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Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with abnormal accumulation of specific lipids.

ABSTRACT: 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.

SUBMITTER: Yamada T

PROVIDER: S-EPMC8648848 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with abnormal accumulation of specific lipids.

Yamada Tomohiro T Horikawa Makoto M Sato Tomohito T Kahyo Tomoaki T Takanashi Yusuke Y Ushirozako Hiroki H Kurosu Kenta K Al Mamun Md M Mihara Yuki Y Oe Shin S Arima Hideyuki H Banno Tomohiro T Yosida Go G Hasegawa Tomohiko T Yamato Yu Y Matsuyama Yukihiro Y Setou Mitsutoshi M

Scientific reports 20211206 1

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 l ...[more]

PMID: 34873238

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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.

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.

Project description:BackgroundLigamentum flavum (LF) hypertrophy is the main cause of lumbar spinal canal stenosis (LSCS). Previous studies have shown that LF hypertrophy tissue exhibits abnormal lipid accumulation, but the regulatory mechanism remains unclear. The objective of this study was to explore the function and potential mechanism of ACSM5 in LF lipid accumulation.MethodsTo assess the ACSM5 expression levels, lipid accumulation and triglyceride (TG) level in LF hypertrophy and normal tissue, we utilized RT-qPCR, western blot, oil red O staining, and TG assay kit. The pearson correlation coefficient assay was used to analyze the correlation between ACSM5 levels and lipid accumulation or TG levels in LF hypertrophy tissue. The role of ACSM5 in free fatty acids (FFA)-induced lipid accumulation in LF cells was assessed in vitro, and the role of ACSM5 in LF hypertrophy in mice was verified in vivo. To investigate the underlying mechanisms of ACSM5 regulating lipid accumulation in LF, we conducted the mRNA sequencing, bioinformatics analysis, and rescue experiments.ResultsIn this study, we found that ACSM5, which was significantly down-regulated in LF tissues, correlated with lipid accumulation. In vitro cell experiments demonstrated that overexpression of ACSM5 significantly inhibited FFA-induced lipid accumulation and fibrosis in LF cells. In vivo animal experiments further confirmed that overexpression of ACSM5 inhibited LF thickening, lipid accumulation, and fibrosis. Mechanistically, ACSM5 inhibited lipid accumulation of LF cells by inhibiting FABP4-mediated PPARγ signaling pathway, thereby improving hypertrophy and fibrosis of LF.Conclusionsour findings elucidated the important role of ACSM5 in the regulation of LF lipid accumulation and provide insight into potential therapeutic interventions for the treatment of LF hypertrophy. This study further suggested that therapeutic strategies targeting lipid deposition may be an effective potential approach to treat LF hypertrophy-induced LSCS.

Dataset Information

Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with abnormal accumulation of specific lipids.

Publications

Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with abnormal accumulation of specific lipids.

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