Severe Intervertebral Disc Degeneration Research Articles

Propionibacterium acnes Induces Intervertebral Disc Degeneration by Promoting iNOS/NO and COX-2/PGE2 Activation via the ROS-Dependent NF-κB Pathway.

Accumulating evidence suggests that Propionibacterium acnes (P. acnes) is a novel pathogenic factor promoting intervertebral disc degeneration (IVDD). However, the underlying mechanisms by which P. acnes induces IVDD have been unclear. In this study, we quantified the severity of IVDD, as well as the expressions of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase (COX-2)/prostaglandin (PGE2) in human intervertebral discs (IVDs) infected with P. acnes. Compared with P. acnes-negative IVDs, P. acnes-positive IVDs showed increased iNOS/NO and COX-2/PGE2 activity concomitant with more severe IVDD. In order to detect the potential correlation between iNOS/NO expression, COX-2/PGE2 expression, and IVDD, we developed a P. acnes-induced IVDD rat model and found that the upregulation of iNOS/NO and COX-2/PGE2 was essential to the occurrence of P. acnes-induced IVDD. This finding was supported by the fact that the inhibition of iNOS/NO and COX-2/PGE2 activity ameliorated IVDD significantly, as evidenced by restored aggrecan and collagen II expression both in vivo and in vitro. Mechanistically, we found that P. acnes induced iNOS/NO and COX-2/PGE2 expressions via a reactive oxygen species- (ROS-) dependent NF-κB cascade. Furthermore, NADPH oxidase participated in P. acnes-induced ROS, iNOS/NO, and COX-2/PGE2 expressions. Overall, these findings further validated the involvement of P. acnes in the pathology of IVDD and provided evidence that P. acnes-induced iNOS/NO and COX-2/PGE2 activation via the ROS-dependent NF-κB pathway is likely responsible for the pathology of IVDD.

Association of COL1A1 rs1800012 polymorphism with musculoskeletal degenerative diseases: a meta-analysis.

It has been reported that the single nucleotide polymorphism (SNP) rs1800012 in COL1A1 gene might be linked to the susceptibility of musculoskeletal degenerative diseases, such as osteoarthritis (OA) and intervertebral disc degeneration (IVDD). However, the data from different studies is contradictory. Here we aimed to comprehensively summarize and clarify the relationship between the SNP and musculoskeletal degenerative diseases. Seven eligible studies including 1339 cases and 5406 controls were screened out from PubMed, Web Of Science and Cochrane library databases. Significant association was identified in sub group analysis of IVDD in homozygote model (GG versus TT: OR = 0.33, 95% CI 0.14–0.78, P = 0.012), heterozygote model (GT versus TT: OR = 0.29, 95% CI 0.11–0.72, P = 0.008) and dominant model (GG/GT versus TT: OR = 0.31, 95% CI 0.13–0.74, P = 0.008). Additionally, significant relationship was also found in sub group analysis of severe degree of IVDD in homozygote model (GG versus TT: OR = 0.37, 95% CI 0.15–0.91, P = 0.031), heterozygote model (GT versus TT: OR = 0.33, 95% CI 0.13–0.87,P = 0.024) and dominant model (GG/GT versus TT: OR = 0.36, 95% CI 0.14–0.88, P = 0.025). Although no significance was observed, there is a trend that the more G allele at COL1A1 rs1800012 site, the less possibility of IVDD and severe IVDD would happen. Our results indicate that COL1A1 rs1800012 polymorphism associates with the susceptibility of IVDD. However, this polymorphism may not be associated with OA risk.

Comparison of Adjacent Segment Degeneration After Nonrigid Fixation System and Posterior Lumbar Interbody Fusion for Single-Level Lumbar Disc Herniation: A New Method of MRI Analysis of Lumbar Nucleus Pulposus Volume

ABSTRACTPurpose: To evaluate the influence of a nonrigid fixation system and posterior lumbar interbody fusion on adjacent intervertebral disc degeneration by using MRI analysis of lumbar nucleus pulposus volume for single-level lumbar disc herniation. Materials and Methods: We selected 112 patients who underwent nonrigid fixation (17 men and 44 women) or posterior lumbar interbody fusion (13 men and 38 women) for this retrospective study. Based on the T2-weighted magnetic resonance imaging (MRI) scans taken preoperatively, and 6, 12, and 24 months after surgery, the nucleus pulposus in the upper segments of the operated level was considered an ellipsoid, and their volumes were measured respectively and then compared between the two groups. Results: The posterior lumbar interbody fusion group had significantly lower lumbar nucleus pulposus volume than the nonrigid fixation group at 12 (4.04 ± 1.42 vs. 5.25 ± 1.47 mm3) and 24 months (4.16 ± 0.89 vs. 5.06 ± 1.23 mm3), and had the highest nucleus pulposus. Meanwhile, the h value in the posterior lumbar interbody fusion group was notably smaller than the preoperative level at 12 (0.46 ± 0.03 vs. 0.55 ± 0.05 mm) and 24 months (0.44 ± 0.03 vs. 0.55 ± 0.05 mm). Conclusions: MRI analysis of lumbar nucleus pulposus volume is a new and quantitative method of analysis, which is a considerable method and contributes to the detection of severe intervertebral disc degeneration. Based on this new method, nonrigid fixation demonstrates excellent outcomes on the adjacent segment in comparison with posterior lumbar interbody fusion.

Inflammatory microRNA-194 and -515 attenuate the biosynthesis of chondroitin sulfate during human intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is characterized by dehydration and loss of extracellular matrixes in the nucleus pulposus region. Chondroitin sulfate has been found to be the water-binding molecule that played a key role in IDD. Although investigators have reported that inflammatory cytokines are involved in the reduction of chondroitin sulfate in IDD, but the underlying mechanism is unrevealed. Since chondroitin sulfate synthesis is controlled by chondroitin sulfate glycosyltransferases CHSY-1/2/3 and CSGALNACT-1/2, their functional role and regulatory mechanism in IDD is not fully studied. Here, we set out to investigate the function and regulatory roles of these factors during IDD development. We found that among these chondroitin sulfate glycosyltransferases, CHSY-1/2/3 are significantly down-regulated in severe IDD samples than mild IDD samples. In vitro experiments revealed that Interleukin-1β and Tumor Necrosis Factor-α stimulation led to significant reduction of CHSY-1/2/3 at protein level than mRNA level in NP cells, indicating a post-transcriptional regulatory mechanisms are involved. By computational prediction and analysis, we found that inflammatory cytokines stimulated microRNA-194 and -515 target CHSY-1/2/3 mRNA and significantly interrupt their translation and downstream chondroitin sulfate deposition. Inhibition of microRNA-194 and -515 however, significantly rescued CHSY-1/2/3 expressions and chondroitin sulfate deposition. These findings together demonstrated a vital role of inflammatory stimulated microRNAs in promoting intervertebral disc degeneration by interrupt chondroitin sulfate synthesis, which may provide new insights into the mechanism and therapeutic approaches in IDD.

Biocompatibility and intradiscal application of a thermoreversible celecoxib-loaded poly-N-isopropylacrylamide MgFe-layered double hydroxide hydrogel in a canine model.

IntroductionChronic low back pain due to intervertebral disc (IVD) degeneration is associated with increased levels of inflammatory mediators. Current medical treatment consists of oral anti-inflammatory drugs to alleviate pain. In this study, the efficacy and safety of a novel thermoreversible poly-N-isopropylacrylamide MgFe-layered double hydroxide (pNIPAAM MgFe-LDH) hydrogel was evaluated for intradiscal controlled delivery of the selective cyclooxygenase (COX) 2 inhibitor and anti-inflammatory drug celecoxib (CXB).MethodsDegradation, release behavior, and the ability of a CXB-loaded pNIPAAM MgFe-LDH hydrogel to suppress prostaglandin E2 (PGE2) levels in a controlled manner in the presence of a proinflammatory stimulus (TNF-α) were evaluated in vitro. Biocompatibility was evaluated histologically after subcutaneous injection in mice. Safety of intradiscal application of the loaded and unloaded hydrogels was studied in a canine model of spontaneous mild IVD degeneration by histological, biomolecular, and biochemical evaluation. After the hydrogel was shown to be biocompatible and safe, an in vivo dose–response study was performed in order to determine safety and efficacy of the pNIPAAM MgFe-LDH hydrogel for intradiscal controlled delivery of CXB.ResultsCXB release correlated to hydrogel degradation in vitro. Furthermore, controlled release from CXB-loaded hydrogels was demonstrated to suppress PGE2 levels in the presence of TNF-α. The hydrogel was shown to exhibit a good biocompatibility upon subcutaneous injection in mice. Upon intradiscal injection in a canine model, the hydrogel exhibited excellent biocompatibility based on histological evaluation of the treated IVDs. Gene expression and biochemical analyses supported the finding that no substantial negative effects of the hydrogel were observed. Safety of application was further confirmed by the absence of clinical symptoms, IVD herniation or progression of degeneration. Controlled release of CXB resulted in a nonsignificant maximal inhibition (approximately 35 %) of PGE2 levels in the mildly degenerated canine IVDs.ConclusionsIn conclusion, this study showed biocompatibility and safe intradiscal application of an MgFe LDH-pNIPAAM hydrogel. Controlled release of CXB resulted in only limited inhibition of PGE2 in this model with mild IVD degeneration, and further studies should concentrate on application of controlled release from this type of hydrogel in animal models with more severe IVD degeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0727-x) contains supplementary material, which is available to authorized users.

Expression profiles of MMP-1 and TIMP-1 in lumbar intervertebral disc degeneration.

Lumbar intervertebral disc degeneration (IDD) is a common clinical pathology and has become a focus for research in recent years. Matrix metalloproteinases (MMPs) are enzymes responsible for the degradation of almost all extracellular matrix proteins (ECM). The over-expression of MMPs or tissue inhibitors of metalloproteinases (TIMPs) may disrupt the dynamic balance of the ECM. Therefore, in the current study, the expression levels of MMP-1 and TIMP-1 in lumbar IDD patients were evaluated in an attempt to elucidate their role in IDD pathogenesis and progression. In total, 60 IDD patients were recruited as the experimental group, along with 20 cases of lumbar vertebral injury without disc degeneration as the control group. Preoperative venous blood samples were collected, and intervertebral disc tissues were collected from the lesion during surgery. Serum and tissue levels of MMP-1 and TIMP-1 were quantified by enzyme-linked immunosorbent assay and immunohistochemical staining, respectively. Serum and tissue MMP-1 levels in IDD patients were significantly higher than those in the control group (P < 0.05). Additionally, sub-group analysis revealed that severe IDD patients had higher MMP-1 levels compared with mild or moderate IDD patients (P < 0.05). However, there were no significant differences in TIMP- 1 levels in either the serum or tissues of IDD patients compared to patients in the control group (P > 0.05). These results demonstrate that MMP-1 expression is increased in IDD, with higher expression observed in more severe cases, whereas TIMP-1 expression was similarly expressed in both normal and degenerated discs.

Intervertebral disc disease in Dachshunds radiographically screened for intervertebral disc calcifications.

BackgroundIntervertebral disc disease (IDD) is a very common neurological disease, Dachshunds being the breed most often affected. In this breed, IDD has a hereditary background and is associated with intervertebral disc calcification (IDC), an indicator of severe intervertebral disc degeneration. In Finland, spinal radiography is used, when screening for IDC before breeding Dachshunds. We evaluated the association between IDC and IDD in Finnish Dachshunds radiographically screened for IDC.A questionnaire was sent to owners of 193 radiographically screened Dachshunds aged at least ten years. Clinical signs indicative of IDD were compared with IDC grade (grade 0 = no calcifications, grade 1 = 1 – 2 calcifications, grade 2 = 3 – 4 calcifications and grade 3 = 5 or more calcifications) and with age at the time of the radiographic examination. The diagnosis of IDD was confirmed by a veterinarian.ResultsIDD was common in the study population with 31% of dogs being affected. IDD and IDC were clearly connected (P < 0.001); IDD was rare in dogs with no calcifications (grade 0) and common in dogs with severe IDC (grade 3). The IDC grade was strongly positively associated with frequency of back pain periods (P < 0.001), and dogs with IDC grade 3 had frequent periods of pain. Reluctance to jump onto a sofa had a strong positive association with back pain. No association existed between age of the dog at the time of the radiographic examination and clinical signs indicative of IDD.ConclusionsRadiographically detected IDC and IDD are common in Finnish Dachshunds and are strongly associated with one another. Spinal radiography is an appropriate screening tool for breeders attempting to diminish IDC and IDD in Dachshunds. A breeding program that screens dogs and selects against IDC can be expected to reduce the occurrence of IDD in future. Twenty-four to 48 months of age is a suitable age for screening.Electronic supplementary materialThe online version of this article (doi:10.1186/s13028-014-0089-4) contains supplementary material, which is available to authorized users.

Interference in the endplate nutritional pathway causes intervertebral disc degeneration in an immature porcine model

Previous studies have shown that blocking the endplate nutritional pathway with bone cement did not result in obvious intervertebral disc degeneration (IDD) in mature animal models. However, there are very few comparable studies in immature animal models. As vertebroplasty currently is beginning to be applied in young, even biologically immature patients, it is important to investigate the effect of cement blocking at the endplate in an immature animal model. Two lumbar intervertebral discs in eight immature pigs were either blocked by cement in both endplate pathways or stabbed with a scalpel in the annulus fibrosus (AF) as a positive control, and with a third disc remaining intact as a normal control. Magnetic resonance imaging (MRI) and histology study were performed. After three months, the cement-blocked discs exhibited severe IDD, with the percentage of disc-height index (DHI), nucleus pulposus (NP) area, and NP T2 value significantly lower than the normal control. These IDD changes were histologically confirmed. Post-contrast MRI showed diseased nutritional diffusion patterns in the cement-blocked discs. Moreover, the degenerative changes of the cement-blocked discs exceeded those of the injured AF positive controls. The endplate nutritional pathway was interfered with and diseased after three months of bone cement intervention in an immature porcine model. Severe interference in the endplate nutritional pathway in an immature porcine model caused IDD. These findings also draw attention to the fact that interference in endplate nutritional pathways in immature or young patients may affect the vitality of adjacent discs.

Effect of intervertebral disc degeneration on biomechanical behaviors of a lumbar motion segment under physiological loading conditions

The consideration of biomechanical alterations due to intervertebral disc (IVD) degeneration is crucial for the accurate analysis of spine biomechanics. In this study, finite element (FE) models of the L4-L5 motion segment with full coverage of the degeneration grades from healthy IVD to severe degeneration were developed. The effects of IVD degeneration on spine biomechanics were analyzed under physiological loading conditions using compressive forces and bending moments. The FE models of all degeneration grades were consistent with published data in terms of the ranges of motion. Severe IVD degeneration showed lower inter-segmental rotations in flexion-extension and lateral bending, lower intradiscal pressure in all motions, higher facet joint forces in lateral bending and axial rotation, and higher von-Mises stress in annulus ground substance in all motions versus the healthy IVD. These findings could provide fundamental information for understanding the characteristics of the biomechanical behaviors of degenerated lumbar motion segments.