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The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-?) in thoracic ossification of the ligamentum flavum.

ABSTRACT: Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-? is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-? increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-? on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-? stimulation. To address the effect of TNF-? on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-?. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-? stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-?. TNF-? activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-? activation of Osx expression. This suggests that TNF-? activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-? involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx.

SUBMITTER: Zhang C

PROVIDER: S-EPMC5456390 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-α) in thoracic ossification of the ligamentum flavum.

Zhang Chi C Chen Zhongqiang Z Meng Xiangyu X Li Mengtao M Zhang Li L Huang Ann A

PloS one 20170602 6

Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein ...[more]

PMID: 28575129

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Project description:INTRODUCTION: Ossification of the ligamentum flavum (OLF) of the spine is associated with serious neurologic compromise, but the pathomechanism of this process remains unclear. The objective of this study was to investigate the pathomechanism of the ossification process, including the roles of various transcriptional factors in the ossification of human thoracic ligamentum flavum. METHODS: Sections of the thoracic ligamentum flavum were obtained from 31 patients with OLF who underwent posterior thoracic decompression, and from six control patients free of OLF. Cultured ligamentum flavum cells (n = 6, each) were examined with real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis for Sry-type high-mobility group box 9 (Sox9), runt-related transcription factor 2 (Runx2), muscle segment homeobox 2 (Msx2), Osterix, distal-less homeobox 5 (Dlx5), and AP-1. The harvested sections were examined with hematoxylin-eosin, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, and immunohistochemistry for the transcriptional factors. RESULTS: Compared with the control, the OLF showed disorganization of the elastic fiber bundles and abundant hypertrophic chondrocytes in the ossification front. TUNEL-positive chondrocytes were found near the ossified plaques. The mRNA expression levels of Sox9, Runx2, Msx2, and AP-1 in cultured cells from the ligamentum flavum of OLF patients were significantly different from those of the control. OLF samples were strongly immunoreactive to Sox9, Runx2, and Msx2 at proliferating chondrocytes in the fibrocartilage area. Hypertrophic chondrocytes were positive for Runx2, Osterix, Dlx5, and AP-1. CONCLUSIONS: The ossification process in OLF seems to involve chondrocyte differentiation under the unique expression of transcriptional factors. Accumulation of hypertrophic chondrocytes was evident around the calcified area at the ossification front, and we suggest that the differentiation of these cells seems to be concerned with the ossification process.

Project description:Background and Objectives: Ossification of the ligamentum flavum (OLF) is a relatively common cause of thoracic myelopathy. Surgical treatment is recommended for patients with myelopathy. Generally, open posterior decompression, with or without fusion, is selected to treat OLF. We performed minimally invasive posterior decompression using a microendoscope and investigated the efficacy of this approach in treating limited type of thoracic OLF. Materials and Methods: Microendoscopic posterior decompression was performed for 19 patients (15 men and four women) with thoracic OLF with myelopathy aged between 35 to 81 years (mean age, 61.9 years). Neurological examination and preoperative magnetic resonance imaging (MRI) and computed tomography (CT) were used to identify the location and morphology of OLF. The surgery was performed using a midline approach or a unilateral paramedian approach depending on whether the surgeon used a combination of a tubular retractor and endoscope. The numerical rating scale (NRS) and modified Japanese Orthopedic Association (mJOA) scores were compared pre- and postoperatively. Perioperative complications and the presence of other spine surgeries before and after thoracic OLF surgery were also investigated. Results: Four midline and 15 unilateral paramedian approaches were performed. The average operative time per level was 99 min, with minor blood loss. Nine patients had a history of cervical or lumbar spine surgery before or after thoracic spine surgery. The mean pre- and postoperative NRS scores were 6.6 and 5.3, respectively. The mean recovery rate as per the mJOA score was 33.1% (mean follow-up period, 17.8 months), the recovery rates were significantly different between patients who underwent thoracic spine surgery alone (50.5%) and patients who underwent additional spine surgeries (13.7%). Regarding adverse events, one patient experienced dural tear, another experienced postoperative hematoma, and one other underwent reoperation for adjacent thoracic stenosis. Conclusion: Microendoscopic posterior decompression was applicable in limited type of thoracic OLF surgery including beak-shaped type and multi vertebral levels. However, whole spine evaluation is important to avoid missing other combined stenoses that may affect outcomes.

Project description:Background Unforeseen dural ossification (DO) increases the risk of complications in the surgical management of thoracic ossification of the ligamentum flavum (OLF). Several methods have been proposed to identify DO; however, these approaches either have low diagnostic accuracy or poor feasibility. Therefore, we aimed to determine the relationship between DO and the severity and range of thoracic OLF compression using a 3-dimensional (3D) imaging analysis and to evaluate its superiority in diagnosing DO over conventional measurement methods. Methods A total of 114 consecutive patients who underwent decompressive laminectomy for thoracic OLF in 4 institutions were retrospectively enrolled and divided into DO and non-DO groups. Univariate analysis was performed to determine the relationship between OLF compression and DO. We measured the 3D occupying ratio (OR; 3D OR = OLF volume/normal canal volume × 100%), calculated its cutoff values, and compared its diagnostic value in DO with that of conventional 1D and 2D radiological parameters in the whole thoracic spine. Results The 3D OR in the DO group (50.9%±7.9%) was significantly higher than that in the non-DO group (30.8%±7.5%; P<0.01). The overall reliability and reproducibility for measurements of the 3D OR (intra- and interobserver correlation coefficients 0.94 and 0.90, respectively) were excellent. Thus, the 3D OR could be used as an indicator to distinguish between DO and non-DO, with high diagnostic accuracy (91.2%). Moreover, a 3D OR of >43%, known as the “ossification zone”, was indicative of DO in OLF, whereas a value of <37% was considered the “safe zone”. Additionally, the 3D OR [area under the curve (AUC) =0.98, 95% confidence interval (CI): 0.93–0.99] showed a statistically higher diagnostic value for DO in the upper, middle, lower, and whole thoracic spine than did both 1D (AUC =0.81; 95% CI: 0.73–0.88) and 2D (AUC =0.87; 95% CI: 0.79–0.92) parameters (P<0.01). Conclusions DO was significantly associated with the severity and range of OLF compression. The 3D OR could be used as a critical diagnostic indicator for identifying DO in the whole thoracic spine, owing to its superiority over conventional radiological parameters. Classification of the 3D OR could maximize the clinical feasibility and thus help surgeons to decrease the incidence of DO-related surgical complications.

Project description:BackgroundThe aim of the present study was to evaluate the curative effect and safety of thoracic full-endoscopic unilateral laminotomy with bilateral decompression (TE-ULBD) for treating ossification of the ligamentum flavum (OLF) with myelopathy.MethodsBetween January 2015 and December 2018, 23 consecutive patients with symptomatic thoracic OLF were treated with TE-ULBD. Of these, 21 (13 women and 8 men, aged 49-75 years) were included in the study and followed up for a minimum of 1 year. The mean blood loss was 15.48 mL (10-30 mL), operative duration was 78.86 min (55-115 min), and hospitalization was 5.05 days (3-15 days). The Japanese Orthopaedic Association (JOA) was used to evaluate spinal cord function, and the curative effect was defined by the JOA improvement rate. The area of OLF (AOLF), the maximum spinal cord compression (MSCC), and the area of spinal cord (ASC) were used to evaluate OLF clearance and spinal cord decompression status.ResultsAt the final follow up,the JOA score was 8.33 points (5-11 points), which was a significant improvement from the preoperative 5.33 points (3-9 points, P<0.01). The excellent and good rate was 76.19% (16/21). The average preoperative AOLF and AOLF ratio were 85.27±23.66 mm2 and 57.86%±11.86%, respectively, and the postoperative AOLF and AOLF ratio were 16.27±11.75 mm2 and 8.13%±5.38%, respectively. The MSCC increased from 27.99%±13.51% preoperatively to 48.02%±6.66% postoperatively. The ASC was 42.90±10.60 mm2 preoperatively and 64.54±21.36 mm2 postoperatively. There were statistically significant differences in all parameters preoperatively and postoperatively (P<0.01). One case had postoperative hematoma, and the symptoms gradually eased after 3 weeks of conservative treatment. There were no other complications. No recurrence of OLF was detected during the follow-up period.ConclusionsTE-ULBD is safe and effective for thoracic OLF with the advantages of reduced trauma and bleeding, and faster recovery.

Dataset Information

The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-?) in thoracic ossification of the ligamentum flavum.

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The involvement and possible mechanism of pro-inflammatory tumor necrosis factor alpha (TNF-α) in thoracic ossification of the ligamentum flavum.

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