Lumbar Ligamentum Flavum Hypertrophy Is Due to Accumulation of Inflammation-Related Scar Tissue

Sairyo, Koichi; Biyani, Ashok; Goel, Vijay K.; Leaman, Douglas W.; Booth, Robert; Thomas, J.; Ebraheim, Nabil A.; Cowgill, Ian A.; Mohan, Suneeth E.

doi:10.1097/01.brs.0000263407.25009.6e

Cited by 149 publications

(177 citation statements)

References 21 publications

(35 reference statements)

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“…12 In our study, there was an increase in expression of the metalloproteinases in both groups, with patients with disc herniation presenting a greater increase, compared with the stenosis of the lumbar canal group, adding the inflammatory factor to the biomechanical hypothesis of Soo and Kee-Young. 12 Saiyro et al 8 detected the presence of inflammatory cytokines, such as COX-2 and interleukin 1, 6, 8 and 15 in ligaments with and without increased thickness. They also demonstrated, in their article, that RNAm expression of these inflammatory cytokines occurs before the actual ligament hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 During hypertrophy of the ligamentum flavum, there is reduction in the content of elastic fibers and an increase in collagen fibers, calcification, ossification and chondrometaplasia. [4][5][6] Sairyo et al 7,8 have shown a correlation between the hardening of the ligamentum flavum and the degree of fibrosis, resulting in repetitive inflammatory processes due to the mechanical stresses that the ligament suffers during the movements of the spine. Park and collaborators demonstrated that an increase in TGFb (transforming growth factor beta) expression, the protein that controls cell proliferation and acts in the early stages of oncogenesis, is related to hypertrophy of the ligamentum flavum.…”

Section: Introductionmentioning

confidence: 99%

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Expression of matrix metalloproteinases 2 and 9 and TGF-b in ligamentum flavum hypertrophy

et al. 2014

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Objective: To evaluate the expression of matrix metalloproteinases and TGFb in patients with spinal stenosis and in younger patients who have herniated disc. Methods: 19 samples of LA were analyzed, nine of them with lumbar canal stenosis and 10 with disc herniation. Of the total, five patients were aged between 15 and 40 years, 10 were between 40 and 65 years and four had more than 65 years. Representative areas of LF were chosen based on the staining of tissues with hematoxylin-eosin. The 3μm-thick sections embedded in paraffin and fixed in formalin were deparaffinized and rehydrated. All ligaments were incubated overnight at 4 °C with primary antibodies. Results: An increase of TGFb was verified in older individuals, although without statistical significance. Conclusion: Metalloproteinases showed no significant difference between both groups with respect to age and type of abnormality of the spine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of matrix metalloproteinases 2 and 9 and TGF-b in ligamentum flavum hypertrophy

et al. 2014

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“…Previous research has demonstrated that TNFa and IL-b have inhibitory effects on elastin gene expression in lung fibroblasts. 8,14 Considering that inflammatory cytokines are frequently observed in degenerative discs and LF, 15,32,41 it could be inferred that TNFa and IL-b play roles in inflammatory ECM remodeling via both elastin degradation by inducing MMP-9 secretion and blocking elastin regeneration at the gene transcription level. Recent studies have identified that MMPs are related not only to ECM remodeling, but also angiogenesis and phagocytosis during inflammation, 26 and they regulate cellular functions and growth factors.…”

Section: Discussionmentioning

confidence: 99%

“…21,25,31 Sairyo et al demonstrated that LF hypertrophy is associated with scarring from inflammatory reactions. 31,32 It is important to understand the roles and cascades of MMPs in human LF cells because theoretically MMPs could be potential treatment targets for spinal stenosis. Additional histochemical and genotypic in vivo studies on inflammatory cytokines and MMPs are warranted in order to better understand the role of MMP-9 in elastin degradation.…”

Section: 44mentioning

confidence: 99%

“…15,41 Additionally, Sairyo et al reported the expression of TNFa and IL-1b genes in LF. 32 Thus, this study hypothesizes that MMPs play an important role in the elastin degradation of LF during the inflammation of LF cells. The expression and activity of MMP-2 and MMP-9 in cultured human LF cells in response to proinflammatory cytokines were examined using an in vitro model.…”

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confidence: 99%

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Expression of matrix metalloproteinase−2 and −9 in human ligamentum flavum cells treated with tumor necrosis factor−α and interleukin-1β

Kim

Hur

Park³

et al. 2016

SPI

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OBJECT An in vitro study was performed to understand the potential roles of matrix metalloproteinase (MMP)-2 and MMP-9 in the elastin degradation of human ligamentum flavum (LF) cells via treatment with tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β). Previous studies have identified a decreased elastin to collagen ratio in hypertrophic LF. Among the extracellular matrix remodeling endopeptidases, MMP-2 and MMP-9 are known to have elastolytic activity. The hypothesis that activated LF cells exposed to inflammation would secrete MMP-2 and MMP-9, thereby resulting in elastin degradation, was examined. METHODS To examine MMP-2 and MMP-9 expression in human LF, cells were isolated and cultured from LF tissues that were obtained during lumbar disc surgery. Isolated LF cells were equally divided into 3 flasks and subcultured. Upon cellular confluency, the LF cells were treated with TNFα, IL-1β, or none (as a control) and incubated for 48 hours. The conditioned media were collected and assayed for MMP-2 and MMP-9 using gelatin zymography and Western blot analysis. The electrophoresis bands were compared on densitometric scans using ImageJ software. RESULTS The conditioned media from the isolated human LF cells naturally expressed 72-kD and 92-kD gelatinolytic activities on gelatin zymography. The IL-1β-treated LF cells presented sustained increases in the proenzyme/zymogen forms of MMP−2 and −9 (proMMP-2 and proMMP-9), and activeMMP-9 expression (p = 0.001, 0.022, and 0.036, respectively); the TNFα-treated LF cells showed the most elevated proMMP9 secretion (p = 0.006), as determined by Western blot analyses. ActiveMMP-2 expression was not observed on zymography or the Western blot analysis. CONCLUSIONS TNFα and IL-1β promote proMMP-2 and proMMP-9 secretion. IL-1β appears to activate proMMP-9 in human LF cells. Based on these findings, selective MMP-9 blockers or antiinflammatory drugs could be potential treatment options for 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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Lumbar Ligamentum Flavum Hypertrophy Is Due to Accumulation of Inflammation-Related Scar Tissue

Abstract: Accumulation of fibrosis (scarring) causes hypertrophy of the ligamentum flavum. Inflammation-related gene expression is found in the ligamentum flavum. It might be possible to prevent the hypertrophy of ligamentum flavum with antiinflammatory drugs.

Cited by 149 publications

References 21 publications

Expression of matrix metalloproteinases 2 and 9 and TGF-b in ligamentum flavum hypertrophy

Expression of matrix metalloproteinases 2 and 9 and TGF-b in ligamentum flavum hypertrophy

Expression of matrix metalloproteinase−2 and −9 in human ligamentum flavum cells treated with tumor necrosis factor−α and interleukin-1β

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

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