Extracellular vesicles derived from mesenchymal stem cells confer protection against intervertebral disc degeneration through a microRNA-217-dependent mechanism.

OBJECTIVE: Extracellular vesicles released by mesenchymal stem cells (MSC-EVs) can be applied to alleviate intervertebral disc degeneration (IVDD) by curbing apoptosis of nucleus pulposus cells (NPCs). The current study aims to evaluate the effect of MSC-EVs on NPC apoptosis and IVDD and the related regulatory mechanisms involving microRNA (miR)-217. METHOD: Expression of miR-217 was examined in tumor necrosis factor-α (TNF-α)-induced NPCs and MSC-EVs, followed by identification in the relationship between miR-217, enhancer of zeste homolog 2 (EZH2) and forkhead box O-3 (FOXO3). After isolation of EVs from MSCs and subsequent co-culture with NPCs, we assessed effects of miR-217 on NPC viability, autophagy, senescence and apoptosis along with extracellular matrix (ECM) degradation. Further in vivo experiments were conducted in rat models of IVDD to substantiate the effect of miR-217 on IVDD. RESULTS: Poor miR-217 expression was found in TNF-α-induced NPCs, while high miR-217 expression was identified in MSC-EVs (P < 0.05). MSC-EVs transferred miR-217 to NPCs and increased its expression, thus attenuating NPC apoptosis and ECM degradation (elevated collagen II and aggrecan but reduced MMP13 and ADAMTS5) (P < 0.05). miR-217 targeted EZH2, and EZH2 bound to the FOXO3 promoter and consequently downregulated its expression. FOXO3 restrained NPC apoptosis and ECM degradation by stimulating cell autophagy (P < 0.05). Furthermore, in vivo experimental results confirmed the suppressive role of miR-217 shuttled by MSC-EVs in IVDD. CONCLUSION: Overall, the delivery of miR-217 may be a novel mechanism underlying the effect of MSC-EVs on NPC apoptosis and ECM degradation following IVDD.

Cartilage endplate stem cells inhibit intervertebral disc degeneration by releasing exosomes to nucleus pulposus cells to activate Akt/autophagy.

Degeneration of the cartilage endplate (CEP) induces intervertebral disc degeneration (IVDD). Nucleus pulposus cell (NPC) apoptosis is also an important exacerbating factor in IVDD, but the cascade mechanism in IVDD is not clear. We investigated the apoptosis of NPCs and IVDD when stimulated by normal cartilage endplate stem cell (CESC)-derived exosomes (N-Exos) and degenerated CESC-derived exosomes (D-Exos) in vitro and in vivo. Tert-butyl hydroperoxide (TBHP) was used to induce inflammation of CESCs. The bioinformatics differences between N-Exos and D-Exos were analyzed using mass spectrometry, heat map, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. NPC apoptosis was examined using TUNEL staining. The involvement of the AKT and autophagy signaling pathways was investigated using the signaling inhibitor LY294002. Magnetic resonance imaging, Western blotting, and immunofluorescence staining were used to evaluate the therapeutic effects of N-Exos in rats with IVDD. TBHP effectively induced inflammation and the degeneration of CEP in rat. N-Exos were more conducive to autophagy activation than D-Exos. The apoptotic rate of NPCs decreased obviously after treatment with N-Exos compared to D-Exos. N-Exos inhibited NPCs apoptosis and attenuated IVDD in rat via activation of the AKT and autophagy pathways. These results are the first findings to confirm that CEP delayed the progression of IVDD via exosomes. The therapeutic effects of N-Exos on NPC apoptosis inhibition and the slowing of IVDD progression were more effective than D-Exos due to activation of the PI3K/AKT/autophagy pathway, which explained the increase in the incidence of IVDD after inflammation of the CEP.

Cyanidin attenuates the apoptosis of rat nucleus pulposus cells and the degeneration of intervertebral disc via the JAK2/STAT3 signal pathway in vitro and in vivo.

CONTEXT: Cyanidin has been shown to have therapeutic potential in osteoarthritis. However, it is unclear whether cyanidin prevents the progression of intervertebral disc degeneration (IVDD). OBJECTIVE: This study evaluates the effects of cyanidin on IVDD in vitro and in vivo. MATERIALS AND METHODS: Nucleus pulposus cells (NPCs) isolated from lumbar IVD of 4-week-old male Sprague-Dawley (SD) rats were exposed to 20 ng/mL IL-1ß, and then treated with different doses (0-120 µM) of cyanidin for 24 h. SD rats were classified into three groups (n = 8) and treated as follows: control (normal saline), IVDD (vehicle), IVDD + cyanidin (50 mg/kg). Cyanidin was administered intraperitoneally for 8 weeks. RESULTS: The IC50 of cyanidin for NPCs was 94.78 µM, and cyanidin had no toxicity at concentrations up to 500 mg/kg in SD rats. Cyanidin inhibited the apoptosis of NPCs induced by IL-1ß (12.73 ± 0.61% vs. 18.54 ± 0.60%), promoted collagen II (0.82-fold) and aggrecan (0.81-fold) expression, while reducing MMP-13 (1.02-fold) and ADAMTS-5 (1.40-fold) expression. Cyanidin increased the formation of autophagosomes in IL-1ß-induced NPCs, and promoted LC3II/LC3I (0.83-fold) and beclin-1 (0.85-fold) expression, which could be reversed by chloroquine. Cyanidin inhibited the phosphorylation of JAK2 (0.47-fold) and STAT3 (0.53-fold) in IL-1ß-induced NPCs. The effects of cyanidin could be enhanced by AG490. Furthermore, cyanidin mitigated disc degeneration in IVDD rats in vivo. DISCUSSION AND CONCLUSIONS: Cyanidin improved the function of NPCs in IVDD by regulating the JAK2/STAT3 pathway, which may provide a novel alternative strategy for IVDD. The mechanism of cyanidin improving IVDD still needs further work for in-depth investigation.

[Research advances in prevention and treatment of intervertebral disc degeneration by targeting mitochondrial quality control].

Intervertebral disc degeneration(IDD) is a common clinical degenerative disease of the musculoskeletal system, which increases the risk of lower back pain, severely reduces patients' quality of life and work efficiency, and imposes a large economic burden on society. Mitochondria, as the "power stations" of eukaryotic cells, are involved in many key biological processes, and their abnormal function can induce cellular dysfunction and lead to the development of a series of degenerative diseases. Recent studies have revealed that mitochondrial quality control(MQC) imbalance, characterized by abnormalities in mitochondrial oxidative stress, kinetics, mitophagy and biogenesis, plays an important role in IDD. The research reviewed the progress of the role of MQC in IDD and summarized traditional Chinese medicine monomers and small molecule compounds targeting MQC for the treatment of IDD, with the aim of providing reference and new ideas for studying novel therapeutic strategies for IDD.

Involvement of oxidative stress-induced annulus fibrosus cell and nucleus pulposus cell ferroptosis in intervertebral disc degeneration pathogenesis.

Ferroptosis is a necrotic form of regulated cell death that was associated with lipid peroxidation and free iron-mediated Fenton reactions. It has been reported that iron deficiency had been implicated in the pathogenesis of intervertebral disc degeneration (IVDD) by activating apoptosis. However, the role of ferroptosis in the process of IVDD has not been illuminated. Here, we demonstrate the involvement of ferroptosis in IVDD pathogenesis. Our in vitro models show the changes in protein levels of ferroptosis marker and enhanced lipid peroxidation level during oxidative stress. Safranin O staining, hematoxylin-eosin staining, and immunohistochemical were used to assess the IVDD after 8 weeks of surgical procedure in vivo. Treatment with ferrostatin-1, deferoxamine, and RSL3 demonstrate the role of ferroptosis in tert-butyl hydroperoxide (TBHP)-treated annulus fibrosus cells (AFCs) and nucleus pulposus cells (NPCs). Ferritinophagy, nuclear receptor coactivator 4 (NCOA4)-mediated ferritin selective autophagy, is originated during the process of ferroptosis in response to TBHP treatment. Knockdown and overexpression NCOA4 further prove TBHP may induce ferroptosis of AFCs and NPCs in an autophagy-dependent way. These findings support a role for oxidative stress-induced ferroptosis in the pathogenesis of IVDD.

Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration.

Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent.

Inhibition of Rac1 activity by NSC23766 prevents cartilage endplate degeneration via Wnt/ß-catenin pathway.

Cartilage endplate (CEP) degeneration has been considered as one of important factors related to intervertebral disc degeneration (IVDD). Previous researches have showed that Rac1 played a pivotal role in chondrocyte differentiation. However, the effect of Rac1 during the process of CEP degeneration remains unclear. Herein, we explored the effect of Rac1 on CEP degeneration and elucidated the underlying molecular mechanism. We found expression of Rac1-GTP increased in human-degenerated CEP tissue and IL-1ß-stimulated rat endplate chondrocytes (EPCs). Our study revealed that Rac1 inhibitor NSC23766 treatment promoted the expression of collagen II, aggrecan and Sox-9, and decreased the expression of ADTAMTS5 and MMP13 in IL-1ß-stimulated rat EPCs. Moreover, we also found that NSC23766 could suppress the activation of Wnt/ß-catenin pathway, suggesting that the beneficial effects of Rac1 inhibition in EPCs are mediated through the Wnt/ß-catenin signalling. Besides, puncture-induced rats models showed that NSC23766 played a protective role on CEP and disc degeneration. Collectively, these findings demonstrated that Rac1 inhibition delayed the EPCs degeneration and its potential mechanism may be associated with Wnt/ß-catenin pathway regulation, which may help us better understand the association between Rac1 and CEP degeneration and provide a promising strategy for delaying the progression of IVDD.

Rapamycin Induced Autophagy Inhibits Inflammation-Mediated Endplate Degeneration by Enhancing Nrf2/Keap1 Signaling of Cartilage Endplate Stem Cells.

Cartilage endplate (CEP) calcification inhibits the transport of metabolites and nutrients in the intervertebral disk and is an important initiating factor of intervertebral disk degeneration. However, the mechanisms governing CEP degeneration have not been thoroughly elucidated. In this study, we established a mouse CEP degeneration model and showed that autophagy insufficiency caused the degeneration of CEP. We found that the inflammatory cytokine tumor necrosis factor-α (TNF-α) increased the level of intracellular reactive oxygen species (ROS) and caused cell senescence and osteogenic differentiation of cartilage endplate stem cells (CESCs), whereas rapamycin-induced autophagy protected CESCs from TNF-α-induced oxidative stress and cell senescence. Furthermore, rapamycin-induced autophagy helped CESCs maintain the chondrogenic properties and inhibited extracellular matrix protease expression and osteogenic differentiation. Further study revealed that autophagy activated by rapamycin or inhibited by chloroquine influenced the expression and nuclear translocation of Nrf2, thereby controlling the expression of antioxidant proteins and the scavenging of ROS. Taken together, the results indicate that rapamycin-induced autophagy enhances Nrf2/Keap1 signaling and promotes the expression of antioxidant proteins, thereby eliminating ROS, alleviating cell senescence, reducing the osteogenic differentiation of CESCs, and ultimately protecting CEPs from chronic inflammation-induced degeneration. Stem Cells 2019;37:828-840.

Intradiscal injection of sesamin protects from lesion-induced degeneration.

Intervertebral disc degeneration-related diseases are common health problems in the department of orthopedics. However, there is no effective treatment protecting the intervertebral disc from degeneration. Sesamin, a kind of sesame lignans extracted from sesame seed oil, has been proved to inhibit lipopolysaccharide-induced inflammation and extracellular matrix catabolism in rat intervertebral disc in vitro and ex vivo. The present study was designed to investigate the effects of sesamin on lesion-induced intervertebral disc degeneration in vivo. Degeneration of rat tail disc was induced by puncture lesion, followed by intradiscal injection of sesamin. Magnetic resonance imaging (MRI), quantitative real-time polymerase chain reaction, histological analysis, and biochemical analysis were carried out to analyze degeneration progression 2 weeks after surgery. As shown by results, intradiscal injection of sesamin inhibited the MRI signal decrease of nucleus pulposus (NP) in T2-weighted images. The upregulated mRNA expression of MMP-3 and ADAMTS-5 induced by lesion was significantly suppressed by sesamin injection. Sesamin partly protected mRNA expression of Col2a1 and Acan from downregulation. Intradiscal injection of sesamin effectively maintained the normal morphology of disc and inhibited lesion-induced degeneration-related histological changes. Immunohistochemical assay demonstrated that the upregulation of degradative enzymes protein expression and the downregulation of type II collagen expression in NP were suppressed by sesamin. According to biochemical analysis, sesamin significantly inhibited the lesion-induced decrease of proteoglycan content in NP. The present study proved the protective effects of sesamin on lesion-induced intervertebral disc degeneration at an early stage.

Ergonomics and musculoskeletal disorders in neurosurgery: a systematic review.

BACKGROUND: Work-related musculoskeletal disorders (WMSDs) are a growing and probably undervalued concern for neurosurgeons and spine surgeons, as they can impact their quality of life and career length. This systematic review aims to ascertain this association and to search for preventive measures. METHODS: We conducted a PRISMA-P-based review on ergonomics and WMSDs in neurosurgery over the last 15 years. Twelve original articles were included, of which 6 focused on spine surgery ergonomics, 5 cranio-facial surgery (mainly endoscopic), and one on both domains. RESULTS: We found a huge methodological and content diversity among studies with 5 surveys, 3 cross-sectional studies, 2 retrospective cohorts, and 2 technical notes. Spine surgeons have sustained neck flexion and neglect their posture during surgery. In a survey, low back pain was found in 62% of surgeons, 31% of them with a diagnosed lumbar disc herniation, and 23% of surgery rate. Pain in the neck (59%), shoulder (49%), finger (31%), and wrist (25%) are more frequent than in the general population. Carpal tunnel syndrome showed a linear relationship with increasing cumulative hours of spine surgery practice. Among cranial procedures, endoscopy was also significantly related to shoulder pain while pineal region surgery received some attempts to optimize ergonomics. CONCLUSIONS: Ergonomics in neurosurgery remains underreported and lack attention from surgeons and authorities. Improvements shall target postural ergonomics, equipment design, weekly schedule adaptation, and exercise.

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats.

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.

Melatonin ameliorates intervertebral disc degeneration via the potential mechanisms of mitophagy induction and apoptosis inhibition.

Intervertebral disc degeneration (IDD) is a complicated disease in patients. The pathogenesis of IDD encompasses cellular oxidative stress, mitochondrion dysfunction and apoptosis. Melatonin eliminates oxygen free radicals, regulates mitochondrial homoeostasis and function, stimulates mitophagy and protects against cellular apoptosis. Therefore, we hypothesize that melatonin has beneficial effect on IDD by mitophagy stimulation and inhibition of apoptosis. The effects of melatonin on IDD were investigated in vitro and in vivo. For the former, melatonin diminished cellular apoptosis caused by tert-butyl hydroperoxide in nucleus pulposus (NP) cells. Mitophagy, as well as its upstream regulator Parkin, was activated by melatonin in both a dose and time-dependent manner. Mitophagy inhibition by cyclosporine A (CsA) partially eliminated the protective effects of melatonin against NP cell apoptosis, suggesting that mitophagy is involved in the protective effect of melatonin on IDD. In addition, melatonin was demonstrated to preserve the extracellular matrix (ECM) content of Collagen II, Aggrecan and Sox-9, while inhibiting the expression of matrix degeneration enzymes, including MMP-13 and ADAMTS-5. In vivo, our results demonstrated that melatonin treatment ameliorated IDD in a puncture-induced rat model. To conclude, our results suggested that melatonin protected NP cells against apoptosis via mitophagy induction and ameliorated disc degeneration, providing the potential therapy for IDD.

Andrographolide prevents human nucleus pulposus cells against degeneration by inhibiting the NF-κB pathway.

Intervertebral disc degeneration (IDD) is among the most common spinal disorders, pathologically characterized by excessive cell apoptosis and production of proinflammatory factors. Pharmacological targeting of nucleus pulposus (NP) degeneration may hold promise in IDD therapy, but it is limited by adverse side effects and nonspecificity of drugs. In this study, we used a natural compound, andrographolide (ANDRO), which has been widely used to intervene inflammatory and apoptotic diseases in the investigation of NP degeneration based on IDD-patients-derived NP cells by lipopolysaccharide (LPS) treatment for the preservation of degeneration. The results showed that LPS maintained the degeneration status of NP cells as evidenced by a high apoptosis rate and the expression of degenerative and inflammatory mediators after LPS treatment. ANDRO reversed the effects of LPS-caused degeneration of NP cells and maintained the phenotype of NP cells, as demonstrated by flow cytometry, degenerative mediators (ADAMTS4 and ADAMTS5), inflammatory factors (COX2, PGE2, MMP-13, and MMP-3), biomarkers of NP cells (SOX9, ACAN, and COL2A1) expressions, and glycosaminoglycan secretion. We also found the involvement of the nuclear factor kappa-light-chain-enhancer of the activated B cells (NF-κB) pathway in ANDRO treatment, indicating that ANDRO prevented the LPS-preserved degeneration of NP cells by inhibiting the NF-κB pathway. This study may provide a reference for clinic medication of IDD therapy.

Effect of lordosis on adjacent levels after lumbar interbody fusion, before and after removal of the spinal fixator: a finite element analysis.

BACKGROUND: Literature indicates that adjacent-segment diseases after posterior lumbar interbody fusion with pedicle screw fixation accelerate degenerative changes at unfused adjacent segments due to the increased motion and intervertebral stress. Sagittal alignment of the spine is an important consideration as achieving proper lordosis could improve the outcome of spinal fusion and avoid the risk of adjacent segment diseases. Therefore, restoration of adequate lumbar lordosis is considered as a major factor in the long-term success of lumbar fusion. This study hypothesized that the removal of internal fixation devices in segments that have already fused together could reduce stress at the disc at adjacent segments, particularly in patients with inadequate lordosis. The purpose of this study was to analyze the biomechanical characteristics of a single fusion model (posterior lumbar interbody fusion with internal fixation) with different lordosis angles before and after removal of the internal fixation device. METHODS: Five finite element models were constructed for analysis; 1) Intact lumbar spine without any implants (INT), 2) Lumbar spine implanted with a spinal fixator and lordotic intervertebral cage at L4-L5 (FUS-f-5c), 3) Lumbar spine after removal of the spinal fixator (FUS-5c), 4) Lumbar spine implanted with a spinal fixator and non-lordotic intervertebral cage at L4-L5 (FUS-f-0c), and 5) Lumbar spine after removal of the spinal fixator from the FUS-f-0c model (FUS-0c). RESULTS: The ROM of adjacent segments in the FUS-f-0c model was found to be greater than in the FUS-f-5c model. After removing the fixator, the adjacent segments in the FUS-5c and FUS-0c models had a ROM that was similar to the intact spine under all loading conditions. Removing the fixator also reduced the contact forces on adjacent facet joints and reduced the peak stresses on the discs at adjacent levels. The greatest increase in stress on the discs was found in the FUS-f-0c model (at both L2/L3 and L3/L4), with intervertebral stress at L3/L4 increasing by 83% when placed in flexion. CONCLUSIONS: This study demonstrated how removing the spinal fixation construct after bone fusion could reduce intradiscal pressure and facet contact forces at adjacent segments, while retaining a suitable level of lumbar lordosis.

Lycorine Suppresses Endplate-Chondrocyte Degeneration and Prevents Intervertebral Disc Degeneration by Inhibiting NF-κB Signalling Pathway.

BACKGROUND/AIMS: Cartilaginous endplate (CEP) degeneration is an important cause for intervertebral disc (IVD) degeneration that leads to low-back pain. The identification of compounds that may prevent CEP degeneration is of interest for the prevention of IVD degeneration. METHODS: Catabolic protease expression in the CEP of disc degeneration patients was first assessed. The toxicity, function and underlying mechanism of lycorine (LY) on CEP-derived chondrocytes degeneration were assessed in vitro by flow cytometry analysis and western blotting. The concentration and function of LY in rat-tail disc-degeneration models were also assessed by HPLC (High Performance Liquid Chromatography) quantification and histological analysis. RESULTS: In CEP cells, Interleukin (IL)-1ß upregulated the expression of matrix metalloproteinase (MMP)-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 that is critical for the degradation of cartilage extracellular matrix. Interestingly, LY suppressed the expression of these enzymes via the inhibition of nuclear factor-κB (NFκB) signalling and thus prevented IL-1ß-induced endplate cell degeneration in vitro. More importantly, LY also reduced the expression of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in CEP and exerted a protective effect on both CEP and nucleus pulposus (NP) degeneration. In addition to its inhibitory effect on matrix-degrading protease expression, LY treatment also reduced positive regulators of proinflammatory cytokines, such as MIF, which can be secreted by CEP cells and subsequently target NP cells. CONCLUSION: LY could serve as a potential drug for treating IVD disease.

The effect of training on lumbar spine posture and intervertebral disc degeneration in active-duty Marines.

Military training aims to improve load carriage performance and reduce risk of injuries. Data describing the lumbar spine (LS) postural response to load carriage throughout training are limited. We hypothesised that training would reduce the LS postural response to load. The LS posture of 27 Marines was measured from upright MR images: with and without load (22.6 kg) at the beginning, middle, and end of School of Infantry (SOI) training. Disc degeneration was graded at L5-S1. No changes in posture and disc degeneration were found throughout training. During load carriage the LS became less lordotic and the sacrum more horizontal. Marines with disc degeneration had larger sacral postural perturbations in response to load. Our findings suggest that the postural response to load is defined more by the task needs than by the physical condition of the Marine. Practitioner Summary: The effect of military training on lumbar spine posture is unknown. The lumbar posture of 27 Marines was measured from upright MR images, with and without load throughout infantry training. No changes in posture or IVD degeneration were found across training. Marines with degeneration at the L5-S1 level had larger sacral postural perturbations in response to load.

PHD/HIF-1 upregulates CA12 to protect against degenerative disc disease: a human sample, in vitro and ex vivo study.

Intervertebral disc degeneration is a major cause of low back pain. The nucleus pulposus (NP) is an important intervertebral disc component. Recent studies have shown that carbonic anhydrase 12 (CA12) is a novel NP marker. However, the mechanism by which CA12 is regulated and its physiological function are unclear. In our study, CA12, hypoxia-inducible factor 1α (HIF-1α) and HIF-2α expression levels were examined in 81 human degenerated NP samples using real-time RT-PCR, immunohistochemistry and western blot. Rat NP cells were cultured in a hypoxic environment, and hypoxia-induced CA12 expression was examined. Rat NP cells were treated with HIF-1α siRNA or the prolyl hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) to evaluate the role of PHD/HIF-1 in regulating CA12 expression. Rat NP cells were treated with CA12 siRNA to determine the function of CA12. A rat ex vivo model was established to confirm that PHD, HIF-1, and CA12 have important roles in disc degeneration. We found that CA12 was significantly downregulated in degenerated human NP samples at the mRNA and protein levels. CA12 expression sharply increased by ~30-fold in response to hypoxia. The expression of HIF-1α, but not HIF-2α, also decreased in degenerated human NP samples and was positively correlated with CA12 expression. HIF-1α knockdown under hypoxia reduced the CA12 mRNA and protein expression levels. DMOG treatment increased HIF-1α and CA12 expression. CA12 knockdown significantly inhibited anabolic protein expression, whereas catabolic enzymes remained unchanged. The ex vivo experiments supported our in vitro studies of the role of PHD/HIF-1/CA12. In conclusion, CA12 is downregulated in degenerated NPs, and its expression may be regulated by the PHD/HIF-1 axis. Decreased CA12 expression may lead to decreased extracellular matrix synthesis, which contributes to degenerative disc disease progression.

Lumbar disc degeneration is associated with modic change and high paraspinal fat content - a 3.0T magnetic resonance imaging study.

BACKGROUND: Degenerative disc disease of the lumbar spine is common, with severe disease increasing the risk for chronic low back pain. This cross-sectional study examined whether disc degeneration is representative of a 'whole-organ' pathology, by examining its association with bone (vertebral endplate) and soft tissue (paraspinal muscle fat) abnormalities. METHODS: Seventy-two community-based individuals unselected for low back pain, had Magnetic Resonance Imaging (MRI). Lumbosacral disc degeneration was determined via the Pfirrmann grading system, a validated method to assess the intervertebral disc, distinguishing the nucleus and annulus, the signal intensity and the height of the intervertebral disc. Modic change and high paraspinal muscle fat content was also measured from MRI. RESULTS: Severe disc degeneration was associated, or tended to be associated with type 2 Modic change from L2 to L5 (OR range 3.5 to 25.3, p ≤ 0.06). Moreover, severe disc degeneration at all intervertebral levels was associated with or tended to be associated with high fat content of the paraspinal muscles (OR range 3.7 to 14.3, p ≤ 0.09). CONCLUSION: These data demonstrate that disc degeneration of the lumbar spine is commonly accompanied by Modic change and high fat content of paraspinal muscles, thus representing a 'whole-organ' pathology. Longitudinal studies are required to determine the temporal relationship between these structural abnormalities. Understanding this may have the potential to identify novel targets for the treatment and prevention of lumbosacral disc degeneration.

The innovative viscoelastic CP ESP cervical disk prosthesis with six degrees of freedom: biomechanical concepts, development program and preliminary clinical experience.

The viscoelastic cervical disk prosthesis ESP is an innovative one-piece deformable but cohesive interbody spacer. It is an evolution of the LP ESP lumbar disk implanted since 2006. CP ESP provides six full degrees of freedom about the three axes including shock absorbtion. The prosthesis geometry allows limited rotation and translation with resistance to motion (elastic return property) aimed at avoiding overload of the posterior facets. The rotation center can vary freely during motion. The concept of the ESP prosthesis is fundamentally different from that of the devices currently used in the cervical spine. The originality of the concept of the ESP® prosthesis led to innovative and intense testing to validate the adhesion of the viscoelastic component of the disk on the titanium endplates and to assess the mechanical properties of the PCU cushion. The preliminary clinical and radiological results with 2-year follow-up are encouraging for pain, function and kinematic behavior (range of motion and evolution of the mean centers of rotation). In this series, we did not observe device-related specific complications, misalignment, instability or ossifications. Additional studies and longer patient follow-up are needed to assess long-term reliability of this innovative implant.