The Evaluation and Observation of "Hidden" Hypertrophy of Cervical Ligamentum Flavum, Cervical Canal, and Related Factors Using Kinetic Magnetic Resonance Imaging.
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ABSTRACT:
SUBMITTER: Zeng C
PROVIDER: S-EPMC4771510 | biostudies-other | 2016 Mar
REPOSITORIES: biostudies-other
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Project description:The purpose of this article is to quantify changes in thickness of the ligamentum flavum (LF) associated with motion of the cervical spine and to compare the thickness of the LF at each cervical level using kinetic magnetic resonance imaging (kMRI). Two hundred fifty-seven symptomatic patients (129 men; 128 women) underwent kMRI in neutral, flexion, and extension positions. Midsagittal images were digitally marked and electronically analyzed by spine surgeons. Thickness of LF in the cervical region from C2-3 to C7-T1 was measured in all three positions. LF at C7-T1 was significantly thicker than C2-3 to C6-7 in neutral, flexion, and extension positions (p < 0.05). LF was significantly thicker in extension than in flexion at C3-4 to C6-7. LF thickness increases with extension and decreases with flexion. LF is uniquely thick at C6-7 and at C7-T1 in the extension position, which may predispose these levels to cord compression syndromes and associated neuropathies.
| S-EPMC3854599 | biostudies-other
Project description:ObjectiveTo study the distribution of sympathetic nerves of the ligamentum flavum (LF), confirm its existence by histological observation and nuclear magnetic resonance spectroscopy, and analyze the relationship between sympathetic nerve fibers and the biomechanical structure of the LF.MethodsRandomly controlled scientific research selected 15 cases of posterior surgery in the affiliated hospital of Qingdao University from January 2013 to December 2019. The average age was 67.5 ± 14.5 years old, eight males and seven females. The LF specimens (completely separated fresh tissue) of different segments (C3-7 ) were taken during the operation. Two pages of LF specimens on the left and right sides of the same segment are randomly allocated by the pairing method for formalin fixation and cryopreservation in liquid nitrogen. LF specimens extracted from seven other adult cadaver specimens (average age at death of about 56.8 ± 4.0 years, three males and four females) were used as a control group; together with formalin- fixed specimens obtained during surgery, 3D slices were given layer by layer. The distribution of sympathetic nerves in different parts of the LF was analyzed by glyoxylic acid-induced biological monoamine fluorescent technique (SPG) and hematoxylin-eosin (HE) staining. Fifteen liquid nitrogen storage specimens were divided into the back of the LF and the spinal canal through frozen sections, and were analyzed by nuclear magnetic resonance spectroscopy-hydrogen spectrum (1 H -NMR) for neurotransmitters and neurometabolites.ResultsThere were type C sympathetic nerve fibers in the LF, which were divided into linear shape (α) and wave shape (β). Experimental group (χ2 = 1.705, P > 0.05) and control group (χ2 = 0.879, P > 0.05) can detect no difference in fluorescence units. Nerve fiber transmitter metabolites choline (Cho), creator (Cr), γ-aminobutyric acid (GABA) also indicate that the sympathetic nerve is present in the LF. LF sympathetic nerve fibers were mainly distributed in the proximal spinal canal surface, nerve fibers on the medial belt (area II) were fewer than the lateral belt (area I) (W = 210, P < 0.05). The 1 HNMR spectrum of LF spinal canal PG / Cho (t = 8.721, P < 0.05), GABA (t = 16.01, P < 0.05) value increased, lactic acid (Lac) / Cr (t = 4.213, P < 0.05), Cho / Cr (t = 2.402, P < 0.05) value decreased, indicating that nerve fibers are actively metabolized on the surface of the spinal canal, mainly distributed in tube surface. βtype fibers were more often distributed around microvessels. A small amount of α type fibers went next to the vascular structures, while α type fibers and β type fibers go cross within LF. Two patients with vertebral artery dissection had no recurrence of sympathetic symptoms within a total of 12 follow-ups 2 years after discharge.ConclusionsThere are many sympathetic nerve fibers distributed on LF, and their distribution may be correlated with histological and mechanical characteristics of LF. It may also be the anatomical basis of cervical vertigo.
| S-EPMC7767696 | biostudies-literature
Project description:Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.
| S-EPMC5217959 | biostudies-literature
Project description:Ligamentum flavum hypertrophy (HLF) is the most important component of lumbar spinal canal stenosis (LSCS). Analysis of hypertrophied ligamentum flavum (HLF) samples from patients with LSCS can be an important que. The current study analyzed the surgical samples of HLF samples in patients with LCSC using quantitative and qualitative high performance-liquid chromatography and mass spectrometry. We collected ligamentum flavum (LF) tissue from twelve patients with LSCS and from four patients with lumbar disk herniation (LDH). We defined LF from LSCS patients as HLF and that from LDH patients as non-hypertrophied ligamentum flavum (NHLF). Total lipids were extracted from the LF samples and evaluated for quantity and quality using liquid chromatography and mass spectrometry. The total lipid amount of the HLF group was 3.6 times higher than that of the NHLF group. Phosphatidylcholines (PCs), ceramides (Cers), O-acyl-ω-hydroxy fatty acids (OAHFAs), and triglycerides (TGs) in the HLF group were more than 32 times higher than those of the NHLF group. PC(26:0)+H+, PC(25:0)+H+, and PC(23:0)+H+ increased in all patients in the HLF group compared to the NHLF group. The thickness of the LF correlated significantly with PC(26:0)+H+ in HLF. We identified the enriched specific PCs, Cers, OAHFAs, and TGs in HLF.
| S-EPMC8648848 | biostudies-literature
Project description:Ligamentum flavum hypertrophy (LFH) is the most important component of lumbar spinal canal stenosis. Although the pathophysiology of LFH has been extensively studied, no method has been proposed to prevent or treat it. Since the transforming growth factor-? (TGF-?) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF-? mechanism. Human LF cells were used for the experiments. First, we created TGF-? receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF-?1 to determine the effects of blocking the TGF-? pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF-? pathway. To assess the predisposition toward fibrosis, ?-smooth muscle actin (?SMA), fibronectin, collagen-1, collagen-3, and CCN2 were evaluated with quantitative real-time polymerase chain reaction, western blotting, and immunocytochemistry. The TGFBR1 KO LF cells were successfully constructed with high KO efficiency. In wild-type (WT) cells, treatment with TGF-?1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis-related factors. However, in KO cells, the responses to TGF-?1 stimulation were significantly lower. In addition, CCN5 and TGF-?1 co-treatment caused a notable reduction in mRNA expression levels compared with TGF-?1 stimulation only. The ?SMA protein expression increased with TGF-?1 but decreased with CCN5 treatment. TGF-?1 induced LF cell transdifferentiation from fibroblasts to myofibroblasts. However, this cell transition dramatically decreased in the presence of CCN5. In conclusion, CCN5 could prevent LFH by modulating the TGF-? pathway. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2634-2644, 2019.
| S-EPMC6899892 | biostudies-literature
Project description:Hypertrophy of the ligamentum flavum (HLF) is one of the common causes of lumbar spinal stenosis (LSS). The key molecules and mechanisms responsible for HLF remain unclear. Here, we used an integrated transcriptome and proteomics analysis of human ligamentum flavum (LF), and subsequent immunohistochemistry and real-time PCR assays, to show upregulation of CRLF1 to be the dominant response to HLF. TGF-β1 significantly increased mRNA expression of CRLF1 through SMAD3 pathway. CRLF1 enhanced LF fibrosis via ERK signaling pathway at the post-transcriptional level and was required for the pro-fibrotic effect of TGF-β1. Knockdown of CRLF1 was shown here to reduce fibrosis caused by inflammatory cytokines and mechanical stress. Furthermore, we found that bipedal standing posture can cause HLF and upregulation of CRLF1 expression in mice LF. Overexpression of CRLF1 was indicated to cause HLF in vivo, whereas CRLF1 knockdown impeded the formation of HLF in bipedal standing mice. These results revealed a crucial role of CRLF1 in LF hypertrophy. We propose that inhibition of CRLF1 is a potential therapeutic strategy to treat HLF.
| S-EPMC7533558 | biostudies-literature
Project description:Chronic inflammation and subsequent fibrosis induced by mechanical stress play an important role in ligamentum flavum (LF) hypertrophy and degeneration in patients with lumbar spinal canal stenosis (LSCS). Angiopoietin-like protein 2 (Angptl2) is a chronic inflammatory mediator induced under various pathological conditions and increases the expression of TGF-β1, which is a well-characterized mediator in LF hypertrophy. We investigated whether Angptl2 is induced by mechanical stress, and whether it contributes to LF hypertrophy and degeneration by activating the TGF-β1 signaling cascade. In this study, we investigated human LF tissue and LF fibroblasts isolated from patients who underwent lumbar surgery. We found that Angptl2 was abundantly expressed in fibroblasts of hypertrophied LF tissues at both the mRNA and protein levels. This expression was not only positively correlated with LF thickness and degeneration but also positively correlated with lumbar segmental motion. Our in vitro experiments with fibroblasts from hypertrophied LF tissue revealed that mechanical stretching stress increases the expression and secretion of Angptl2 via activation of calcineurin/NFAT pathways. In hypertrophied LF tissue, expression of TGF-β1 mRNA was also increased and TGF-β1/Smad signaling was activated. Angptl2 expression in LF tissue was positively correlated with the expression of TGF-β1 mRNA, suggesting cooperation between Angptl2 and TGF-β1 in the pathogenesis of LF hypertrophy. In vitro experiments revealed that Angptl2 increased levels of TGF-β1 and its receptors, and also activated TGF-β1/Smad signaling. Mechanical stretching stress increased TGF-β1 mRNA expression, which was partially attenuated by treatment with a calcineurin/NFAT inhibitor or Angptl2 siRNA, indicating that induction of TGF-β1 expression by mechanical stretching stress is partially mediated by Angptl2. We conclude that expression of Angptl2 induced by mechanical stress in LF fibroblasts promotes LF tissue degeneration by activation of TGF-β1/Smad signaling, which results in LF hypertrophy in patients with LSCS.
| S-EPMC3894965 | biostudies-literature
Project description:Study Design Case report. Objective To report the first case of ligamentum flavum hematoma after cervical spine instrumentation 11 years after the index surgery. Methods After performing bilateral C3 and C4 laminectomy, we observed a dark greenish discoloration over the ligamentum flavum, which was opened. We evacuated 15 mL of subacute hematoma. Results The first ligamentum flavum hematoma of the cervical spine that occurred after spinal instrumentation with sublaminar hooks. Conclusion Ligamentum flavum hematoma might happen even after a long delay (in our case, 11 years) from spinal instrumentation (sublaminar hooks). In symptomatic patients, evacuation is the treatment of choice. In cases of instrument adhesion to the surrounding intracanal tissues, removal should be done meticulously after performing a complete release.
| S-EPMC4733368 | biostudies-other
Project description:BackgroundLigamentum flavum hypertrophy (LFH) is among the most crucial factors in degenerative lumbar spinal stenosis, which can cause back pain, lower extremity pain, cauda equina syndrome and neurogenic claudication. The exact pathogenesis of LFH remains elusive despite extensive research. Most in vitro studies investigating LFH have been carried out using conventional two-dimensional (2D) cell cultures, which do not resemble in vivo conditions, as they lack crucial pathophysiological factors found in three-dimensional (3D) LFH tissue, such as enhanced cell proliferation and cell cluster formation. In this study, we generated ligamentum flavum (LF) clusters using spheroid cultures derived from primary LFH tissue.ResultsThe cultured LF spheroids exhibited good viability and growth on an ultra-low attachment 96-well plate (ULA 96-plate) platform according to live/dead staining. Our results showed that the 100-cell culture continued to grow in size, while the 1000-cell culture maintained its size, and the 5000-cell culture exhibited a decreasing trend in size as the culture time increased; long-term culture was validated for at least 28 days. The LF spheroids also maintained the extracellular matrix (ECM) phenotype, i.e., fibronectin, elastin, and collagen I and III. The 2D culture and 3D culture were further compared by cell cycle and Western blot analyses. Finally, we utilized hematoxylin and eosin (H&E) staining to demonstrate that the 3D spheroids resembled part of the cell arrangement in LF hypertrophic tissue.ConclusionsThe developed LF spheroid model has great potential, as it provides a stable culture platform in a 3D model that can further improve our understanding of the pathogenesis of LFH and has applications in future studies.
| S-EPMC7460798 | biostudies-literature
Project description:ObjectiveTo explore the main causes of hypertrophied ligamentum flavum (HLF) and the possibility of using bipedal standing mouse model to simulate the pathological changes in human HLF.MethodsThirty-two 8-week-old C57BL/6 male mice were randomly assigned to the experimental group (n = 16) and control group (n = 16). In the experimental group, mice were induced to adopt a bipedal standing posture by their hydrophobia. The experimental mice were maintained bipedal standing for 8 h a day with an interval of 2 h to consume food and water. The control mice were placed in a similar environment without bipedal standing. Eight 18-month-old C57BL/6 male mice were compared to evaluate the LF degeneration due to aging factor. Three-dimensional (3D) reconstruction and finite element models were carried out to analyze the stress and strain distribution of the mouse LF in sprawling and bipedal standing postures. Hematoxylin and Eosin (HE), Verhoeff-Van Gieson (VVG), and immunohistochemistry (IHC) staining were used to evaluate the LF degeneration of mice and humans. RT-qPCR and immunofluorescence analysis were used to evaluate the expressions of fibrosis-related factors and inflammatory cytokines of COL1A1, COL3A1, α-SMA, MMP2, IL-1β, and COX-2.ResultsThe von Mises stress (8.85 × 10-2 MPa) and maximum principal strain (6.64 × 10-1 ) in LF were increased 4944 and 7703 times, respectively, in bipedal standing mice. HE staining showed that the mouse LF area was greater in the bipedal standing 10-week-old group ([10.01 ± 2.93] × 104 μm2 ) than that in the control group ([3.76 ± 1.87] × 104 μm2 ) and 18-month-old aged group ([6.09 ± 2.70] × 104 μm2 ). VVG staining showed that the HLF of mice (3.23 ± 0.58) and humans (2.23 ± 0.31) had a similar loss of elastic fibers and an increase in collagen fibers. The cell density was higher during the process of HLF in mice (39.63 ± 4.81) and humans (23.25 ± 2.05). IHC staining showed that the number of α-SMA positive cells were significantly increased in HLF of mice (1.63 ± 0.74) and humans (3.50 ± 1.85). The expressions of inflammatory cytokines and fibrosis-related factors of COL1A1, COL3A1, α-SMA, MMP2, IL-1β, and COX-2 were consistently higher in bipedal standing group than the control group.ConclusionOur study suggests that 3D finite element models can help analyze the abnormal stress and strain distributions of LF in modeling mice. Mechanical stress is the main cause of hypertrophied ligamentum flavum compared to aging. The bipedal standing mice model can reflect the pathological characteristics of human HLF. The bipedal standing mice model can provide a standardized condition to elucidate the molecular mechanisms of mechanical stress-induced HLF in vivo.
| S-EPMC8654658 | biostudies-literature