6 treatment abrogated the effects induced by miR-98 upregulation. Moreover, miR-98 dramatically suppressed expression of STAT3 target gene, MMP2. IL-6 treatment antagonized this effect, whereas knockdown of IL-6 by IL-6 short hairpin RNA (shIL-6) induced inhibitory effects on the expression of p-STAT3 and its main target genes, similar to miR-98. The mRNA level of IL-6 was inversely correlated with that of miR-98 in degenerative NP tissues. These results suggest the downregulation of miR-98 could promote IDD through the IL-6/STAT3 signaling pathway. Our findings also highlight miR-98 as a novel hopeful therapeutic target for IDD. © 2015 American Society for Bone and Mineral Research. PMID:26587789

  8. Comparison of T1ρ and T2* Relaxation Mapping in Patients with Different Grades of Disc Degeneration at 3T MR

    PubMed Central

    Zhang, Xinjuan; Yang, Li; Gao, Fei; Yuan, Zhenguo; Lin, Xiangtao; Yao, Bin; Chen, Weibo; Chan, Queenie; Wang, Guangbin

    2015-01-01

    Background T1ρ and T2* relaxation times are capable of providing information about early biochemical changes in intervertebral disk degeneration (IVDD). The purpose of this study was to assess and compare T1ρ and T2* mapping in IVDD with reference to Pfirrmann grade. Material/Methods Lumbar sagittal T2-weighted, T1ρ and T2* relaxation MRI were performed at 3.0T in 42 subjects covering discs L1–L2 to L5–S1. All the discs were morphologically assessed according to the Pfirrmann grade. Regions of interest (ROIs) were drawn over the T1ρ and T2*mappings, including nucleus pulposus (NP) and annulus fibrosus (AF). Wilcoxon signed rank test, Kruskal-Wallis test, and Spearman rank correlation were performed. Results The difference in T1ρ and T2* values between NP and AF were highly significant (P<0.001). The trends of decreasing T1ρ and T2* values of both NP and AF with increasing Pfirrmann grades was significant (P<0.01), particularly between Pfirrmann grade II and III (P<0.001), whereas T2* mapping was additionally able to detect changes in the AF between Pfirrmann grade I and II (P<0.05). Pfirrmann grades were inversely significantly correlated with both T1ρ and T2* values in the NP (r=–0.69, P<0.001; r=−0.56, P<0.001) and AF (r=−0.45, P<0.001; r=−0.26, P<0.001). Conclusions The process of IVDD can be detected by T1ρ and T2* mapping, particularly at early stage, and both methodologies displayed roughly comparable performance. PMID:26141783

  9. Radiative seesaw model with degenerate Majorana dark matter

    NASA Astrophysics Data System (ADS)

    Nomura, Takaaki; Okada, Hiroshi; Orikasa, Yuta

    2016-06-01

    We study a three-loop-induced neutrino mass model with exotic vectorlike isospin doublet leptons which contain a dark matter candidate. Then we explore lepton flavor violations and dark matter physics in a coannihilation system. In this paper, the nearly degenerate Majorana fermion dark matter can naturally be achieved at the two-loop level, while the mass splitting can be larger than O (200 ) keV which is required from the constraint of the direct detection search with spin-independent inelastic scattering through the Z -boson portal. As a result, a monochromatic photon excess, with threshold energy greater than O (200 ) keV , is predicted in our model and could be measured through indirect detection experiments such as INTEGRAL.

  10. Adverse effects of stromal vascular fraction during regenerative treatment of the intervertebral disc: observations in a goat model.

    PubMed

    Detiger, Suzanne E L; Helder, Marco N; Smit, Theodoor H; Hoogendoorn, Roel J W

    2015-09-01

    Stromal vascular fraction (SVF), an adipose tissue-derived heterogeneous cell mixture containing, among others, multipotent adipose stromal cells (ASCs) and erythrocytes, has proved beneficial for a wide range of applications in regenerative medicine. We sought to establish intervertebral disc (IVD) regeneration by injecting SVF intradiscally during a one-step surgical procedure in an enzymatically (Chondroitinase ABC; cABC) induced goat model of disc degeneration. Unexpectedly, we observed a severe inflammatory response that has not been described before, including massive lymphocyte infiltration, neovascularisation and endplate destruction. A second study investigated two main suspects for these adverse effects: cABC and erythrocytes within SVF. The same destructive response was observed in healthy goat discs injected with SVF, thereby eliminating cABC as a cause. Density gradient removal of erythrocytes and ASCs purified by culturing did not lead to adverse effects. Following these observations, we incorporated an extra washing step in the SVF harvesting protocol. In a third study, we applied this protocol in a one-step procedure to a goat herniation model, in which no adverse responses were observed either. However, upon intradiscal injection of an identically processed SVF mixture into our goat IVD degeneration model during a fourth study, the adverse effects surprisingly occurred again. Despite our quest for the responsible agent, we eventually could not identify the mechanism through which the observed destructive responses occurred. Although we cannot exclude that the adverse effects are species-dependent or model-specific, we advertise caution with the clinical application of autologous SVF injections into the IVD until the responsible agent(s) are identified. PMID:25682272

  11. Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration

    PubMed Central

    Yang, Chen; Cao, Peng; Gao, Yang; Wu, Ming; Lin, Yun; Tian, Ye; Yuan, Wen

    2016-01-01

    P38MAPK mediates cytokine induced inflammation in nucleus pulposus (NP) cells and involves in multiple cellular processes which are related to intervertebral disc degeneration (IDD). The aim of this study was to investigate the expression, activation and function of p38 MAPK isoforms (α,β, γ and δ) in degenerative NP and the effect of p38 activation in NP cells on macrophage polarization. P38 α, β and δ isoforms are preferential expressed, whereas the p38γ isoform is absent in human NP tissue. LV-sh-p38α, sh-p38β transfection in NP cells significantly decreased the ADAMTS-4,-5, MMP-13,CCL3 expression and restored collagen-II and aggrecan expression upon IL-1β stimulation. As compared with p38α and p38β, p38δ exhibited an opposite effect on ADAMTS-4,-5, MMP-13 and aggrecan expression in NP cells. Furthermore, the production of GM-CSF and IFNγ which were trigged by p38α or p38β in NP cells induced macrophage polarization into M1 phenotype. Our finding indicates that p38 MAPK α, β and δ isoform are predominantly expressed and activated in IDD. P38 positive NP cells modulate macrophage polarization through the production of GM-CSF and IFNγ. Hence, Our study suggests that selectively targeting p38 isoforms could ameliorate the inflammation in IDD and regard IDD progression. PMID:26911458

  12. Clinical and radiological outcome of anterior-posterior fusion versus transforaminal lumbar interbody fusion for symptomatic disc degeneration: a retrospective comparative study of 133 patients.

    PubMed

    Faundez, Antonio A; Schwender, James D; Safriel, Yair; Gilbert, Thomas J; Mehbod, Amir A; Denis, Francis; Transfeldt, Ensor E; Wroblewski, Jill M

    2009-02-01

    Abundant data are available for direct anterior/posterior spine fusion (APF) and some for transforaminal lumbar interbody fusion (TLIF), but only few studies from one institution compares the two techniques. One-hundred and thirty-three patients were retrospectively analyzed, 68 having APF and 65 having TLIF. All patients had symptomatic disc degeneration of the lumbar spine. Only those with one or two-level surgeries were included. Clinical chart and radiologic reviews were done, fusion solidity assessed, and functional outcomes determined by pre- and postoperative SF-36 and postoperative Oswestry Disability Index (ODI), and a satisfaction questionnaire. The minimum follow-up was 24 months. The mean operating room time and hospital length of stay were less in the TLIF group. The blood loss was slightly less in the TLIF group (409 vs. 480 cc.). Intra-operative complications were higher in the APF group, mostly due to vein lacerations in the anterior retroperitoneal approach. Postoperative complications were higher in the TLIF group due to graft material extruding against the nerve root or wound drainage. The pseudarthrosis rate was statistically equal (APF 17.6% and TLIF 23.1%) and was higher than most published reports. Significant improvements were noted in both groups for the SF-36 questionnaires. The mean ODI scores at follow-up were 33.5 for the APF and 39.5 for the TLIF group. The patient satisfaction rate was equal for the two groups. PMID:19125304

  13. Clinical and radiological outcome of anterior–posterior fusion versus transforaminal lumbar interbody fusion for symptomatic disc degeneration: a retrospective comparative study of 133 patients

    PubMed Central

    Schwender, James D.; Safriel, Yair; Gilbert, Thomas J.; Mehbod, Amir A.; Denis, Francis; Transfeldt, Ensor E.; Wroblewski, Jill M.

    2009-01-01

    Abundant data are available for direct anterior/posterior spine fusion (APF) and some for transforaminal lumbar interbody fusion (TLIF), but only few studies from one institution compares the two techniques. One-hundred and thirty-three patients were retrospectively analyzed, 68 having APF and 65 having TLIF. All patients had symptomatic disc degeneration of the lumbar spine. Only those with one or two-level surgeries were included. Clinical chart and radiologic reviews were done, fusion solidity assessed, and functional outcomes determined by pre- and postoperative SF-36 and postoperative Oswestry Disability Index (ODI), and a satisfaction questionnaire. The minimum follow-up was 24 months. The mean operating room time and hospital length of stay were less in the TLIF group. The blood loss was slightly less in the TLIF group (409 vs. 480 cc.). Intra-operative complications were higher in the APF group, mostly due to vein lacerations in the anterior retroperitoneal approach. Postoperative complications were higher in the TLIF group due to graft material extruding against the nerve root or wound drainage. The pseudarthrosis rate was statistically equal (APF 17.6% and TLIF 23.1%) and was higher than most published reports. Significant improvements were noted in both groups for the SF-36 questionnaires. The mean ODI scores at follow-up were 33.5 for the APF and 39.5 for the TLIF group. The patient satisfaction rate was equal for the two groups. PMID:19125304

  14. Conduction model covering non-degenerate through degenerate polycrystalline semiconductors with non-uniform grain-boundary potential heights based on an energy filtering model

    NASA Astrophysics Data System (ADS)

    Kajikawa, Y.

    2012-12-01

    We propose a new conduction model associated with thermionic emission of carriers over potential barriers at grain boundaries, which is applicable to non-degenerate through degenerate polycrystalline semiconductors. We first assume the grain-boundary potential barriers of a uniform height and derive an analytical expression of the electrical conductivity on the basis of an energy filtering model with fully incorporating the Fermi-Dirac distribution of carriers. We then introduce fluctuations of the potential barrier height as a Gaussian distribution into the model. It is shown that the non-linear curves of Arrhenius plots of electrical conductivity in various polycrystalline semiconductors (Si, CdS, CdSe, ZnO, WO3, In2Se3) in literature are well fitted using the model with the effect of fluctuations taken into account, being regardless of whether carriers are degenerate or non-degenerate, without assuming other conduction mechanisms such as tunneling and variable range hopping.

  15. Inner disc obscuration in GRS 1915+105 based on relativistic slim disc model

    NASA Astrophysics Data System (ADS)

    Vierdayanti, K.; Sadowski, A.; Mineshige, S.; Bursa, M.

    2013-11-01

    We study the observational signatures of the relativistic slim disc of 10 M⊙ black hole, in a wide range of mass accretion rate, dot{m}, dimensionless spin parameter, a*, and viewing angle, i. In general, the innermost temperature, Tin, increases with the increase of i for a fixed value of dot{m} and a*, due to the Doppler effect. However, for i > 50° and dot{m}>dot{m}_turn, Tin starts to decrease with the increase of dot{m}. This is a result of self-obscuration - the radiation from the innermost hot part of the disc is blocked by the surrounding cooler part. The value of dot{m}_turn and the corresponding luminosities depend on a* and i. Such obscuration effects cause an interesting behaviour on the disc luminosity (Ldisc)-Tin plane for high inclinations. In addition to the standard disc branch which appears below dot{m}_turn and which obeys L_disc ∝ T_in4 relation, another branch above dot{m}_turn, which is nearly horizontal, may be observed at luminosities close to the Eddington luminosity. We show that these features are likely observed in a Galactic X-ray source, GRS 1915+105. We support a high spin parameter (a* > 0.9) for GRS 1915+105 since otherwise the high value of Tin and small size of the emitting region (rin < 1rS) cannot be explained.

  16. Design and fabrication of 3D-printed anatomically shaped lumbar cage for intervertebral disc (IVD) degeneration treatment.

    PubMed

    Serra, T; Capelli, C; Toumpaniari, R; Orriss, I R; Leong, J J H; Dalgarno, K; Kalaskar, D M

    2016-01-01

    Spinal fusion is the gold standard surgical procedure for degenerative spinal conditions when conservative therapies have been unsuccessful in rehabilitation of patients. Novel strategies are required to improve biocompatibility and osseointegration of traditionally used materials for lumbar cages. Furthermore, new design and technologies are needed to bridge the gap due to the shortage of optimal implant sizes to fill the intervertebral disc defect. Within this context, additive manufacturing technology presents an excellent opportunity to fabricate ergonomic shape medical implants. The goal of this study is to design and manufacture a 3D-printed lumbar cage for lumbar interbody fusion. Optimisations of the proposed implant design and its printing parameters were achieved via in silico analysis. The final construct was characterised via scanning electron microscopy, contact angle, x-ray micro computed tomography (μCT), atomic force microscopy, and compressive test. Preliminary in vitro cell culture tests such as morphological assessment and metabolic activities were performed to access biocompatibility of 3D-printed constructs. Results of in silico analysis provided a useful platform to test preliminary cage design and to find an optimal value of filling density for 3D printing process. Surface characterisation confirmed a uniform coating of nHAp with nanoscale topography. Mechanical evaluation showed mechanical properties of final cage design similar to that of trabecular bone. Preliminary cell culture results showed promising results in terms of cell growth and activity confirming biocompatibility of constructs. Thus for the first time, design optimisation based on computational and experimental analysis combined with the 3D-printing technique for intervertebral fusion cage has been reported in a single study. 3D-printing is a promising technique for medical applications and this study paves the way for future development of customised implants in spinal

  17. Cell Therapy Using Bone Marrow-Derived Stem Cell Overexpressing BMP-7 for Degenerative Discs in a Rat Tail Disc Model.

    PubMed

    Liao, Jen-Chung

    2016-01-01

    Degenerative discs can cause low back pain. Cell-based transplantation or growth factors therapy have been suggested as a strategy to stimulate disc regeneration. Bone marrow-derived mesenchymal stem cells (BMDMSC) containing bone morphogenetic protein-7 (BMP-7) gene were constructed. We evaluated the effectiveness of these BMP-7 overexpressing cells on degenerative discs in rat tails. In vitro and in vivo studies were designed. In the first stage, the rats were divided into two group according to discs punctured by different needle gauges (18 gauge and 22 gauge). In the second stage, the ideal size of needle was used to induce rat tail disc degeneration. These animals are divided into three groups according to timing of treatment (zero-week, two-week, four-week). Each group was divided into three treating subgroups: control group, BMDMSC group, and Baculo-BMP-7-BMDMSC group. Each rat undergoes radiography examination every two weeks. After eight weeks, the discs were histologically examined with hematoxylin and eosin stain and Alcian blue stain. The 18-gauge group exhibited significant decrease in disc height index (%) than 22-gauge group at eight weeks at both Co6-7 (58.1% ± 2.8% vs. 63.7% ± 1.0%, p = 0.020) and Co8-9 discs (62.7% ± 2.8% vs. 62.8% ± 1.5%, p = 0.010). Baculo-BMP-7-BMDMSCs group showed significant difference in disc height index compared to the BMDMSCs group at both Co6-7 (93.7% ± 1.5% vs. 84.8% ± 1.0%, p = 0.011) and Co8-9 (86.0% ± 2.1% vs. 81.8% ± 1.7%, p = 0.012). In Baculo-BMP-7-BMDMSCs group, the zero-week treatment subgroup showed significant better in disc height index compared to two-week treatment group (p = 0.044), and four-week treatment group (p = 0.011). The zero-week treatment subgroup in Baculo-BMP-7-BMDMSCs group also had significant lower histology score than two-week treatment (4.3 vs. 5.7, p = 0.045) and four-week treatment (4.3 vs. 6.0, p = 0.031). In conclusion, Baculo-BMP-7-BMDMSC can slow down the progression of disc

  18. Cell Therapy Using Bone Marrow-Derived Stem Cell Overexpressing BMP-7 for Degenerative Discs in a Rat Tail Disc Model

    PubMed Central

    Liao, Jen-Chung

    2016-01-01

    Degenerative discs can cause low back pain. Cell-based transplantation or growth factors therapy have been suggested as a strategy to stimulate disc regeneration. Bone marrow-derived mesenchymal stem cells (BMDMSC) containing bone morphogenetic protein-7 (BMP-7) gene were constructed. We evaluated the effectiveness of these BMP-7 overexpressing cells on degenerative discs in rat tails. In vitro and in vivo studies were designed. In the first stage, the rats were divided into two group according to discs punctured by different needle gauges (18 gauge and 22 gauge). In the second stage, the ideal size of needle was used to induce rat tail disc degeneration. These animals are divided into three groups according to timing of treatment (zero-week, two-week, four-week). Each group was divided into three treating subgroups: control group, BMDMSC group, and Baculo-BMP-7-BMDMSC group. Each rat undergoes radiography examination every two weeks. After eight weeks, the discs were histologically examined with hematoxylin and eosin stain and Alcian blue stain. The 18-gauge group exhibited significant decrease in disc height index (%) than 22-gauge group at eight weeks at both Co6-7 (58.1% ± 2.8% vs. 63.7% ± 1.0%, p = 0.020) and Co8-9 discs (62.7% ± 2.8% vs. 62.8% ± 1.5%, p = 0.010). Baculo-BMP-7-BMDMSCs group showed significant difference in disc height index compared to the BMDMSCs group at both Co6-7 (93.7% ± 1.5% vs. 84.8% ± 1.0%, p = 0.011) and Co8-9 (86.0% ± 2.1% vs. 81.8% ± 1.7%, p = 0.012). In Baculo-BMP-7-BMDMSCs group, the zero-week treatment subgroup showed significant better in disc height index compared to two-week treatment group (p = 0.044), and four-week treatment group (p = 0.011). The zero-week treatment subgroup in Baculo-BMP-7-BMDMSCs group also had significant lower histology score than two-week treatment (4.3 vs. 5.7, p = 0.045) and four-week treatment (4.3 vs. 6.0, p = 0.031). In conclusion, Baculo-BMP-7-BMDMSC can slow down the progression of disc

  19. The fate of transplanted xenogeneic bone marrow-derived stem cells in rat intervertebral discs.

    PubMed

    Wei, Aiqun; Tao, Helen; Chung, Sylvia A; Brisby, Helena; Ma, David D; Diwan, Ashish D

    2009-03-01

    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. PMID:18853431

  20. Cellular models and therapies for age-related macular degeneration

    PubMed Central

    Forest, David L.; Johnson, Lincoln V.; Clegg, Dennis O.

    2015-01-01

    ABSTRACT Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. PMID:26035859

  1. System modeling with the DISC framework: evidence from safety-critical domains.

    PubMed

    Reiman, Teemu; Pietikäinen, Elina; Oedewald, Pia; Gotcheva, Nadezhda

    2012-01-01

    The objective of this paper is to illustrate the development and application of the Design for Integrated Safety Culture (DISC) framework for system modeling by evaluating organizational potential for safety in nuclear and healthcare domains. The DISC framework includes criteria for good safety culture and a description of functions that the organization needs to implement in order to orient the organization toward the criteria. Three case studies will be used to illustrate the utilization of the DISC framework in practice. PMID:22317179

  2. The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome

    PubMed Central

    Liu, Wei; An, Jing; Wang, Bin; Xue, Jun-Hui; Zhang, Zuo-Ming

    2016-01-01

    Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P) days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL) and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome. PMID:27186975

  3. The Time Course of Deafness and Retinal Degeneration in a Kunming Mouse Model for Usher Syndrome.

    PubMed

    Yao, Lu; Zhang, Lei; Qi, Lin-Song; Liu, Wei; An, Jing; Wang, Bin; Xue, Jun-Hui; Zhang, Zuo-Ming

    2016-01-01

    Usher syndrome is a group of autosomal recessive diseases characterized by congenital deafness and retinitis pigmentosa. In a mouse model for Usher syndrome, KMush/ush, discovered in our laboratory, we measured the phenotypes, characterized the architecture and morphology of the retina, and quantified the level of expression of pde6b and ush2a between postnatal (P) days 7, and 56. Electroretinograms and auditory brainstem response were used to measure visual and auditory phenotypes. Fundus photography and light microscopy were used to measure the architecture and morphology of the retina. Quantitative real-time PCR was used to measure the expression levels of mRNA. KMush/ush mice had low amplitudes and no obvious waveforms of Electroretinograms after P14 compared with controls. Thresholds of auditory brainstem response in our model were higher than those of controls after P14. By P21, the retinal vessels of KMush/ush mice were attenuated and their optic discs had a waxy pallor. The retinas of KMush/ush mice atrophied and the choroidal vessels were clearly visible. Notably, the architecture of each retinal layer was not different as compared with control mice at P7, while the outer nuclear layer (ONL) and other retinal layers of KMush/ush mice were attenuated significantly between P14 and P21. ONL cells were barely seen in KMush/ush mice at P56. As compared with control mice, the expression of pde6b and ush2a in KMush/ush mice declined significantly after P7. This study is a first step toward characterizing the progression of disease in our mouse model. Future studies using this model may provide insights about the etiology of the disease and the relationships between genotypes and phenotypes providing a valuable resource that could contribute to the foundation of knowledge necessary to develop therapies to prevent the retinal degeneration in patients with Usher Syndrome. PMID:27186975

  4. Physical optics model of side lobe nulling by discs on a parabolic reflector

    NASA Astrophysics Data System (ADS)

    Trapp, D. A.

    1985-12-01

    By mounting small disc reflectors that are moveable relative to the inner reflector surface of a parabolic dish antenna, nulls can be generated in the side lobe region of the power radiation pattern with minimal distortion effects to the main beam. A physical optics model of this antenna system is developed to investigate in a simplified direct manner the phenomena of phase nulling caused by disc movement. Array theory using isotropic radiators is used to sample the aperture distribution to approximate the far field electric field of the dish. A physical optics approximation for scattering off a flat metal disc is used for discs and feed blockage effects.

  5. Kinematic modelling of disc galaxies using graphics processing units

    NASA Astrophysics Data System (ADS)

    Bekiaris, G.; Glazebrook, K.; Fluke, C. J.; Abraham, R.

    2016-01-01

    With large-scale integral field spectroscopy (IFS) surveys of thousands of galaxies currently under-way or planned, the astronomical community is in need of methods, techniques and tools that will allow the analysis of huge amounts of data. We focus on the kinematic modelling of disc galaxies and investigate the potential use of massively parallel architectures, such as the graphics processing unit (GPU), as an accelerator for the computationally expensive model-fitting procedure. We review the algorithms involved in model-fitting and evaluate their suitability for GPU implementation. We employ different optimization techniques, including the Levenberg-Marquardt and nested sampling algorithms, but also a naive brute-force approach based on nested grids. We find that the GPU can accelerate the model-fitting procedure up to a factor of ˜100 when compared to a single-threaded CPU, and up to a factor of ˜10 when compared to a multithreaded dual CPU configuration. Our method's accuracy, precision and robustness are assessed by successfully recovering the kinematic properties of simulated data, and also by verifying the kinematic modelling results of galaxies from the GHASP and DYNAMO surveys as found in the literature. The resulting GBKFIT code is available for download from: http://supercomputing.swin.edu.au/gbkfit.

  6. Linking continuous and discrete intervertebral disc models through homogenisation.

    PubMed

    Karajan, N; Röhrle, O; Ehlers, W; Schmitt, S

    2013-06-01

    At present, there are two main numerical approaches that are frequently used to simulate the mechanical behaviour of the human spine. Researchers with a continuum-mechanical background often utilise the finite-element method (FEM), where the involved biological soft and hard tissues are modelled on a macroscopic (continuum) level. In contrast, groups associated with the science of human movement usually apply discrete multi-body systems (MBS). Herein, the bones are modelled as rigid bodies, which are connected by Hill-type muscles and non-linear rheological spring-dashpot models to represent tendons and cartilaginous connective tissue like intervertebral discs (IVD). A possibility to benefit from both numerical methods is to couple them and use each approach, where it is most appropriate. Herein, the basic idea is to utilise MBS in simulations of the overall body and apply the FEM only to selected regions of interest. In turn, the FEM is used as homogenisation tool, which delivers more accurate non-linear relationships describing the behaviour of the IVD in the multi-body dynamics model. The goal of this contribution is to present an approach to couple both numerical methods without the necessity to apply a gluing algorithm in the context of a co-simulation. Instead, several pre-computations of the intervertebral disc are performed offline to generate an approximation of the homogenised finite-element (FE) result. In particular, the discrete degrees of freedom (DOF) of the MBS, that is, three displacements and three rotations, are applied to the FE model of the IVD, and the resulting homogenised forces and moments are recorded. Moreover, a polynomial function is presented with the discrete DOF of the MBS as variables and the discrete forces an moments as function values. For the sake of a simple verification, the coupling method is applied to a simplified motion segment of the spine. Herein, two stiff cylindrical vertebrae with an interjacent homogeneous

  7. Building disc structure and galaxy properties through angular momentum: The DARK SAGE semi-analytic model

    NASA Astrophysics Data System (ADS)

    Stevens, Adam R. H.; Croton, Darren J.; Mutch, Simon J.

    2016-06-01

    We present the new semi-analytic model of galaxy evolution, DARK SAGE, a heavily modified version of the publicly available SAGE code. The model is designed for detailed evolution of galactic discs. We evolve discs in a series of annuli with fixed specific angular momentum, which allows us to make predictions for the radial and angular-momentum structure of galaxies. Most physical processes, including all channels of star formation and associated feedback, are performed in these annuli. We present the surface density profiles of our model spiral galaxies, both as a function of radius and specific angular momentum, and find the discs naturally build a pseduobulge-like component. Our main results are focussed on predictions relating to the integrated mass-specific angular momentum relation of stellar discs. The model produces a distinct sequence between these properties in remarkable agreement with recent observational literature. We investigate the impact Toomre disc instabilities have on shaping this sequence and find they are crucial for regulating both the mass and spin of discs. Without instabilities, high-mass discs would be systematically deficient in specific angular momentum by a factor of ˜2.5, with increased scatter. Instabilities also appear to drive the direction in which the mass-spin sequence of spiral galaxy discs evolves. With them, we find galaxies of fixed mass have higher specific angular momentum at later epochs.

  8. Building disc structure and galaxy properties through angular momentum: the DARK SAGE semi-analytic model

    NASA Astrophysics Data System (ADS)

    Stevens, Adam R. H.; Croton, Darren J.; Mutch, Simon J.

    2016-09-01

    We present the new semi-analytic model of galaxy evolution, DARK SAGE, a heavily modified version of the publicly available SAGE code. The model is designed for detailed evolution of galactic discs. We evolve discs in a series of annuli with fixed specific angular momentum, which allows us to make predictions for the radial and angular-momentum structure of galaxies. Most physical processes, including all channels of star formation and associated feedback, are performed in these annuli. We present the surface density profiles of our model spiral galaxies, both as a function of radius and specific angular momentum, and find that the discs naturally build a pseudo-bulge-like component. Our main results are focused on predictions relating to the integrated mass-specific angular momentum relation of stellar discs. The model produces a distinct sequence between these properties in remarkable agreement with recent observational literature. We investigate the impact Toomre disc instabilities have on shaping this sequence and find they are crucial for regulating both the mass and spin of discs. Without instabilities, high-mass discs would be systematically deficient in specific angular momentum by a factor of ˜2.5, with increased scatter. Instabilities also appear to drive the direction in which the mass-spin sequence of spiral galaxy discs evolves. With them, we find galaxies of fixed mass have higher specific angular momentum at later epochs.

  9. A Simple ``Sticky Disc'' Model for Crystalline and Amorphous Networks

    NASA Astrophysics Data System (ADS)

    Huerta, Adrian; Chubynsky, Nikita; Naumis, Gerardo; Thorpe, Michael

    2005-03-01

    Using Monte Carlo simulations, we study the structural and thermodynamic behavior of a simple one component network forming model made up of ``sticky discs.'' Central and bond bending forces was included, modeling such interactions as a simple square well radial and angular three body term in the potential respectively. The main feature of this model is the ability to form crystalline and amorphous networks upon cooling, similar to that obtained using the so called WWW methodology to describe the network of some vitreous structures [1]. With the ``pebble game'' algorithm [2], we evaluate the number of degrees of freedom and the amount of stress in both the amorphous and crystalline structures. We discuss the connection between the configurational entropy (associated with the topology) and the degrees of freedom. Other effects such as elasticity of these structures are also discussed. 1. Wooten, F., Winer, K. and Weaire, D., Phys. Rev. Lett., 54 1392- 1395 (1985). 2. Jacobs, D.J. and Thorpe, M.F., Phys. Rev. Lett., 75 4051- 4054 (1995).

  10. Utility and validity of DISC1 mouse models in biological psychiatry.

    PubMed

    Tomoda, T; Sumitomo, A; Jaaro-Peled, H; Sawa, A

    2016-05-01

    We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10-15years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of the major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future. PMID:26768401