Myofibroblast in the ligamentum flavum hypertrophic activity

Hur, Junseok W.; Bae, Taegeun; Ye, Sunghyeok; Kim, Joo Hyun; Lee, Sun Hye; Kim, Kyoungmi; Lee, Seung Hwan; Lee, Jang Bo; Cho, Tai Hyoung; Park, Jung Youl

doi:10.1007/s00586-017-4981-2

Cited by 37 publications

(29 citation statements)

References 19 publications

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“…These results indicate that TGF‐β1 stimulated the fibroblast to myofibroblast transition, and ultimately promoted fibrosis by over‐producing the ECM components listed above. These results are consistent with our previous study.…”

Section: Resultssupporting

confidence: 94%

“…The transition of fibroblasts to myofibroblasts is found in many cell types, and it is especially well documented in the field of cardiology as a key pathway leading to cardiac failure via myocardial hypertrophy and fibrosis . Hur et al for the first time, introduced the concept of fibrosis/hypertrophy pathomechanism into the field of LF and proposed that the myofibroblast transition induced by TGF‐β1 might be a key link between inflammation and LFH. The study showed the presence of myofibroblasts, which have contractile and ECM secretory functions, in the LF of LSCS patients by detecting αSMA.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to bulging discs and facet joint hypertrophy, ligamentum flavum hypertrophy (LFH) is a key contributing factor to LSCS. Research on the pathophysiology of LFH has been of great interest to spine specialists, and the majority of specialists have suggested that tissue inflammation, angiogenesis, and fibrosis lead to LFH . Although the development of LFH cannot be described by a single pathway or a single biomechanical change, the relationships between LFH and several key factors, including transforming growth factor‐β1 (TGF‐β1), angiopoietin‐like protein 2 (ANGPTL2), vascular endothelial growth factor (VEGF), and several other cytokines have been investigated .…”

mentioning

confidence: 99%

“…It is widely known that among these cytokines, TGF‐β1 is the main component of LFH that leads to LSCS. Several studies have elucidated the key links of TGF‐β to inflammation, angiogenesis, extracellular matrix (ECM) regulation, and myofibroblast transdifferentiation leading to LFH. However, convincing evidence is still lacking regarding whether inhibition of the TGF‐β pathway can actually prevent LFH.…”

mentioning

confidence: 99%

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CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

Ye¹,

Kwon

Bae

et al. 2019

Journal Orthopaedic Research

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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‐β (TGF‐β) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF‐β mechanism. Human LF cells were used for the experiments. First, we created TGF‐β receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF‐β1 to determine the effects of blocking the TGF‐β pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF‐β pathway. To assess the predisposition toward fibrosis, α‐smooth muscle actin (αSMA), 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‐β1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis‐related factors. However, in KO cells, the responses to TGF‐β1 stimulation were significantly lower. In addition, CCN5 and TGF‐β1 co‐treatment caused a notable reduction in mRNA expression levels compared with TGF‐β1 stimulation only. The αSMA protein expression increased with TGF‐β1 but decreased with CCN5 treatment. TGF‐β1 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‐β 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

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

Ye¹,

Kwon

Bae

et al. 2019

Journal Orthopaedic Research

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“…It is believed that when suffering from increased mechanical stress, the ligamentum flavum is constantly damaged, causing a local release of inflammationrelated factors, such as TNF-α, TGF-b1, IL-1 and IL-6, which can stimulate LF fibrosis and contribute to the pathological process of HLF [12,[33][34][35][36]. Although inflammatory factors are believed to play a crucial role in HLF [5,11,[37][38][39][40], the molecular basis for LF tissue fibrosis remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway

Yan¹,

Huang²,

Zeng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Narrowing of the lumbar spinal canal is a condition called lumbar spinal stenosis (LSS) and is a high-morbidity problem in the elderly. LSS is commonly caused by hypertrophy of the ligamentum flavum (HLF). Previous studies showed that fibrosis of the ligamentum flavum (LF) largely contributed to HLF. However, the underlying pathomechanism remains unclear. Insulin-like growth factor-1 (IGF-1) is known to have an intimate relationship with fibrosis in various tissues. Nevertheless, currently, there are few studies regarding IGF-1 in HLF. In this study, we investigated the role of IGF-1 in HLF and its potential molecular mechanism of action. Methods: First, the IGF-1, phosphorylation of IGF-1 receptor (pIGF-1R), phosphorylation of AKT (pAKT), phosphorylation of S6(pS6), collagen I and collagen III expression levels were examined via immunohistochemistry and Western blotting in LF tissues from patients with LSS or Non-LSS. Second, primary LF cells were isolated from adults with a normal LF thickness and were cultured with different concentrations of IGF-1 with or without NVP-AEW541/rapamycin. Results: The results showed that IGF-1, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression in the LSS group was significantly higher than that in the Non-LSS group. Meanwhile, pIGF-1R, pAKT, pS6, collagen I and collagen III protein expression was significantly enhanced in LF cells after IGF-1 exposure, which can be notably blocked by NVP-AEW541. In addition, pS6, collagen I and collagen III protein expression was blocked by rapamycin. Conclusions: Enhanced IGF-1 promotes the synthesis of collagen I and collagen III via the mTORC1 signaling pathway, which eventually contributes to hypertrophy of the ligamentum flavum.

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Comparative proteome analysis of the ligamentum flavum of patients with lumbar spinal canal stenosis

et al. 2022

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Background Thickening of the ligamentum flavum is considered to be the main factor for lumbar spinal canal stenosis (LSCS). Although some mechanisms have been speculated in the thickening of the ligamentum flavum, there are only a few comprehensive approaches to investigate its pathology. The objective of this study was to investigate the pathology of thickened ligamentum flavum in patients with LSCS based on protein expression levels using shotgun proteome analysis. Methods Ligamentum flavum samples were collected from four patients with LSCS (LSCS group) and four patients with lumbar disc herniation (LDH) as controls (LDH group). Protein mixtures were digested and analyzed by liquid chromatography/mass spectrometry analysis. To compare protein expression levels between the LSCS and LDH groups, the mean Mascot score was compared. Biological processes were assessed using Gene Ontology analysis. Results A total of 1151 proteins were identified in some samples of ligamentum flavum. Among these, 145 proteins were detected only in the LSCS group, 315 in the LDH group, and 691 in both groups. The demonstrated biological processes occurring in the LSCS group included: extracellular matrix organization, regulation of peptidase activity, extracellular matrix disassembly, and negative regulation of cell growth. Proteins related to fibrosis, chondrometaplasia, and amyloid deposition were found highly expressed in the LSCS group compared with those in the LDH group. Conclusions Tissue repair via fibrosis, chondrometaplasia, and amyloid deposits may be important pathologies that occur in the thickened ligamentum flavum of patients with LSCS.

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Myofibroblast in the ligamentum flavum hypertrophic activity

Abstract: We conclude that the transition of fibroblast to myofibroblasts via TGF-β pathway is a key linker between inflammation and fibrosis in LFH mechanism.

Cited by 37 publications

References 19 publications

CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

CCN5 Reduces Ligamentum Flavum Hypertrophy by Modulating the TGF‐β Pathway

Locally Produced IGF-1 Promotes Hypertrophy of the Ligamentum Flavum via the mTORC1 Signaling Pathway

Comparative proteome analysis of the ligamentum flavum of patients with lumbar spinal canal stenosis

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