• extracellular matrix
• ligamentum flavum hypertrophy
• mechanical property
• myofibroblast

• National Cheng Kung University Hospital
• National Science and Technology Council

• MRI
• hypertrophy of ligamentum flavum
• immunohistochemistry
• rat model
• western blot

• Raman spectroscopy
• biomechanics
• ligamentum flavum
• microstructure
• nanoindentation
• radiology assessment

• cysts
• fat necrosis
• ischemia
• ligamentum flavum

• Humans
• Female
• Male
• Aged
• Ligamentum Flavum/pathology
• Middle Aged
• Adult
• Aged, 80 and over
• Cysts/pathology
• Ischemia/pathology

• RANKL
• back pain
• degenerative disc disease
• dog
• inflammation
• nerve growth factor
• tumor necrosis factor superfamily

• Humans
• Spinal Stenosis/complications
• Glycogen Synthase Kinase 3 beta/metabolism
• Ligamentum Flavum/pathology
• Myofibroblasts/metabolism
• Myofibroblasts/pathology
• beta Catenin/metabolism
• Actins/metabolism
• Signal Transduction
• Lumbar Vertebrae/pathology
• Hypertrophy/metabolism

• fibrosis
• histological analysis
• hypertrophy
• inflammation
• ligamentum flavum
• rat model

• R01 AR069668 NIAMS NIH HHS
• R01 AR077760 NIAMS NIH HHS
• R21 AR080516 NIAMS NIH HHS
• National Institutes of Health

• N-acetylcysteine
• ligamentum flavum hypertrophy
• lumbar spinal canal stenosis
• oxidative stress
• reactive oxygen species

• epidural steroid injection
• ligamentum flavum
• lumbar spinal stenosis
• triamcinolone acetonide

• Gait analysis
• Joint kinematics
• Paraspinal muscle activation
• Spatiotemporal gait parameters
• Symptomatic lumbar spinal stenosis

• Humans
• Biomechanical Phenomena/physiology
• Paraspinal Muscles
• Spinal Stenosis/complications
• Walking/physiology
• Electromyography
• Muscle, Skeletal/physiology
• Pain

• epidural fat
• histological characteristics
• inflammation
• ossification of the ligament flavum

• National Natural Science Foundation of China

We developed a novel multi-torsional mechanical stretch stress loading device for ligamentum flavum cells and evaluated its influence on the development of ligamentum flavum hypertrophy, a common cause of lumbar spinal canal stenosis.

Stretch strength of the device was optimized by applying 5% and 15% MSS loads for 24, 48, and 72 h. A cytotoxicity assay of human ligamentum flavum cells was performed and the results were compared to control (0% stress). Inflammatory markers (interleukin [IL]-6, IL-8), vascular endothelial growth factor [VEGF], and extracellular matrix (ECM)-regulating cytokines (matrix metalloproteinase [MMP]-1, MMP-3 and MMP-9, and tissue inhibitor of metalloproteinase [TIMP]-1 and TIMP-2) were quantified via enzyme-linked immunosorbent assay.

Using our multi-torsional mechanical stretch stress loading device, 5% stress for 24 hour was optimal for ligamentum flavum cells. Under this condition, the IL-6 and IL-8 levels, VEGF level, and MMP-1, MMP-3, and TIMP-2 were significantly increased, compared to the control.

Using the novel multi-torsional mechanical stretch stress loading device we confirmed that, mechanical stress enhances the production of inflammatory cytokines and angiogenic factors, and altered the expression of ECM-regulating enzymes, possibly triggering ligamentum flavum hypertrophy.

Ligament flavum (LF) hypertropy is the main etiopathogenesis of lumbar canal stenosis (LCS). The purely elastic LF undergoes a morphological adaptation including a reduction in the elastic fibers and a consequent increase in the collagen content, fibrosis, cicatrization, and calcification. However, the morphometric analysis can delineate the LF in patients with LCS from those without LCS, which would help in better understanding LCS pathogenesis.

To compare the histopathological changes in LF between the degenerative LCS and non-stenotic (non-LCS) group.

The present prospective study was conducted in 82 patients who were divided into two groups, namely LCS and non-LCS. Demographic details of the patients such as duration of symptoms, level of involvement, and number of segments were recorded. The LF obtained from both groups was histopathologically examined for the fibrosis score, elastic fiber degeneration, calcification, and chondroid metaplasia. Morphometrical details included a change in elastin and collagen percentages, elastin/collagen ratio, elastic fiber fragmentation, and ligamentocyte numbers. All parameters were compared between the two groups by using the independent t test, Chi-square test, and Pearson’s correlation test.

Out of 82 cases, 74 were analysed, 34 in LCS and 40 in non-LCS group. The mean ± SD age of presentation in LCS and non- LCS group was 49.2 ± 8.9 and 43.1 ± 14.3 respectively. The LCS group (n = 34) exhibited significant differences in fibrosis (P = 0.002), elastic fiber degeneration (P = 0.01), % elastic fragmentation (66.5 ± 16.3 vs 29.5 ± 16.9), % elastic, content (26.9 ± 6.7 vs 34.7 ± 8.4), % collagen content (63.6 ± 10.4 vs 54.9 ± 6.4), reduction of elastic/collagen (0.4 ± 0.1 vs 0.6 ± 0.1), and ligamentocyte number (39.1 ± 19.1 vs 53.5 ± 26.9) as compared to non-LCS group (n = 40). The calcification (P = 0.08) and Pearson’s correlation between duration and loss of elastin was not significant. The difference in LF morphology is consistent in patient’s ≥ 40 years of age among the groups as found in subgroup analysis. Similarly in the patents < 40 and > 40 in the non-LCS group.

LF is vital in the pathogenesis of LCS. The purely elastic LF undergoes a morphological adaptation that includes a reduction in the elastic fibers with a consequent increase in the collagen content, fibrosis, cicatrization, and calcification. The present study provides a detailed morphometric analysis to semiquantitatively delineate the LF changes in patients with LCS from those in patients without LCS.

• Spinal stenosis
• Lumbar spine
• Ligamentum flavum
• histopathology
• Morphometry

• claudication
• disc
• hypertrophy
• ligamentum flavum
• stenosis

• Back Pain
• Chronic Pain
• Constriction, Pathologic
• Humans
• Hypertrophy
• Intermittent Claudication/etiology
• Leg
• Ligamentum Flavum/surgery
• Spinal Canal
• Spinal Stenosis/complications
• Spinal Stenosis/diagnostic imaging
• Spinal Stenosis/surgery

• Case-control
• Dietary factors
• Lumbar spinal stenosis
• Mediterranean diet
• Ultra-processed food

• Case-Control Studies
• Diet/adverse effects
• Diet, Mediterranean
• Fast Foods
• Food Handling
• Humans
• Prospective Studies
• Spinal Stenosis/diagnosis
• Spinal Stenosis/epidemiology

Mechanical stress promotes human ligamentum flavum cells (LFCs) to synthesize multitype collagens, leading to ligamentum flavum hypertrophy (LFH). However, the mechanism of mechanical stress in the formation of collagen remains unclear. Therefore, we investigated the relationship between mechanical stress and collagen synthesis in the present study. First, LFCs were isolated from 9 patients and cultured with or without mechanical stress exposure for different times. IGF-1, collagen I (col-I), and collagen III (col-III) protein and mRNA levels were then detected via ELISA and qPCR, respectively. Moreover, the activation of pIGF-1R, pAKT, and pS6 was examined by Western blot analysis. To further explore the underlying mechanism, an IGF-1 neutralizing antibody, NVP-AEW541, and rapamycin were used. IGF-1, col-I, and col-III were significantly increased in stressed LFCs compared to nonstressed LFCs. In addition, the activation of pIGF-1R, pAKT, and pS6 was obviously enhanced in stressed LFCs. Interestingly, col-I protein, col-I mRNA, col-III protein, col-III mRNA, and IGF-1 protein, but not IGF-1 mRNA, were inhibited by IGF-1 neutralizing antibody. In addition, col-I and col-III protein and mRNA, but not IGF-1, were inhibited by both NVP-AEW541 and rapamycin. Moreover, the activation of pIGF-1R, pAKT, and pS6 was reduced by the IGF-1 neutralizing antibody and NVP-AEW541, and the activation of pS6 was reduced by rapamycin. In summary, these results suggested that mechanical stress promotes LFCs to produce IGF-1, which facilitates col-I and col-III synthesis via the IGF-1R/AKT/mTORC1 signaling pathway.

The most common spinal disorder in elderly is lumbar spinal stenosis (LSS), resulting partly from ligamentum flavum (LF) hypertrophy. Its pathophysiology is not completely understood. The present study wants to elucidate the role of estrogen receptor α (ER α) in fibroblasts of hypertrophied LF. LF samples of 38 patients with LSS were obtained during spinal decompression. Twelve LF samples from patients with disk herniation served as controls. Hematoxylin & Eosin (H&E) and Elastica stains and immunohistochemistry for ER α were performed. The proportions of fibrosis, loss and/or degeneration of elastic fibers and proliferation of collagen fibers were assessed according to the scores of Sairyo and Okuda. Group differences in the ER α and Sairyo and Okuda scores between patients and controls, male and female sex and absence and presence of additional orthopedic diagnoses were assessed with the Mann–Whitney U test. There was a tendency towards higher expression of ER α in LF fibroblasts in the hypertrophy group (p = 0.065). The Sairyo and Okuda scores were more severe for the hypertrophy group but, in general, not statistically relevant. There was no statistically relevant correlation between the expression of ER α and sex (p = 0.326). ER α expression was higher in patients with osteochondrosis but not statistically significant (p = 0.113). In patients with scoliosis, ER α expression was significantly lower (p = 0.044). LF hypertrophy may be accompanied by a higher expression of ER α in fibroblasts. No difference in ER α expression was observed regarding sex. Further studies are needed to clarify the biological and clinical significance of these findings.

• Full-endoscopic
• Interlaminar
• Lumbar disc herniation
• Lumbar discectomy
• Spinal stenosis

• Experimental study
• Fibrotic factor
• Hypertrophy
• Immunohistochemistry
• Increased motion
• Inflammatory factor
• Ligamentum flavum
• Lumbar degenerative disease
• Masson trichrome staining
• Rat model
• Real‐time PCR

• Ligament flavum cell
• Smad2
• TGF-β(1)
• siRNA

• Adult
• Aged
• Collagen/metabolism
• Female
• Fibroblasts/pathology
• Fibrosis
• Humans
• Hypertrophy
• Ligamentum Flavum/pathology
• Male
• Middle Aged
• Primary Cell Culture
• RNA, Small Interfering/genetics
• Signal Transduction
• Smad2 Protein/genetics
• Smad3 Protein/genetics
• Smad4 Protein/genetics
• Transfection
• Transforming Growth Factor beta1

• Fetus
• Human
• Ligament
• Neck
• Zygapophysial joint

• Japanese Orthopaedic Association score
• Oswestry Disability Index
• calcification of ligamentum flavum
• lumbar degenerative disease
• microendscopic surgery
• minimally invasive surgery
• ossification of ligamentum flavum
• surgical outcome

• TGF-β1
• extracellular matrix
• fibroblasts
• fibrosis
• ligamentum flavum

Lumbar spinal stenosis (LSS) is a common degenerative disease, which can lead to neurological dysfunction and requires surgical treatment. In the previous study, we used H&E staining and immunohistochemistry to qualitatively analyze the expression of S100 and P16 in the pathological process of ligamentum flavum (LF) hypertrophy in patients with LSS. To further explore the relationship between P16, S100 and LF hypertrophy in patients with LSS, we quantitatively detected S100 and P16 and their expressed products based on molecular biology techniques, and analyzed their imaging correlation.

Before posterior lumbar surgery, LF thickness was measured by Magnetic Resonance Imaging (MRI). Through the operation, we obtained the specimens of LF from 120 patients, all of whom were L4/5 LF. They were designated: simple lumbar disc herniation (LDH), single-segment spinal stenosis (SLSS), and double-segment LSS (DLSS). The detection of each side of LF was assessed. S100 and P16 and their expression products were detected by western blot and quantitative polymerase chain reaction (qPCR).

The dorsal mRNA expression of P16 in DLSS group was significantly higher than that in SLSS group. On the dorsal and dural side of LF, the expression of P16 mRNA and proteins in the LDH group was significantly lower than that in SLSS and DLSS groups. We found a correlation between the thickness of LF and the expression of P16. However, there was no significant difference in the expression of S100 mRNA and S100 protein on both sides of the ligament and among the three groups, and no significant correlation between the expression of S100 and the thickness of LF.

P16 is involved in the process of LF hypertrophy in patients with LSS, and the imaging thickness of LF is related to the expression of P16. No obvious evidence proves that S100 may be related to the hypertrophy of LF in patients with LSS.

• Hypertrophy
• Ligamentum Flavum
• Magnetic resonance imaging
• P16
• Quantitative PCR
• S100
• Western blot

Prospective, comparative.

To compare the histopathological and electron microscopic changes in the ligamentum flavum (LF) between degenerative lumbar canal stenosis (LCS) and lumbar disk herniation (LDH).

The LF has been implicated as a key structure in the pathogenesis of LCS. With aging, the LF undergoes morphological changes–a decrease in the elastic component and an increase in the collagen component, in addition to other focal changes. By comparing the histopathological and electron microscopic picture of the LF in elderly patients with LCS with that in young patients with LDH, the role of this ligament in the pathogenesis of LCS may be clarified.

Forty patients were prospectively recruited and divided into two groups: group 1 included 20 patients with degenerative LCS aged >55 years and group 2 included patients with LDH aged <35 years. The ligament flava were collected during the patients’ surgery. The features noted on histopathological examination included the fibrosis score, the loss of elastic fibers, calcification, chondroid metaplasia, mucinous degeneration, vascularization, long septa, clefts, granulation tissue, and ganglion-like cysts. The features noted on electron microscopic examination included the elastic fiber thickness, the quality of elastic fibers, the elastic:collagen ratio, calcification, melanin fibers, remnants of necrotic cells, and electron-dense material in the LF. All parameters were compared between group 1 and group 2.

On histopathological examination, the two groups exhibited significant differences regarding three parameters: chondroid metaplasia, long septa, and ganglion-like cysts. On electron microscopy examination, significant differences were observed between the two groups regarding two parameters: the quality of elastic fibers and the elastic:collagen ratio.

Characteristic morphological changes may be noted on histopathological and electron microscopic examination that mark the degenerative changes in the LF that contribute to the occurrence and pathogenesis of degenerative LCS.

• Degenerative intervertebral disks
• Electron microscopy
• Histopathology
• Ligamentum flavum
• Lumbar region

This study aims to determine the methods of percutaneous release procedures in the lumbar ligamentum flavum (LF) under ultrasound guidance by acupotomy and provide an anatomical basis for intrusive treatment of lumbar disc herniation and lumbar spinal canal stenosis.

Twelve cadavers including 4 females and 8 males aged 60 to 90 years (73.42 ± 14.57 years), without formalin fixation, were selected. Guided by an ultrasound transducer, we punctured acupotomy to release lumbar LF in L3/L4, L4/L5, and L5/S1 segments. In the transverse-axis approach, the probe was placed transversely, while in the longitudinal-axis approach, the probe was placed longitudinally. The depth of needle penetration (A), the distance between the puncture point and spinous process (B), and the distance between the puncture point and sacral cornu (C) were measured on cadavers, and the depth of needle penetration (U-A), the distance between the puncture point and spinous process (U-B), and the angle for acupotomy (D) on ultrasound images were also measured. Statistical analyses were carried out using SPSS. Paired sample t-tests and homogeneity of variance tests and one-way analysis of variance (ANOVA) were performed. The Pearson correlation coefficients and linear correlation coefficients were calculated for the data obtained from ultrasound and cadaver measurements.

No obvious blood vessels and nerves were observed in the puncture path, and the spinal dura was intact. There was no statistical difference between the left and right side measurements obtained from the ultrasound images and the cadavers. The penetration depth in the transverse-axis approach was less than that in the longitudinal-axis approach, and the angle of the needle in the transverse-axis approach was greater than that in the longitudinal-axis approach. The measured data for the transverse-axis approach for L3/L4, L4/L5, and L5/S1 segments showed that there were no differences in the needle angle, the depth of needle penetration, and the distance from the spinous process to the puncture point among the three segments. There was a strong correlation between the depth of needle penetration and the distance from the spinous process to the puncture point on the ultrasonic images and the cadavers on the path of acupotomy. Linear equation A = 2.02 + 0.83 ∗ U-A, R² = 0.352; B = 1.37 + 0.71 ∗ U-B, R² = 0.252, where A/B refers to the data measured on the cadavers and U-A/U-B refers to the data measured on the ultrasound images.

In this study, ultrasound guidance was applied, which better guaranteed the safety and feasibility of acupotomy therapy. Before performing the treatment, the depth of needle penetration in the human body can be determined by measuring the distance between the needle point and the target position on the ultrasound image. Under ultrasound guidance, the transverse-axis approach has a smaller puncture depth and greater puncture angle than the longitudinal-axis approach. Hence, this study believes that the transverse-axis approach is safer for the clinical application of ultrasound-guided LF acupotomy lysis.

• Degenerative spine
• Endoscopic spine surgery
• Interlaminar approach
• Ligamentum flavum cyst
• Lumbar spine
• Minimally invasive spine surgery

• Calcification
• Calcium pyrophosphate dehydrate
• Cervical spine
• Ligamentum flavum
• Myelopathy
• Ossification

• Calcinosis/pathology
• Calcinosis/surgery
• Cervical Vertebrae/pathology
• Cervical Vertebrae/surgery
• Decompression, Surgical
• Humans
• Ligamentum Flavum/pathology
• Ligamentum Flavum/surgery
• Ossification, Heterotopic/pathology
• Ossification, Heterotopic/surgery
• Spinal Cord Diseases/pathology
• Spinal Cord Diseases/surgery

• Collagenous fiber
• Epiligament
• Fibrosis
• Ligamentum flavum
• Lumbar spinal canal stenosis

Ossification of the ligamentum flavum of the spine (OLF) is rarely reported in individuals of European ancestry. It has, however, been observed in archaeological skeletons from Europe. The aim of this study was to revisit OLF rates, utilising a mid-nineteenth-century skeletal sample from Ireland. The hypothesis was that the OLF prevalence rate was similar to studies on non-Europeans. Spines from 345 individuals were analysed, and the extent of OLF recorded on the cranial and caudal attachment sites of each vertebra using the following classification system: Grade 0 (no change); Grade 1 (<2 mm); Grade 2 (2–4 mm); Grade 3 (≥4 mm). OLF was observed at prevalence rates of 83.6%. There was no disparity in prevalence based on sex, except for individuals aged 36–45 years at death in which the male rate was higher. Advancing age was a determining factor in the OLF occurrence with an onset in young adulthood (18–25 years), and most severe grades occurring over the age of 25 years. OLF coincides with spinal osteoarthritis, spondylosis deformans and Schmorl’s nodes in both sexes, and with intervertebral osteochondrosis in females. The results of this study indicate that OLF is likely to be an understudied rather than rare condition in European populations.

• Cerebrospinal fluid leakage
• Dural adhesion
• Dural laceration
• Dural ossification
• Myelopathy
• Ossification of ligamentum flavum

• Adult
• Aged
• Decompression, Surgical/adverse effects
• Decompression, Surgical/methods
• Dura Mater/diagnostic imaging
• Dura Mater/pathology
• Female
• Humans
• Lacerations/diagnostic imaging
• Lacerations/etiology
• Laminectomy/adverse effects
• Laminectomy/methods
• Ligamentum Flavum/diagnostic imaging
• Ligamentum Flavum/surgery
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Ossification, Heterotopic/diagnostic imaging
• Ossification, Heterotopic/etiology
• Postoperative Complications/diagnostic imaging
• Postoperative Complications/etiology
• Radiography
• Tissue Adhesions/diagnostic imaging
• Tissue Adhesions/etiology

Gender differences may play a role in the pathogenesis of lumbar spinal stenosis. However, few reports that discuss the effects of gender differences in ligamentum flavum (LF) hypertrophy have been published, and no study has investigated the relationship between LF thickness and the quantitative value of intervertebral disc (IVD) degeneration. This study aimed to investigate the impact of gender on the pathomechanisms underlying LF hypertrophy, focusing on the relationship among LF thickness, IVD degeneration, and age.

The subjects include 100 patients with low back pain and leg numbness, tingling, or pain. We measured LF thickness and the T2 values of IVDs using MR imaging and analyzed the relationship among LF thickness, T2 values of IVDs, and age. The interclass correlation coefficient (ICC) was calculated as the inter-rater reliability between the LF thickness values measured by two investigators.

ICC was calculated for the two measurements of LF thickness (r = 0.923, 95% CI: 0.907-0.936). No statistically significant difference in the T2 values of IVDs was observed between females and males from L2/3 to L5/S. There were significantly negative linear correlations between LF thickness and the T2 values of IVDs at all levels, but this correlation was not observed in females at L4/5. There were significantly negative linear correlations between age and the T2 values of IVDs from L2/3 to L5/S for all patients, females, and males (r = 0.422-0.756). In addition, there were significantly positive linear correlations between age and LF thickness from L2/3 to L4/5 for all patients (r = 0.329-0.361) and females (r = 0.411-0.481). Correlations were not observed for males at all levels or for all patients at L5/S.

The relationships identified among LF thickness, age, and IVD degeneration suggest that gender differences play a role in the pathogenesis of LF hypertrophy.

• Ligamentum flavum hypertrophy
• T2 value
• gender
• intervertebral disc degeneration

• Computed tomography
• Ligamentum flavum
• Ossification
• Prevalence
• Thoracic kyphosis
• Thoracic spine

• dural sac cross-sectional area
• lumbar central canal spinal stenosis
• spinal canal cross-sectional area

• Aged
• Aged, 80 and over
• Case-Control Studies
• Dura Mater/diagnostic imaging
• Dura Mater/pathology
• Female
• Humans
• Lumbar Vertebrae/diagnostic imaging
• Lumbar Vertebrae/pathology
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Pain Management
• Retrospective Studies
• Spinal Stenosis/diagnostic imaging
• Spinal Stenosis/pathology

• Diabetes mellitus
• Elastin
• Ligamentum flavum
• Lumbar spinal stenosis

• Contralateral decompression
• Endoscopy
• Foraminal stenosis
• Interlaminar
• Lateral recess stenosis
• Spine

• Adult
• Aged
• Blood Loss, Surgical
• Decompression, Surgical
• Disability Evaluation
• Dura Mater/injuries
• Female
• Follow-Up Studies
• Foraminotomy
• Humans
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Neuroendoscopy
• Operative Time
• Pain Measurement
• Prospective Studies
• Radiculopathy/diagnostic imaging
• Radiculopathy/etiology
• Radiculopathy/surgery
• Retrospective Studies
• Spinal Stenosis/complications
• Spinal Stenosis/diagnostic imaging
• Spinal Stenosis/surgery
• Treatment Outcome

• Fibrosis
• Hypertrophy
• Ligamentum flavum
• Lumbar spinal canal stenosis
• miR-21

Histopathological analyses were performed in ligamentum flavum (LF) hypertrophy patients with lumbar spinal stenosis (LSS) and lumbar disc herniation (LDH).

The aim of the present study was to evaluate histopathological changes in LF patients with LSS and LDH.

LSS is the most common spinal disorder in elderly patients. This condition causes lower back and leg pain and paresis, and occurs as a result of degenerative changes in the lumbar spine, including bulging of the intervertebral discs, bony proliferation of the facet joints, and LF thickening; among these, LF thickening is considered a major contributor to the development of LSS.

A total of 71 patients operated with the surgical indications of LSS and LDH were included. LF samples were obtained from 31 patients who underwent decompressive laminectomy for symptomatic degenerative LSS (stenotic group) and from 40 patients who underwent lumbar discectomy for LDH (discectomy group). LF materials were examined histopathologically, and other specimens were examined for collagen content, elastic fiber number and array, and presence of calcification.

The stenotic and discectomy groups did not differ with regard to mean collagen concentration or mean elastic fiber number (p=0.430 and p=0.457, respectively). Mean elastic fiber alignment was 2.36±0.99 in the stenotic group and 1.38±0.54 in the discectomy group (p<0.001). Mean calcification was 0.39±0.50 in the stenotic group, whereas calcification was not detected (0.00±0.00) in the discectomy group; a statistically significant difference was detected (p<0.001) between groups.

LF hypertrophy in spinal stenosis may occur as a result of elastic fiber misalignment along with the development of calcification over time. Further studies determining the pathogenesis of LSS are needed.

• Hypertrophy
• Ligamentum flavum
• Pathology
• Spinal stenosis

Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.

• Adult
• Aged
• Animals
• Collagen/metabolism
• Disease Models, Animal
• Female
• Fibrosis
• Gene Expression
• Humans
• Hypertrophy
• Ligamentum Flavum/diagnostic imaging
• Ligamentum Flavum/metabolism
• Ligamentum Flavum/pathology
• Lumbar Vertebrae
• Macrophages/metabolism
• Mice
• Mice, Transgenic
• RNA, Messenger/genetics
• Stress, Mechanical
• Young Adult