MicroRNA-221 Regulates Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis by Targeting TIMP-2

Xu, Yunqiang; Zhang, Zhenhui; Zheng, Yiming; Feng, Shiqing

doi:10.1097/brs.0000000000001226

Cited by 27 publications

(36 citation statements)

References 23 publications

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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%

“…Chen et al compared LSS and LDH samples and showed that the level of miR-155 in the LF was associated with LF thickness (r=0.958, p<0.01), and the mRNA and protein expression levels of type I and III collagen were increased 20) . Xu et al employed a microarray technique to samples from patients with LSS and LDH, miR-221, whose expression level was increased in the LF from patients with LSS, regulates LF hypertrophy by suppressing TIMP2, which inhibits the degradation of type I and III collagen, and consequently increases the amount of these collagens 7) . In this study, neither these miRNAs were extracted as those significantly related to LF hypertrophy; however, miR-29c and miR-223, which were identified as age-related miRNAs in this study, were also listed as differentially expressed miRNAs by Xu et al 7) .…”

Section: Discussionmentioning

confidence: 99%

“…Xu et al employed a microarray technique to samples from patients with LSS and LDH, miR-221, whose expression level was increased in the LF from patients with LSS, regulates LF hypertrophy by suppressing TIMP2, which inhibits the degradation of type I and III collagen, and consequently increases the amount of these collagens 7) . In this study, neither these miRNAs were extracted as those significantly related to LF hypertrophy; however, miR-29c and miR-223, which were identified as age-related miRNAs in this study, were also listed as differentially expressed miRNAs by Xu et al 7) . This difference is possibly due to the selection of control samples, but further analysis is required for a detailed explanation.…”

Section: Discussionmentioning

confidence: 99%

“…The pathology of degenerative hypertrophy is characterized by loss of elastic fibers and the appearance of a focal disorganized collagenous matrix, which is often associated with chondrometaplasia 3,4) . Although several cytokines such as TGFβ, CTGF, FGF2, and Angptl2 have been identified to be involved in LF hypertrophy, the molecular mechanism underlying the hypertrophy still remains largely unknown 3,[5][6][7][8][9] . MicroRNAs (miRNAs) are short non-coding RNAs that predominantly bind to the coding or 3'-untranslated region of the target mRNA to inhibit translation by promoting the degradation and/or blocking of the translational complex of the target mRNA, thereby playing important roles as posttranscriptional regulators 10,11) .…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Mori

Sakai²,

Kayano

et al. 2017

Spine Surg Relat Res

View full text Add to dashboard Cite

show abstract

“…Studies have found that the initial stage of hypertrophic LF is associated with different cytokines, including TGF-β and VEGF secreted by degenerated and herniated intervertebral disks and facet arthrosis [11]. With the progression of intervertebral space instability and chronic inflammation, a high degree of macrophage infiltration was identified as a major cellular source of various molecules [12], including matrix metalloproteases (MMPs) [13, 14], tissue inhibitors of matrix metalloproteases (TIMPs) [15, 16] during LF hypertrophy. The LF ECM can become disorganized and show decreased levels and degeneration of elastic fibers and increased levels of collagen fibers [17].…”

Section: Discussionmentioning

confidence: 99%

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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Molecular profile of ultrastructure changes of the ligamentum flavum related to lumbar spinal canal stenosis

Sidon

Shemesh

Moldovan

et al. 2019

J of Cellular Biochemistry

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Lumbar spinal canal stenosis (LSCS) is a degenerative disease observed by hypertrophy of the ligamentum flavum (LF) that cause compression of the lumbar neural content. Diabetes mellitus (DM) is a risk factor for the disease and we have shown previously that DM increases the fibrosis and elastic fiber loss in patients with LSCS. The purpose of this study was to find the proteins that play a role in the development of this clinical pathogenesis and the effect of DM on protein expression. LF tissue retrieved from patients diagnosed with LSCS, some were also diagnosed with DM, were compared with LF from patients diagnosed with herniated nucleus pulposus (HNP). The tissues were analyzed by mass spectrometry for proteins profile alteration. We found that LF of LSCS/DM patients exhibited significantly higher levels of proteoglycan proteins and latent transforming growth factor β-binding protein (LTBP2 and LTBP4). Additionally, an increase of HTRA serine protease 1 and insulin-like growth factor binding protein-5 were noted. The higher fibrosis was also associated with proteins related to inflammation and slower tissue repair. Collagen 6 and transforming growth factor inhibitor are related to activation of the anti-inflammatory M2 pathway that is associated with tissue repair. The decrease of these proteins expression in LSCS/DM is associated with increased levels and activation of M1 pro-inflammatory pathways. Interestingly, C3 and C4b members of the complement complex and mannose receptorlike protein (CLEC18) paralogous proteins were detectable solely at the LSCS/DM patients' samples. Histology analysis shows that inflammatory was induced by the hyperglycemic conditions in diabetic patients involve in altering the matrix compositions. Thus, the protein profiles associated with inflammatory pathways affecting the LF suggested increasing susceptibility of developing the degeneration under hyperglycemic conditions. K E Y W O R D S diabetes mellitus, fibrosis, ligamentum flavum, mass spectrometry, spinal stenosis J Cell Biochem. 2019;120:11716-11725. wileyonlinelibrary.com/journal/jcb 11716 |

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MicroRNA-221 Regulates Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis by Targeting TIMP-2

Abstract: 3.

Cited by 27 publications

References 23 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

Molecular profile of ultrastructure changes of the ligamentum flavum related to lumbar spinal canal stenosis

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