Caspase 3 Silencing Inhibits Biomechanical Overload–Induced Intervertebral Disk Degeneration

Yamada, Kei; Sudo, Hideki; Iwasaki, Koji; Sasaki, Naoki; Higashi, Hideaki; Kameda, Yutaka; Ito, Manabu; Takahata, Masahiko; Abumi, Kuniyoshi; Minami, Akio; Iwasaki, Norimasa

doi:10.1016/j.ajpath.2013.11.010

Cited by 43 publications

(83 citation statements)

References 59 publications

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“…Theoretically, it may be possible that this finding was due to changes in antibody binding, for example, due to mechanically induced changes in tissue density. On the other hand, it is theoretically possible that local PCM degradation may be associated with catabolic processes induced by cell death or high stress levels during injury (Yamada et al, ). Interestingly, in the analysed trauma disks, the PCM fraction was markedly reduced, suggesting that the PCM is a structure susceptible to early posttraumatic degeneration.…”

Section: Discussionmentioning

confidence: 99%

Chondrocyte death after mechanically overloading degenerated human intervertebral disk explants is associated with a structurally impaired pericellular matrix

Hofmann

Steidle

Danalache

et al. 2018

J Tissue Eng Regen Med

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A type VI collagen-rich pericellular matrix (PCM) encloses both intervertebral disk (IVD) and articular cartilage chondrocytes. In the latter, the PCM protects the chondrocytes from mechanical overload, whereas tissue degeneration is associated with PCM destruction. As little is known about the IVD PCM, we investigated chondrocyte survival after mechanical overload as well as PCM structural integrity as a function of clinical tissue degeneration. The hypothesis was that IVD degeneration may affect PCM integrity and overload-related chondrocyte survival. Cylindrical human IVD explants from patients undergoing surgical procedures for lumbar disk degeneration, disk prolapse, or spinal trauma were generated and scored. Mechanical overload was applied by single uniaxial 50% compression followed by immediate release, and the explants were live-dead stained (n = 20 explants). Type VI collagen, the major PCM component, was fluorescent stained and the extent was determined, in which individual cells were enclosed by a recognizable PCM; this was termed PCM fraction. More than 50% of chondrocytes in all degenerative IVD explants displayed <25% PCM fraction and a lower PCM fraction correlated with higher cell numbers (p < 0.001), suggesting a PCM structural impairment in IVD degeneration that is associated with chondrocyte clustering. Mechanical overload-induced significantly increased cell death (p = 0.005), and the PCM fraction was significantly lower in overload-induced cell death than in live cells (p = 0.042), suggesting that a fully present PCM has a protective role in mechanical overload. Collectively, human IVD degeneration is associated with a structural impairment of the PCM, which may promote cell death under mechanical overload.

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Section: Discussionmentioning

confidence: 99%

Chondrocyte death after mechanically overloading degenerated human intervertebral disk explants is associated with a structurally impaired pericellular matrix

Hofmann

Steidle

Danalache

et al. 2018

J Tissue Eng Regen Med

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“…Healthy intact human NP samples were obtained from five patients (mean age ± standard deviation, 14.8±5.2 years) [11], [12] who underwent anterior spinal fusion for adolescent idiopathic scoliosis. Before surgery, all IVDs were analyzed by magnetic resonance imaging and graded for degenerative changes using the Pfirrmann classification system [13].…”

Section: Methodsmentioning

confidence: 99%

“…The NP cells were isolated and cultured as previously described [11], [12] using an extended 4 hour enzymatic digestion step. Briefly, each gel-like NP was separated from AF using a dissecting microscope.…”

Section: Methodsmentioning

confidence: 99%

Cytotoxic Effects of the Radiocontrast Agent Iotrolan and Anesthetic Agents Bupivacaine and Lidocaine in Three-Dimensional Cultures of Human Intervertebral Disc Nucleus Pulposus Cells: Identification of the Apoptotic Pathways

et al. 2014

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BackgroundDiscography and discoblock are imaging procedures used to diagnose discogenic low back pain. Although needle puncture of the intervertebral disc (IVD) itself induces disc degeneration, the agents used in these procedures may also have harmful effects on IVD cells. The purpose of this study was to analyze whether radiocontrast agents and local anesthetic agents have detrimental effects on human nucleus pulposus (NP) cells.MethodsHealthy human NP cells were cultured for 7 days in three-dimensional (3D) cell–alginate bead composites, and were then exposed to clinically relevant doses of a radiocontrast agent (iotrolan) or local anesthetic (lidocaine or bupivacaine). Cell viability and apoptosis were measured by confocal microscopy and flow cytometry. On the basis of caspase expression profiles, the apoptotic pathways activated by the agents were identified by Western blot analysis.ResultsThe radiocontrast agent iotrolan did not affect NP cell viability or induce apoptosis. In contrast, both the anesthetic agents significantly decreased cell viability and increased the apoptotic cell number in a time- and dose-dependent manner. After 120 min, 2% lidocaine and 0.5% bupivacaine decreased percent live cells to 13% and 10%, respectively (p<0.05). The number of apoptotic cells was doubled by increasing lidocaine dosage from 1% to 2% (23% and 42%) and bupivacaine from 0.25% to 0.50% (25% and 48%) (p<0.05). Western blot analysis revealed that both anesthetic agents upregulated cleaved caspase-3 and caspase-8, whereas only bupivacaine upregulated cleaved caspase-9.Conclusions/SignificanceThe present study demonstrates that iotrolan does not affect the viability of healthy human NP cells. In contrast, the two anesthetic agents commonly used in discography or discoblock may cause extensive damage to IVDs by inducing apoptotic cell death.

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“…The pathogenesis of intervertebral disc (IVD) degeneration is unclear, but it is a major cause of several spinal diseases and has a great impact on quality of life . A large percentage of the aging human population is afflicted with seemingly irreversible IVD degeneration: Approximately 40% of people less than 30 years old and upwards of 90% of people 55 years old or older are afflicted with moderate‐to‐severe levels of IVD degeneration in their lumbar spine .…”

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confidence: 99%

Age‐related spontaneous lumbar intervertebral disc degeneration in a mouse model

Ohnishi

Sudo

Tsujimoto

et al. 2017

Journal Orthopaedic Research

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The pathogenesis of intervertebral disc degeneration is unclear, but it is a major cause of several spinal diseases. Animal models have historically provided an appropriate benchmark for understanding the human spine. However, there is little information about when intervertebral disc degeneration begins in the mouse or regarding the relationship between magnetic resonance imaging and histological findings. The aim for this study was to obtain information about age-related spontaneous intervertebral disc degeneration in the mouse lumbar spine using magnetic resonance imaging and a histological score regarding when the intervertebral disc degeneration started and how rapidly it progressed, as well as how our histological score detected the degeneration. The magnetic resonance imaging index yielded a moderate correlation with our Age-related model score. The Pfirrmann grade and magnetic resonance imaging index had moderate correlations with age. However, our Age-related model score had a high correlation with age. Intervertebral disc level was not a significant variable for the severity of disc degeneration. Both Pfirrmann grade and the Age-related model score were higher in the ≥14-month-old group than in the 6-month-old group. The present results indicated that mild but significant intervertebral disc degeneration occurred in 14-month-old mice, and the degree of degeneration progressed slowly, reaching a moderate to severe condition for 22-month-old mice. At least a 14-month follow-up is mandatory for evaluating spontaneous age-related mouse intervertebral disc degeneration. The histological classification score can precisely detect the gradual progression of age-related spontaneous intervertebral disc degeneration in the mouse lumbar spine, and is appropriate for evaluating it. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:224-232, 2018.

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Caspase 3 Silencing Inhibits Biomechanical Overload–Induced Intervertebral Disk Degeneration

Cited by 43 publications

References 59 publications

Chondrocyte death after mechanically overloading degenerated human intervertebral disk explants is associated with a structurally impaired pericellular matrix

Chondrocyte death after mechanically overloading degenerated human intervertebral disk explants is associated with a structurally impaired pericellular matrix

Cytotoxic Effects of the Radiocontrast Agent Iotrolan and Anesthetic Agents Bupivacaine and Lidocaine in Three-Dimensional Cultures of Human Intervertebral Disc Nucleus Pulposus Cells: Identification of the Apoptotic Pathways

Age‐related spontaneous lumbar intervertebral disc degeneration in a mouse model

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