Mechanical stress induces elastic fibre disruption and cartilage matrix increase in ligamentum flavum

Hayashi, Kazunori; Suzuki, Akinobu; Ahmadi, Sayed Abdullah; Terai, Hidetomi; Yamada, Kentaro; Hoshino, Minoru; Toyoda, Hiromitsu; Takahashi, Shinji; Tamai, Katsuto; Ohyama, Shoichiro; Javid, Akgar; Rahmani, Amir M.; Hasib, Maruf Mohammad; Nakamura, Hiroaki

doi:10.1038/s41598-017-13360-w

Cited by 31 publications

(33 citation statements)

References 24 publications

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“…Histopathologically, it has been proposed that HLF and OLF, in its essence, are the process of fibrosis and endochondral osteogenesis of ligamentum fibroblasts under numerous external stimuli (Yayama et al, 2007;Sun et al, 2020). Extensive evidence has shown that genetic background (Hou et al, 2014;, mechanical stress (Hayashi et al, 2017;Shunzhi et al, 2017), aging and gender (Safak et al, 2010;Moon et al, 2015;Kim et al, 2018), endocrine and metabolic abnormalities (Dario et al, 2015;Shemesh et al, 2018;Chaput et al, 2019), local inflammation, and angiogenesis (Zhang K. et al, 2017;Sun et al, 2018;Yang et al, 2018a;Jezek et al, 2020) are potential predisposing factors in the development of HLF/OLF. In addition, intrinsic alterations in multiple cellular activities, growth factors, and molecular mediators have been implicated in this intricate process (Chao et al, 2016;Qu et al, 2016a;Sidon et al, 2019;Ye et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

et al. 2021

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Pathological changes in the ligamentum flavum (LF) can be defined as a process of chronic progressive aberrations in the nature and structure of ligamentous tissues characterized by increased thickness, reduced elasticity, local calcification, or aggravated ossification, which may cause severe myelopathy, radiculopathy, or both. Hypertrophy of ligamentum flavum (HLF) and ossification of ligamentum flavum (OLF) are clinically common entities. Though accumulated evidence has indicated both genetic and environmental factors could contribute to the initiation and progression of HLF/OLF, the definite pathogenesis remains fully unclear. MicroRNAs (miRNAs), one of the important epigenetic modifications, are short single-stranded RNA molecules that regulate protein-coding gene expression at posttranscriptional level, which can disclose the mechanism underlying diseases, identify valuable biomarkers, and explore potential therapeutic targets. Considering that miRNAs play a central role in regulating gene expression, we summarized current studies from the point of view of miRNA-related molecular regulation networks in HLF/OLF. Exploratory studies revealed a variety of miRNA expression profiles and identified a battery of upregulated and downregulated miRNAs in OLF/HLF patients through microarray datasets or transcriptome sequencing. Experimental studies validated the roles of specific miRNAs (e.g., miR-132-3p, miR-199b-5p in OLF, miR-155, and miR-21 in HLF) in regulating fibrosis or osteogenesis differentiation of LF cells and related target genes or molecular signaling pathways. Finally, we discussed the perspectives and challenges of miRNA-based molecular mechanism, diagnostic biomarkers, and therapeutic targets of HLF/OLF.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

et al. 2021

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“…The ligamentum flavum (LF) is located between the upper and lower vertebrae lamina, extends from the cervical vertebra to the sacral vertebra, and provides protection and stability to the spinal column. Recent findings suggest that the factors leading to LFH include age-related degeneration [ 1 , 2 ] inflammation [ 3 , 4 ] mechanical strain [ 5 , 6 ] elastic degradation and fibrosis [ 7 , 8 ]. However, the current treatments for LFH are primarily limited to invasive surgical resection, underscoring the need to explore new alternatives for novel treatments or better prevention of the occurrence of LFH.…”

Section: Introductionmentioning

confidence: 99%

Development of an In Vitro 3D Model for Investigating Ligamentum Flavum Hypertrophy

et al. 2020

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Background: Ligamentum 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. Results: The 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. Conclusions: The 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.

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“…Previous study reported that intervertebral mechanical stress induced LFH with posterolateral fusion instrumentation in a rabbit model over 16 weeks [ 17 ]. saito et al [ 18 ] established a mouse model of LFH using a loading device for applying consecutive mechanical flexion-extension stress to lumbar over 12 weeks.…”

Section: Discussionmentioning

confidence: 99%

The increased motion of lumbar induces ligamentum flavum hypertrophy in a rat model

Wang

Gao

Zhang

et al. 2021

BMC Musculoskelet Disord

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Background The purpose of this study was to establish a novel rat model for ligamentum flavum (LF) hypertrophy using increased motion of lumbar and to elucidate the etiology of (LFH). Methods A total number of 30 male rats were used. The increased motion of lumbar was induced by surgical resection of L5/6 posterior elements (n = 15). The other rats underwent a sham operation (n = 15). After 8 weeks, all rats were taken lateral plain X-rays. The LF from L5/6 in both groups were harvested to investigate histological, immunohistological, and real-time PCR analysis. Results According to radiological results, the disc height ratio, flexion ratio, and extension ratio were larger in the rats in the experimental group than that of in the sham group. The HE staining showed that the LF thickness in the experimental group significantly increased in comparison to the sham group. The Masson trichrome staining showed that the ratio of elastic fibers to collagen fibers in experimental group was lower than that in the sham group. The protein and gene expression of TGF-β1, TNF-α, IL-1β, and Col 1 were significantly higher in the experimental group than that in the sham group. Conclusion A relatively safe, simple, and rapid rat model of LFH using increased motion of lumbar was established. The increased motion of lumbar could lead to high expression of inflammatory and fibrotic factors in LF, causing the accumulation of collagen fibers and decreasing of elastic fibers.

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Mechanical stress induces elastic fibre disruption and cartilage matrix increase in ligamentum flavum

Cited by 31 publications

References 24 publications

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

Development of an In Vitro 3D Model for Investigating Ligamentum Flavum Hypertrophy

The increased motion of lumbar induces ligamentum flavum hypertrophy in a rat model

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