Chondrogenic and Fibrotic Process in the Ligamentum Flavum of Patients With Lumbar Spinal Canal Stenosis

Yabe, Yutaka; Hagiwara, Yoshihiro; Andõ, Akira; Tsuchiya, Masahiro; Minowa, Takashi; Takemura, Tamiko; Honda, Masahito; Hatori, Kouki; Sonofuchi, Kazuaki; Kanazawa, Kenji; Koide, Masashi; Sekiguchi, Takuya; Itoi, Eiji

doi:10.1097/brs.0000000000000795

Cited by 64 publications

(106 citation statements)

References 36 publications

(21 reference statements)

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“…The number of comprehensive 'omics' studies to elucidate the molecular pathology of LF degenerative hypertrophy in LSS patients has been increasing 7,14,15) . In these cases, LF samples from LDH patients, for which the age group is often younger than that of patients with LSS, were used as controls.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA transcriptome analysis on hypertrophy of ligamentum flavum in patients with lumbar spinal stenosis

Mori

Sakai²,

Kayano

et al. 2017

Spine Surg Relat Res

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Abstract:Introduction: Molecular pathways involved in ligamentum flavum (LF) hypertrophy are still unclarified. The purpose of this study was to characterize LF hypertrophy by microRNA (miRNA) profiling according to the classification of lumbar spinal stenosis (LSS).Methods: Classification of patients with LSS into ligamentous and non-ligamentous cases was conducted by clinical observation and the morphometric parameter adopting the LF/spinal canal area ratio (LSAR) from measurements of magnetic resonance imaging (MRI) T2 weighed images. LF from patients with ligamentous stenosis (n=10) were considered as the degenerative hypertrophied samples, and those from patients with non-ligamentous LSS (n=7) and lumbar disc herniation (LDH, n=3) were used as non-hypertrophied controls. Profiling of miRNA from all samples was conducted by Agilent microarray. Microarray data analysis was performed with GeneSpring GX, and pathway analysis was performed using Ingenuity Pathway Analysis.Results: The mean LSAR in the ligamentous group was significantly higher than that in the control group (0.662±0.154 vs 0.301±0.068, p=0.0000171). Ten significantly differentially expressed miRNA were identified and taken as a signature of LF hypertrophy: nine miRNA showed down-regulated expression, and one showed up-regulated expression in the ligamentous LF. Among those, miR-423-5p (rs=-0.473, p<0.05), miR-4306 (rs=-0.628, p<0.01), miR-516b-5p (rs=-0.629, p<0.01), and miR-497-5p (rs=0.461, p<0.05) were correlated to the LSAR. Pathway analysis predicted aryl hydrocarbon receptor signaling (p<0.01), Wnt/β-catenin signaling (p<0.01), and insulin receptor signaling (p<0.05) as canonical pathways associated with the miRNA signature.Conclusions: Classification based on quantification of the MRI axial image is useful for studying hypertrophy of the LF. Aryl hydrocarbon receptor and Wnt/β-catenin signaling may be involved in LF hypertrophy.

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Section: Discussionmentioning

confidence: 99%

MicroRNA transcriptome analysis on hypertrophy of ligamentum flavum in patients with lumbar spinal stenosis

Mori

Sakai²,

Kayano

et al. 2017

Spine Surg Relat Res

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“…This was already indicated by the pathological findings in LF hypertrophy [3]. However, the underlying pathophysiological mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 76%

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

Zhou

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. Results: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. Conclusion: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

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“…According to previous reports [13][14][15], the increased collagen fibers are mainly collagen I and collagen III. As collagen I and collagen III production is believed to strongly correlate with HLF [14,31,32], in our study, we measured collagen I and collagen III expression in LF tissues of the Non-LSS group and LSS group. In the current study, the expression of collagen I and collagen III in LF tissues was found to be increased significantly and was associated with the increases in LF tissue thickness and degree of fibrosis in the LSS group compared with the Non-LSS group.…”

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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Chondrogenic and Fibrotic Process in the Ligamentum Flavum of Patients With Lumbar Spinal Canal Stenosis

Abstract: 5.

Cited by 64 publications

References 36 publications

MicroRNA transcriptome analysis on hypertrophy of ligamentum flavum in patients with lumbar spinal stenosis

MicroRNA transcriptome analysis on hypertrophy of ligamentum flavum in patients with lumbar spinal stenosis

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

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

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