Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with increased bFGF expression

Honsawek, Sittisak; Poonpukdee, Jariya; Chalermpanpipat, Chookiet; Payungporn, Sunchai; Limthongkul, Worawat; Yingsakmongkol, Wicharn; Thanakit, Voranuch; Parkpian, Vinai

doi:10.1007/s00264-013-1864-y

Cited by 18 publications

(22 citation statements)

References 21 publications

(19 reference statements)

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“…Another growth factor, connective tissue growth factor (CTGF) was related to LF thickness . Others found increased expression of basic fibroblast growth factor and platelet‐derived growth factor BB …”

Section: Discussionmentioning

confidence: 99%

Increased pain and sensory hyperinnervation of the ligamentum flavum in patients with lumbar spinal stenosis

Benditz

Sprenger

Rauch

et al. 2019

Journal Orthopaedic Research

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Nociceptive sensory nerve fibers have never been investigated in the ligamentum flavum (LF) of patients with LSS. The aim was to analyze nociceptive sensory nerve fibers in the ligamentum flavum (LF) of patients with LSS. A prospective study in patients with lumbar spinal stenosis (LSS) undergoing invasive surgical treatment for lumbar spinal stenosis (LSS) with flavectomy was performed. Patients with LSS were subjected to flavectomy and density of sensory and sympathetic nerve fibers, macrophages, vessels, activated fibroblasts, and cells were investigated by immunostaining techniques. A group of patients with acute disc herniation served as control group. We found a higher density of sensory nerve fibers in LSS patients versus controls. These findings support the role of LF in associated low back pain. Density of sensory nerve fibers in LSS, was positively correlated with typical markers of clinical pain and functional disability, but not with LF density of activated fibroblasts. Inflammation as estimated by macrophage infiltration and higher vascularity does not play a marked role in LF in our LSS patients. In the present study, compared to men with LSS, women with LSS demonstrate more pain and depression, and show a higher density of sensory nerve fibers in LF. This study shed new light on nociceptive nerve fibers, which are increased in LSS compared to controls. The findings speak against a strong inflammatory component in LSS. A higher pain levels in women compared to men can be explained by a higher density of nociceptive nerve fibers. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1–7, 2019.

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Section: Discussionmentioning

confidence: 99%

Increased pain and sensory hyperinnervation of the ligamentum flavum in patients with lumbar spinal stenosis

Benditz

Sprenger

Rauch

et al. 2019

Journal Orthopaedic Research

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“…Previous studies suggested a link between LF hypertrophy and inflammation‐induced fibrosis . Park et al reported that proinflammatory mediators, including IL‐6, TNF‐α, PGE 2 , and NO, can induce fibrosis and ossification of human LF cells, while Cui et al found that high MMP13 expression contributes to LF hypertrophy .…”

Section: Discussionmentioning

confidence: 99%

“…Park et al reported that proinflammatory mediators, including IL‐6, TNF‐α, PGE 2 , and NO, can induce fibrosis and ossification of human LF cells, while Cui et al found that high MMP13 expression contributes to LF hypertrophy . Zhang et al reported that the PDGF‐BB levels are proportional to the severity of LF fibrosis in LSCS, and others indicated that TGF‐β and bFGF play crucial roles in LF hypertrophy . However, most of the previous studies investigated the roles of inflammatory cytokines in LF hypertrophy in normoglycemic LSCS patients.…”

Section: Discussionmentioning

confidence: 99%

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Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis

et al. 2017

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The pathomechanism of the ligamentum flavum (LF) hypertrophy in diabetic patients with lumbar spinal canal stenosis (LSCS) remains unclear. A cross-sectional study was undertaken to investigate the mechanism of LF hypertrophy in these patients. Twenty-four diabetic and 20 normoglycemic patients with LSCS were enrolled in the study. The structure of the LF in the study subjects was evaluated using histological and immunohistochemical methods, and the levels of sorbitol, pro-inflammatory cytokines, and the fibrogenic factor, TGF-β1, in the LF were analyzed. In vitro experiments were performed using NIH3T3 fibroblasts to evaluate the effect of high-glucose conditions and an aldose reductase inhibitor on the cellular production of sorbitol, pro-inflammatory factors, and TGF-β1. We found that the LF of diabetic patients exhibited significantly higher levels of sorbitol and pro-inflammatory cytokines, TGF-β1 and of CD68-positive staining than that of the normoglycemic subjects. The diabetic LF was significantly thicker than that of the controls, and showed evidence of degeneration. The high glucose-cultured fibroblasts exhibited significantly higher levels of sorbitol, pro-inflammatory factors, and TGF-β1 compared to the low glucose-cultured cells, and these levels were dose-dependently reduced by treatment with the aldose reductase inhibitor. Taken together, our data suggests that increased sorbitol levels in the LF of diabetic patients results in increased production of pro-inflammatory and fibrogenic factor, which contribute to LF hypertrophy, and could increase the susceptibility of diabetic patients to LSCS. Furthermore, aldose reductase inhibition effectively reduced the levels of sorbitol and sorbitol-induced pro-inflammatory factor expression in high glucose-cultured fibroblasts. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1058-1066, 2017.

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“…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%

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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Hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis is associated with increased bFGF expression

Cited by 18 publications

References 21 publications

Increased pain and sensory hyperinnervation of the ligamentum flavum in patients with lumbar spinal stenosis

Increased pain and sensory hyperinnervation of the ligamentum flavum in patients with lumbar spinal stenosis

Increased sorbitol levels in the hypertrophic ligamentum flavum of diabetic patients with lumbar spinal canal stenosis

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

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