Matrix Metalloproteinase-3 on Ligamentum Flavum in Degenerative Lumbar Spondylolisthesis

Department of Orthopaedic Surgery, Kang-Nam St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Spine (Impact Factor: 2.3). 07/2009; 34(16):E552-7. DOI: 10.1097/BRS.0b013e3181aa0232
Source: PubMed


Human ligamentum flavum (LF) was examined for the activity level of matrix metalloproteinase-3 (MMP-3) in degenerative spondylolithesis (DS) patients using immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time PCR.
To investigate the hypothesis that the activity of MMP-3 is elevated in LF of DS patients, which might contribute to DS pathogenesis.
MMP-3 is a proteinase produced by connective tissue cells and is responsible for the degradation and modification of extracellular matrix molecules. MMP-3 activity has been established in articular cartilage, synovial membrane, and intervertebral discs, but not in the LF.
The experimental group consisted of 18 patients with DS and the control group consisted of 18 patients with spinal stenosis (SS) without any instabilities. MMP-3 expression was measured with in situ using immunohistochemistry and both for mRNA and protein levels.
The MMP-3 positive cell ratio in the LF observed in DS patients was substantially higher than in SS patients (P = 0.030). In Western blot, the average optical density (OD) of MMP-3 was higher in LF of DS than of SS (P = 0.028). There was greater MMP-3 expression in DS patients as quantified by RT-PCR (P = 0.004).
Our study shows that MMP-3 expression in the LF of DS patients was significantly higher than in SS patients. Increased MMP-3 expression may be associated with the degenerative changes of LF in DS patients comprising one of the mechanisms of pathogenesis in DS.

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    • "Hypertrophied LF tissues become disorganized and show decreased levels and degeneration of elastic fibers but increased levels of collagen fibers [6, 7]. During LF hypertrophy, there are increases in the expression and activity of various molecules, including matrix metalloproteases (MMPs) [8–10], tissue inhibitors of matrix metalloproteases (TIMPs) [11], platelet-derived growth factor-BB (PDGF-BB) [12], connective tissue growth factor (CTGF) [13], bone morphogenetic protein (BMP) [14], and inflammatory cytokines [15–17]. "
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    ABSTRACT: Hypertrophy of ligamentum flavum (LF) contributes to lumbar spinal stenosis (LSS) and is caused mainly by fibrosis. Recent data indicate that miR-155 plays a crucial role in the pathogenesis of different fibrotic diseases. This study aimed to test the hypothesis that miR-155 exerts effects on LF thickness by regulating collagen expression. We found that LF thickness and the expression of collagen I and, collagen III were higher in LF from LSS patients than in LF from lumbar disc herniation (LDH) patients (P < 0.01). The expression of miR-155 was significantly higher in LF from LSS group than in LF from LDH group (P < 0.01). miR-155 level was positively correlated with LF thickness (r = 0.958, P < 0.01), type I collagen level (r = 0.825, P < 0.01), and type III collagen level (r = 0.827, P < 0.01). miR-155 mimic increased mRNA and protein expression of collagen I and collagen III in fibroblasts isolated from LF, while miR-155 sponge decreased mRNA and protein expression of collagen I and III in fibroblasts. In conclusions, miR-155 is a fibrosis-associated miRNA and may play important role in the pathogenesis of LF hypertrophy.
    Disease markers 05/2014; 2014(3):786543. DOI:10.1155/2014/786543 · 1.56 Impact Factor
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    • "Very few of the studies have looked beyond morphology of the spine when looking for differences between degenerative spondylolisthesis and spinal stenosis. One study has shown different amounts of matrix metalloproteinases in ligamentum flavum in these two patient groups, suggesting a biochemical pathway for increased collagen laxity, which subsequently could lead to the slip [9]. Bone mineral density has been shown to be independently associated with degenerative disc disease [10], and one study, on bone mineral density of the lumbar spine in elderly women, with degenerative spondylolisthesis, has suggested different pathomechanisms on different levels. "
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    ABSTRACT: Spinal stenosis and degenerative spondylolisthesis share many symptoms and the same treatment, but their causes remain unclear. Bone mineral density has been suggested to play a role. The aim of this study was to investigate differences in spinal bone density between spinal stenosis and degenerative spondylolisthesis patients. 81 patients older than 60 years, who underwent DXA-scanning of their lumbar spine one year after a lumbar spinal fusion procedure, were included. Radiographs were assessed for disc height, vertebral wedging, and osteophytosis. Pain was assessed using the Low Back Pain Rating Scale pain index. T-score of the lumbar spine was significantly lower among degenerative spondylolisthesis patients compared with spinal stenosis patients (-1.52 versus -0.52, P = 0.04). Thirty-nine percent of degenerative spondylolisthesis patients were classified as osteoporotic and further 30% osteopenic compared to only 9% of spinal stenosis patients being osteoporotic and 30% osteopenic (P = 0.01). Pain levels tended to increase with poorer bone status (P = 0.06). Patients treated surgically for symptomatic degenerative spondylolisthesis have much lower bone mass than patients of similar age treated surgically for spinal stenosis. Low BMD might play a role in the development of the degenerative spondylolisthesis, further studies are needed to clarify this.
    08/2013; 2013:123847. DOI:10.1155/2013/123847
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    ABSTRACT: Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in the elderly, and ligamentum flavum (LF) hypertrophy is an important cause of LSCS. Matrix metalloproteinase 13 (MMP13) can degrade fibrillar collagens and elastic microfibrils, and is involved in inflammation and fibrosis. The purpose of this study was to compare the expression of MMP13 in the LF from LSCS patients with diabetes mellitus [DM (+)] with that in the LF from patients without DM [DM (-)] and to analyze the relationship among DM, MMP13 expression, and LF hypertrophy. LFs from 11 DM (+) and 24 DM (-) LSCS patients were analyzed in this study. Histology analysis using hematoxylin and eosin and Masson's trichrome stain was performed for each LF. The expression of MMP13 was analyzed by quantitative real-time PCR. The thickness of LF was measured by CT. In the LF from DM (+) LSCS patients, the elastic fibers were more disorganized and had lower volumes than in the LF from DM (-) LSCS patients, while more fibrotic tissue was observed in the LF from DM (+) than from DM (-) LSCS patients. MMP13 expression was significantly higher in the LF from DM (+) LSCS patients (0.46 ± 0.61 vs. 0.05 ± 0.09, P = 0.002). The LF from the DM (+) LSCS patients was significantly thicker than that from the DM (-) LSCS patients (5.0 ± 0.9 vs. 3.1 ± 0.8 mm, P < 0.01), and the thickness was correlated with the expression of MMP13 (correlation coefficient = 0.43, P = 0.01, Pearson's correlation test). DM-related MMP13 expression can be one of the factors contributing to fibrosis and hypertrophy of the LF. Further research on the mechanism of this process may lead to new therapies for LF hypertrophy.
    Journal of Orthopaedic Science 08/2011; 16(6):785-90. DOI:10.1007/s00776-011-0135-2 · 0.94 Impact Factor
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