https://www.oarsijournal.com/article/S1063-4584(15)00877-8/pdf

Mechanics and biology in intervertebral disc degeneration: a vicious circle

Degeneration of the intervertebral discs, a process characterized by a cascade of cellular, biochemical, structural and functional changes, is strongly implicated as a cause of low back pain. Current treatment strategies for disc degeneration typically address the symptoms of low back pain without treating the underlying cause or restoring mechanical function. A more in-depth understanding of disc degeneration, as well as opportunities for therapeutic intervention, can be obtained by considering aspects of intervertebral disc development. Development of the intervertebral disc involves the coalescence of several different cell types through highly orchestrated and complex molecular interactions. The resulting structures must function synergistically in an environment that is subjected to continuous mechanical perturbation throughout the life of an individual. Early postnatal changes, including altered cellularity, vascular regression and altered extracellular matrix composition, might set the disc on a slow course towards symptomatic degeneration. In this Perspective, we review the pathogenesis and treatment of intervertebral disc degeneration in the context of disc development. Within this scope, we examine how model systems have advanced our understanding of embryonic morphogenesis and associated molecular signaling pathways, in addition to the postnatal changes to the cellular, nutritional and mechanical microenvironment. We also discuss the current status of biological therapeutic strategies that promote disc regeneration and repair, and how lessons from development might provide clues for their refinement.

Degeneration and regeneration of the intervertebral disc: lessons from development.

https://www.oarsijournal.com/article/S1063-4584(15)01333-3/pdf

Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration.

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, as well as 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 tumour necrosis factor-α (TNF-α) and interleukin-1β (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 both cellular and tissue level, as well as new evidence suggesting a link between infection of the spine and low back pain, and the emerging therapeutic modalities aimed at combating these processes.

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Disc in flames: Roles of TNF-α and IL-1β in intervertebral disc degeneration.

Mechanical design criteria for intervertebral disc tissue engineering.

Study Design. In 2 studies, the injection of chondroitinase ABC into intervertebral discs of mature goats was evaluated as an experimental disc degeneration model. The first study analyzed the development of degeneration in time; the second study determined the optimal enzyme concentration. Objectives. To develop reproducible, slowly progressive disc degeneration in a large animal model. Summary of Background Data. Currently available, small animal models of intervertebral disc degeneration have shortcomings in the comparability to humans in terms of size, geometry, and cell population. Also, the methods to induce degeneration in the current models do not mimic human degeneration, which starts with the loss of proteoglycans. Injecting the enzyme chondroitinase ABC into the nucleus pulposus mimics the loss of proteoglycans. Methods. In Study 1, lumbar intervertebral discs of 17 goats were injected with chondroitinase ABC (0.25 U/mL) or phosphate-buffered saline. Degeneration was analyzed with radiograph analysis, MR imaging, and macroscopic and histologic scoring at 5 different time points (4, 8, 12, 18, and 26 weeks). Six control goats were analyzed. The second study used 6 goats in which 4 different concentrations of chondroitinasa ABC (0.2-0.35 U/mL) or phosphate-buffered saline were injected. After 12 weeks, similar analyses as in Study 1 were performed. Results. After 12 weeks, degenerative signs were observed in all parameters in Study 1. The degeneration increased up to 18 weeks and leveled off after 26 weeks. The variability, however, was high. The second study showed a concentration dependent effect of chondroitinase ABC with all analyzed parameters. The injection of 0.25 U/mL chondroitinase ABC resulted in disc degeneration after 12 weeks without signs of severe degeneration. Conclusion. Injection of chondroitinase ABC in the caprine intervertebral disc results in mild, slowly progressive disc degeneration. This effect was optimal at a concentration of 0.25 U/mL. This is a promising model of disc degeneration that deserves further study.

Experimental intervertebral disc degeneration induced by chondroitinase ABC in the goat.

Introduction Degenerative disc disease and emerging biological treatment approaches Stem cell sources Integration of ASC-based regenerative medicine and surgery In vitro studies Animal models Cells in disc regeneration in vivo In vivo studies Perspective Conclusions Abstract New regenerative treatment strategies are being developed for intervertebral disc degeneration of which the implantation of various cell types is promising. All cell types used so far require in vitro expansion prior to clinical use, as these cells are only limited available. Adipose-tissue is an abundant, expendable and easily accessible source of mesenchymal stem cells. The use of these cells therefore eliminates the need for in vitro expansion and subsequently one-step regenerative treatment strategies can be developed. Our group envisioned, described and evaluated such a one-step procedure for spinal fusion in the goat model. In this review, we summarize the current status of cell-based treatments for intervertebral disc degeneration and identify the additional research needed before adipose-derived mesenchymal stem cells can be evaluated in a one-step procedure for regenerative treatment of the intervertebral disc. We address the selection of stem cells from the stromal vascular fraction, the specific triggers needed for cell differentiation and potential suitable scaffolds. Although many factors need to be studied in more detail, potential application of a one-step procedure for intervertebral disc regeneration seems realistic. © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1582-4934.2008.00291.x

Adipose stem cells for intervertebral disc regeneration: current status and concepts for the future

STUDY DESIGN. Twelve goats were chemically degenerated and the development of the degenerative signs was followed for 26 weeks to evaluate the progression of the induced degeneration. The results were also compared with a previous study to determine the reproducibility. OBJECTIVES. The purpose of this study was determine whether this Chondroitinase ABC (CABC) induced goat model is reproducible and to study the development of the degeneration in time up to 26 weeks. SUMMARY OF BACKGROUND DATA. Injecting CABC into goat intervertebral discs results in mild disc degeneration after 12 weeks. Spontaneous recovery or leveling off of the degeneration has been reported before and is relevant when the goat model is used in regeneration studies. Reproducibility of the induced degeneration is relevant as well. METHODS. Twelve goats were used in this study. The development of degeneration was studied after the injection of 0.25 U/mL CABC intradiscally. The development of degenerative signs was studied after 18 (n = 6) and 26 (n = 6) weeks by means of radiograph, magnetic resonance imaging, macroscopic analysis, and histology and biochemical evaluation. The induced degeneration was compared with the results from a previous study, in which degeneration was induced similarly and analysis was performed after 12 weeks. RESULTS. The severity of the degenerative signs was mild and was consequently present in all parameters analyzed. When compared with the results after 12 weeks, the degeneration was similar in the present study. Spontaneous recovery was not observed up to 26 weeks. CONCLUSION. The injection with CABC in the intervertebral disc reproducibly results in mild disc degeneration in the goat. These findings corroborate the goat model as a suitable large animal model to evaluate mild disc degeneration and potential new therapies. © 2008 Lippincott Williams & Wilkins, Inc.

Reproducible long-term disc degeneration in a large animal model

Study Design. The adjacent discs of 13 goats, originally used in a lumbar spinal fusion model study, were analyzed for symptoms of intervertebral disc degeneration by means of magnetic resonance imaging (MRI), macroscopy, and histology. These goats were followed for 6 months and the results were compared with 6 control goats. Objective. To evaluate the development of adjacent segment disc degeneration in vivo in a goat lumbar spinal fusion model. Summary of Background Data. There is ongoing debate on whether adjacent segment degeneration (ASD) develops through increased biomechanical load on discs adjacent to fusion sites, or by the natural process of pre-existing degenerative disease. Animal models offer an opportunity to separate these factors by evaluating the development of ASD in nondegenerated animal spines. Methods. In a spinal fusion model study 2 segments (L3-L4 and L1-L2) were fixated and followed for 3 months (n = 6) and 6 months (n = 7) in 13 skeletally mature goats. Two adjacent discs (T13-L1 and L4-L5), 1 interjacent disc (L2-L3) and a control disc (L5-L6) were analyzed by means of magnetic resonance imaging, macroscopy, and histology. These results were compared with the discs of 6, nonoperated "normal" goats. Results. No differences were observed in the adjacent and interjacent intervertebral discs after both follow-up periods. However, severe degenerative changes were observed in the L5-L6 level, originally included as controls. Conclusion. Large animal fusion models offer an excellent opportunity to study ASD in vivo, as pre-existing degenerative disc disease is not present and biomechanical effects of the fusion can be studied more isolated. Our results suggest that adjacent disc degeneration does not develop in our spinal goat fusion model. There is, however, an increased risk of disc degeneration in the L5-L6 level through an unclear mechanism.

Roel J. W. Hoogendoorn

Papers

Mechanics and biology in intervertebral disc degeneration: a vicious circle

Experimental intervertebral disc degeneration induced by chondroitinase ABC in the goat.

Adipose stem cells for intervertebral disc regeneration: current status and concepts for the future

Reproducible long-term disc degeneration in a large animal model

Adjacent segment degeneration: observations in a goat spinal fusion study