The paradoxical relationship between ligamentum flavum hypertrophy and developmental lumbar spinal stenosis

Cheung, Pty; Tam, Vivian; Leung, Victor; Samartzis, D; Cheung, Kenneth M.C.; Luk, K.D.K.; Cheung, Jason Pui Yin

doi:10.1186/s13013-016-0088-5

Cited by 28 publications

(17 citation statements)

References 32 publications

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“…Predisposing factors of symptomatic DSS includes degeneration of intervertebral discs, facet joints, or the ligamentum flavum. 1,11,20,23,41 Some genetic factors have been implicated in the etiology of lumbar spinal degeneration. 36,37,[42][43][44] There is likely a direct correlation between spinal stenosis and disc degeneration because these two pathologies usually coexist.…”

Section: Discussionmentioning

confidence: 99%

“…Pathological changes in DSS include narrowing of the dorsal aspect of the spinal canal due to bulging of the inferior articular facets. A paradoxical relationship with the degree of ligamentum flavum fibrosis has also been observed . The lamina is also enlarged with narrowed interlaminar spaces and the pedicles are also shortened leading to decreased interpedicular distances .…”

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confidence: 96%

“…A paradoxical relationship with the degree of ligamentum flavum fibrosis has also been observed. 11 The lamina is also enlarged with narrowed interlaminar spaces and the pedicles are also shortened leading to decreased interpedicular distances. 12 Vertebral bodies may also be wedged and present with posterior lipping, contributing to the narrow spinal canal.…”

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confidence: 99%

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Etiology of developmental spinal stenosis: A genome‐wide association study

Cheung

Kao

Sham

et al. 2017

Journal Orthopaedic Research

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Our study aimed to identify possible single nucleotide polymorphisms (SNPs) via a genome-wide association study (GWAS) approach and a candidate gene platform that were associated with lumbar developmental spinal stenosis (DSS). Southern Chinese population-based study volunteers were assessed (age range: 18-55 years). DSS was defined as the anteroposterior bony spinal canal diameter on T1-weighted axial MRI of L1 to S1. Genotyping was performed using the Illumina HumanOmniZhongHua-8 BeadChip. Using the canal diameter as the quantitative trait, genomic statistical analyses was performed. A total of 469 subjects were recruited. The mean axial AP measurements noted were: L1: 21.8 mm, L2: 21.9 mm, L3: 22.4 mm, L4: 20.2 mm, L5: 19.6 mm, and S1: 17.3 mm. Q-Q plots of genome-wide associations found significant differences in L4 and L5 measurements. More significant SNPs were found on chromosomes 8, 11, and 18. Low-density lipoprotein receptor-related protein 5 on chromosome 11 was found to be an important functional gene in canal bony development via candidate gene approach. We found two clusters in the findings with one including the upper levels (L1-L4) and the other the lower levels (L5 and S1). This is the first GWAS addressing DSS. The presence of multiple SNPs suggests a multi-factorial origin of DSS. Further analyses noted region-specific genetic predisposition, delineating distinct upper to lower lumbar regions of DSS. With better understanding of the DSS phenotype and genetic markers, the at-risk population can be identified early, preventative measures can be initiated, lifestyle/activity modification can be implemented, and more novel and precision-based therapeutics can be developed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1262-1268, 2018.

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Section: Discussionmentioning

confidence: 99%

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confidence: 96%

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Etiology of developmental spinal stenosis: A genome‐wide association study

Cheung

Kao

Sham

et al. 2017

Journal Orthopaedic Research

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“…One must appreciate the unique pathological characteristics of DSS that distinguish it from degenerative/acquired lumbar spinal stenosis. Previous studies have characterized DSS with both x‐ray and magnetic resonance imaging (MRI) phenotyping, having a paradoxical relationship with ligamentum flavum hypertrophy, and possible genetic origins . Yet, further understanding of its pathophysiology is necessary to determine the clinical significance of DSS.…”

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Novel compression rat model for developmental spinal stenosis

2019

Journal Orthopaedic Research

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Developmental spinal stenosis (DSS) is characterized by pre-existing circumferential narrowing of the bony spinal canal which predisposes neural tissue to compression. This study aims to create a reproducible animal model mimicking DSS for investigation of its pathoanatomy. Developmental spinal canal constriction was simulated using circumferential compression. Eighteen female Sprague-Dawley rats (13.0-14.5 weeks-old) underwent circumferential compression at L4-L5 using silicone sheets; or dorsal compression using overlapping silicone sheets; or as controls. A series of outcome scores were used for locomotor function assessment, together with electrophysiological and histological assessment. Assessment time-points were at preoperative, postoperative 1-week, 2weeks, 3-weeks, 1-month, and pre-sacrifice. Statistical analyses were performed. At all postoperative time-points, circumferential group had the worst mean Basso, Beattie and Bresnahan locomotor scores with significant difference from the control group (p < 0.05), as well as the lowest mean Louisville Swim Scale scores, as compared to the dorsal (p < 0.05) and to the control (p < 0.01) groups. Circumferential group had worse mean foot fault score for both hindlimbs (p < 0.01 to p < 0.05) and highest error rate in foot placement accuracy, especially higher than dorsal (p < 0.05) and control (p < 0.05) groups at pre-sacrifice. Electrophysiological assessment revealed postoperative increase in P1 latency was higher in circumferential than dorsal compression. Highest postoperative mean P1 latency was observed for both paws at all postoperative time-points for circumferential group (except at postoperative 1-week). Circumferential group had lower myelin-to-axonal area ratio and higher g-ratio than both the dorsal and control groups (p < 0.001). For each study group, hindlimb P1 latency and P1-N1 amplitude were each correlated with g-ratio (p < 0.05); and mean myelin-to-axonal area ratio correlated with P1 latency of both hindlimbs (p < 0.05). Based on these more severe axonal demyelination and neurological deficits, a valid DSS rat model is created with somatosensory evoked potential neuro-monitoring technique. ß 2019 Orthopaedic Research METHODS Model CreationA total of 18 female Sprague-Dawley (SD) rats of 13.0-14.5 week-old were utilized. All animal experiments involved in this study were approved by the Animal Ethics Committee. The rats were randomly allocated into 3 groups: Circumferential compression (n ¼ 6), dorsal compression (n ¼ 6), control (n ¼ 6). Circumferential compression was achieved using 0.51 mm thick silicone sheet. The silicone sheet was guided circumferentially to the dural sac from the operator side, and the ends of the silicone sheet were approximated and secured by a non-absorbable suture over the dorsal aspect (Fig. 1a). Dorsal compression was conducted by firstly removing the spinous process of L5, followed by insertion of silicone sheets dorsal to the dura, inducing compression at the region of L4-L5. Silicone sheets were doubled and ove...

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“…There are several pathogenic factors that lead to LSS, such as disc degeneration, facet degeneration, and hypertrophy of the ligamentum flavum (HLF) [6]. Among these pathogenic factors, HLF plays a vital role in LSS [7][8][9][10]. Previous studies have indicated that fibrosis of the ligamentum flavum stimulated by chronic inflammation is considered to be the most important pathological process of HLF [11,12].…”

Section: Introductionmentioning

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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The paradoxical relationship between ligamentum flavum hypertrophy and developmental lumbar spinal stenosis

Cited by 28 publications

References 32 publications

Etiology of developmental spinal stenosis: A genome‐wide association study

Etiology of developmental spinal stenosis: A genome‐wide association study

Novel compression rat model for developmental spinal stenosis

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

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