The involvement of immune system in intervertebral disc herniation and degeneration.

Intervertebral disc (IVD) herniation and degeneration contributes significantly to low back pain (LBP), of which the molecular pathogenesis is not fully understood. Disc herniation may cause LBP and radicular pain, but not all LBP patients have disc herniation. Degenerated discs could be the source of pain, but not all degenerated discs are symptomatic. We previously found that disc degeneration and herniation accompanied by inflammation. We further found that anti-inflammatory molecules blocked immune responses, alleviated IVD degeneration and pain. Based on our recent findings and the work of others, we hypothesize that immune system may play a prominent role in the production of disc herniation or disc degeneration associated pain. While the nucleus pulposus (NP) is an immune-privileged organ, the damage of the physical barrier between NP and systemic circulation, or the innervation and vascularization of the degenerated NP, on one hand exposes NP as a foreign antigen to immune system, and on the other hand presents compression on the nerve root or dorsal root ganglion (DRG), which both elicit immune responses induced by immune cells and their mediators. The inflammation can remain for a long time at remote distance, with various types of cytokines and immune cells involved in this pain-inducing process. In this review, we aim to revisit the autoimmunity of the NP, immune cell infiltration after break of physical barrier, the inflammatory activities in the DRG and the generation of pain. We also summarize the involvement of immune system, including immune cells and cytokines, in degenerated or herniated IVDs and affected DRG.

TNF-α suppresses SHOX2 expression via NF-κB signaling pathway and promotes intervertebral disc degeneration and related pain in a rat model.

This study was conducted to verify the relative expression patterns of SHOX2 and its regulation by tumor necrosis factor alpha (TNF-α) during the development of intervertebral disc degeneration (IVDD). A rat disc-degeneration model was subjected to disc puncture (DP) and intradiscal injections with TNF-α to determine the roles of TNF-α and SHOX2 expression in IVDD in vivo. TNF-α and SHOX2 expression patterns in different degenerative rat nucleus pulposus (NP) tissues were measured by immunohistochemistry (IHC). The effects of TNF-α on IVDD were determined by magnetic resonance imaging (MRI) and pain development of wet-dog shakes (WDS) were blinded assessment by pain-behavior testing, respectively. Changes in TNF-α on SHOX2 expression were measured by Western blot analysis and real-time reverse transcription polymerase chain reaction (RT-PCR). The roles of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) in TNF-α-mediated SHOX2 activation were studied using viral transfection, Western blot analysis, and real-time RT-PCR. In vivo, TNF-α accelerated the process of IVDD and suppressed SHOX2 expression; compared to the DP group, WDS was significantly increased in TNF-α intradiscal injection group at 2 to 6 weeks after puncture (P < .05); In NP cells, TNF-α negatively affected the IVDD-associated SHOX2 suppression. While TNF-α promotes IVDD through activation of both MAPK and NF-κB signaling, it seemed that only NF-κB signaling controlled the TNF-α-mediated SHOX2 suppression that is associated with IVDD. The results of this study indicated that TNF-α inhibits SHOX2 expression and has promoted effects on IVDD in the rat model, and these effects might be associated with through NF-κB signaling pathway and promotes IVDD and related pain in a rat model.

Risk Factors Associated with Pain Severity in Patients with Non-specific Low Back Pain in Southern China.

STUDY DESIGN: A prospective cross-sectional study. PURPOSE: To evaluate the risk factors associated with the severity of pain intensity in patients with non-specific low back pain (NSLBP) in Southern China. OVERVIEW OF LITERATURE: Low back pain (LBP) is the leading cause of activity limitation and work absence throughout the world, so a firm understanding of the risk factor associated with NSLBP can provide early and prompt interventions that are aimed at attaining long-term results. METHODS: Participants were recruited from January 2014 to January 2016 and were surveyed using a self-designed questionnaire. Anonymous assessments included Short Form 36-Item Health Survey (SF-36) and Visual Analogue Scale (VAS). The association between the severity of NSLBP and these potential risk factors were evaluated. RESULTS: A total of 1,046 NSLBP patients were enrolled. The patients with primary school education, high body mass index (BMI), those exposed to sustained durations of driving and sitting, smoking, recurrent LBP had increased VAS and Oswestry Disability Index (ODI) scores with lower SF-36 scores (p <0.01). Workers and drivers compared with waiters and patients who lifted >10 kg objects in a quarter of their work time for >10 years had higher VAS and ODI scores with lower SF-36 scores (p <0.01). Multiple logistic regression showed lower levels of education, LBP for 1-7 days, long-lasting LBP in last year, smoking, long duration driving, and higher BMI were associated with more severe VAS score. CONCLUSIONS: The severity of NSLBP is associated with lower levels of education, poor standards of living, heavy physical labor, long duration driving, and sedentary lifestyle. Patients with recurrent NSLBP have more severe pain. Reducing rates of obesity, the duration of heavy physical work, driving or riding, and attenuating the prevalence of sedentary lifestyles and smoking may reduce the prevalence of NSLBP.

Comparison of the use of rhBMP-7 versus iliac crest autograft in single-level lumbar fusion: a meta-analysis of randomized controlled trials.

The aim of this study was to evaluate the safety and clinical effectiveness of rhBMP-7 (or osteogenic protein-1) versus that of autogenous iliac crest bone graft (ICBG) in single-level posterolateral fusion (PLF) of the lumbar spine. A systematic search of all articles published through July 1, 2016 was conducted in databases such as PubMed, EMBASE, Scopus, and the Cochrane Collaboration Library. Randomized controlled trials (RCTs) that compared rhBMP-7 with ICBG for the treatment of single-level degenerative spondylolisthesis, provided the fusion rate, clinical success rate, safety and adverse events report, operation time, and hospital stay durations as the outcome were assessed. As a result, a total of five RCTs involving 539 patients met the inclusion criteria. The outcomes of subgroup analysis demonstrated that when compared with autogenous ICBG, rhBMP-7 appear to yield lower fusion rates in instrumented posterolateral fusion patients (RR = 0.76, 95% CI [0.60, 0.98], P = 0.03), despite the test for overall fusion rates suggested that there was no significant difference between the two groups (RR = 0.89, 95% CI [0.78, 1.02], P = 0.09). Patients treated with OP-1 had shorter operation times versus those treated with ICBG (WMD = -16.70,95% CI [-25.83, -7.57], P = 0.0003). Additionally, the outcomes demonstrated a lack of significant differences between rhBMP-7 and ICBG in terms of clinical success of ODI, overall adverse events, revision rates and duration of hospitalization. In conclusion, with the exception of reducing the operation time, our review suggests that the use of the rhBMP-7 instead of ICBG produce no any additional beneficial effect on the fusion rates, clinical success of ODI, overall adverse events, revision rates and duration of hospitalization in single level PLF. On the contrary, it appeared to yield lower fusion rate in the instrumented posterolateral fusion patients and cannot be recommended as an effective tool for this set of patients.

Systemic Administration of Exosomes Released from Mesenchymal Stromal Cells Attenuates Apoptosis, Inflammation, and Promotes Angiogenesis after Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is one of the most common devastating injuries, which causes permanent disabilities such as paralysis and loss of movement or sensation. The precise pathogenic mechanisms of the disease remain unclear, and, as of yet, there is no effective cure. Mesenchymal stem cells (MSCs) show promise as an effective therapy in the experimental models of SCI. MSCs secrete various factors that can modulate a hostile environment, which is called the paracrine effect. Among these paracrine molecules, exosome is considered to be the most valuable therapeutic factor. Thus, exosomes from MSCs (MSCs-exosomes) can be a potential candidate of therapeutic effects of stem cells. The present study was designed to investigate the effect of whether systemic administration of exosomes generated from MSCs can promote the function recovery on the rat model of SCI in vivo. In the present study, we observed that systemic administration of MSCs-exosomes significantly attenuated lesion size and improved functional recovery post-SCI. Additionally, MSCs-exosomes treatment attenuated cellular apoptosis and inflammation in the injured spinal cord. Expression levels of proapoptotic protein (Bcl-2-associated X protein) and proinflammatory cytokines (tumor necrosis factor alpha and interleukin [IL]-1ß) were significantly decreased after MSCs-exosomes treatment, whereas expression levels of antiapoptotic (B-cell lymphoma 2) and anti-inflammatory (IL-10) proteins were upregulated. Further, administration of MSCs-exosomes significantly promoted angiogenesis. These results show, for the first time, that systemic administration of MSCs-exosomes attenuated cell apoptosis and inflammation, promoted angiogenesis, and promoted functional recovery post-SCI, suggesting that MSCs-exosomes hold promise as a novel therapeutic strategy for treating SCI.

Role of SHOX2 in the development of intervertebral disc degeneration.

Intervertebral disc (IVD) degeneration is the most common cause of low back pain, which affect 80% of the population during their lives, with heavy economic burden. Many factors have been demonstrated to participate in IVD degeneration. In this study, we investigated the role of short stature homeobox 2 (SHOX2) in the development of IVD degeneration. First, we detected the expression of SHOX2 in different stages of human IVD degeneration; then explored the role of SHOX2 on nucleus pulposus (NP) cells proliferation and apoptosis, finally we evaluated the effect of SHOX2 on the production of extracellular matrix in NP cells. Results showed that the expression of SHOX2 is mainly in NP compared with AF tissues, its expression decreased with the severity of human IVD degeneration. TNF-α treatment led to dose- and time-dependent decrease in SHOX2 mRNA, protein expression and promoter activity in NP cells. The silencing of SHOX2 inhibited NP cells proliferation and induced NP cells apoptosis. Finally, SHOX2 silencing led to decreased aggrecan and collagen II expression, along with increased ECM degrading enzymes MMP3 and ADAMTS-5 in NP cells. In summary, our results indicated that SHOX2 plays an important role in the process of IVD degeneration, and might be a protective factor for IVD degeneration. Further studies are required to confirm its exact role, and clarify the mechanism. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1047-1057, 2017.

Comparison of Percutaneous Vertebroplasty and Balloon Kyphoplasty for the Treatment of Single Level Vertebral Compression Fractures: A Meta-analysis of the Literature.

BACKGROUND: Percutaneous vertebroplasty (PVP) and percutaneous balloon kyphoplasty (PKP) can increase bone strength as well as alleviate the pain caused by vertebral compression fractures (VCFs), and both procedures rely on polymethyl methacrylate (PMMA) cement injected into the fractured vertebra for mechanical stabilization of the VCFs. However, there is debate over which of these 2 surgical procedures can give better short-term and long-term outcomes. A lot of studies and meta-analysis were designed to assess the advantages and drawbacks of PKP and PVP in the treatment of VCFs, but most of them didn't consider the effect of VCF levels on the treatment outcome, which can influence the results. OBJECTIVE: To assess the safety and efficacy of PKP compared to PVP in the treatment of single level osteoporotic vertebral compression fractures (OVCF). STUDY DESIGN: Studies with the following criteria were included: patients with VCFs due to osteoporosis; PKP comparing PVP; study design, RCT or prospective or retrospective comparative studies. Furthermore, the studies which reported at least one of the following outcomes: subjective pain perception, quality of life evaluation, incidence of new adjacent vertebral fracture, bone cement leakage, and post-operative kyphotic angle. Articles were excluded in our meta-analysis if they had a neoplastic etiology (i.e., metastasis or myeloma), infection, neural compression, traumatic fracture, neurological deficit, spinal stenosis, severe degenerative diseases of the spine, previous surgery at the involved vertebral body, and PKP or PVP with other invasive or semi-invasive intervention treatment. SETTING: University hospital. METHODS: A systematic search of all articles published through May 2014 was performed by Medline, EMASE, OVID, and other databases. All the articles that compared PKP with PVP on single level OVCF were identified. The evidence quality levels of the selected articles were evaluated by Grade system. Data about the clinical outcomes and complications were extracted and analyzed. RESULTS: Eight studies, encompassing 845 patients, met the inclusion criteria. Overall, the results indicated that there were significant differences between the 2 groups in the short-term visual analog scale (VAS) scores, the long-term Oswestry Disability Index (ODI), short- and long-term kyphosis angle, the kyphosis angle improvement, the injected cement, and the cement leakage rates. However, there were no significant differences in the long-term VAS scores, the short-term ODI scores, the short- and long-term SF-36 scores, or the adjacent-level fracture rates. LIMITATIONS: Statistical efficacy can be improved by more studies, low evidence based non-RCT articles are likely to induce various types of bias, no accurate definition of short-term and long-term outcome time points. CONCLUSION: PKP and PVP are both safe and effective surgical procedures in treating OVCF. PKP has a similar long-term pain relief, function outcome (short-term ODI scores, short-and long-term SF-36 scores), and new adjacent VCFs in comparison to PVP. PKP is superior to PVP for the injected cement volume, the short-term pain relief, the improvement of short- and long-term kyphotic angle, and lower cement leakage rate. However, PKP has a longer operation time and higher material cost than PVP. To confirm this evaluation, a large multi-center randomized controlled trial (RCT) should be conducted.

Comparison of pullout strength of the thoracic pedicle screw between intrapedicular and extrapedicular technique: a meta-analysis and literature review.

BACKGROUND: Intrapedicular fixation in thoracic spine is often limited, because of high risk of complication, especially in scoliosis patients. Extrapedicular screws fixation techniques provide an alternate solution for extremely small or abnormal thoracic pedicles deformity. However, the pullout resistance of extrapedicular screws has not been clearly defined. The aim of our study was to systematically review the existing evidence regarding the pullout resistance of thoracic extrapedicular screws compared with intrapedicular screws. METHODS: A systematic search of all studies published through Nov 2014 was performed using Medline, EMBASE, OVID and other databases. All studies that compared the pullout resistance of thoracic extrapedicular screws with intrapedicular screws were selected. The data from the included studies were extracted and analyzed regarding pullout resistance force. Forest plots were constructed to summarize the data and compare the biomechanical stability achieved. RESULTS: Five studies were included, with a total of 27 cadaveric specimens and 313 screws. The vertebral levels of the cadavers potted were T1-T8, T2-T12, T7-T9, T6-T11 and T4-T12 respectively. Overall, the results demonstrated that there was no significant difference in ultimate pullout strength between intrapedicular screws and extrapedicular screws (95% CI=-63.73 to 27.74; P=0.44); extrapedicular screws significantly increased the length of placements by a mean of 6.24 mm (95% CI=5.38 to 7.10; P<0.001); while the stiffness in intrapedicular screws was significantly stronger by a mean of 45.82 N/mm compared with extrapedicular screws (95% CI=-70.09 to -21.56; P<0.001). CONCLUSIONS: Meta-analysis of the existing literature showed that thoracic extrapedicular screws provided comparable but slightly lower pullout strength compared with intrapedicular screws, extrapedicular screws placement is much safer than intrapedicular screws. So thoracic extrapedicular screws offer a good alternative when it is hard to insert by intrapedicular approach, especially in scoliosis patients with severe vertebral deformities.

[Radiological factors influencing pulmonary function test in severe spinal deformity].

OBJECTIVE: To investigate the pulmonary dysfunction patterns in severe spinal deformity and to identify radiological factors affecting the pulmonary function. METHODS: From September 2009 to December 2014, a total of 66 patients were involved in this Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University. Preoperative pulmonary function testing (PFTs) and radiographic examination were performed on all of the involved patients. Correlation analysis and subsequent stepwise multiple regression analysis were carried out to assess the associations between radiographic measurements of deformity and the results of pulmonary function testing. RESULTS: Fifty-seven out of 66 patients had impaired pulmonary dysfunction, and more than half of were ≤59% predicted forced expiratory volume in 1 second (FEV1). Most of the patients with severe spinal deformity demonstrated a restrictive pattern of pulmonary function. The magnitude of the major curve, the number of involved thoracic vertebrae had significant effect on pulmonary function. While these 2 factors were associated with an increased risk of pulmonary impairment, they explained only 46.2%-55.1% of the observed variability in vital capacity, forced vital capacity, and forced expiratory volume in one second. CONCLUSIONS: Preoperative PFTs are clinically impaired in 86% of patients with severe spinal deformity, and more than half of that were moderate and severe pulmonary dysfunction. The magnitude of the major curve and the number of involved thoracic vertebrae are the main risk factors influencing the pulmonary dysfunction.