The Increased Expression of Matrix Metalloproteinases Associated with Elastin Degradation and Fibrosis of the Ligamentum Flavum in Patients with Lumbar Spinal Stenosis

Abstract

BackgroundOne of the characteristics of spinal stenosis is elastin degradation and fibrosis of the extracellular matrix of the ligamentum flavum. However, there have been no investigations to determine which biochemical factors cause these histologic changes. So we performed the current study to investigate the hypothesis that matrix metalloproteinases (MMPs), which possess the ability to cause extracellular matrix remodeling, may play a role as a mediator for this malady in the ligamentum flavum.MethodsThe ligamentum flavum specimens were surgically obtained from thirty patients with spinal stenosis, as well as from 30 control patients with a disc herniation. The extents of ligamentum flavum elastin degradation and fibrosis were graded (grade 0-4) with performing hematoxylin-eosin staining and Masson's trichrome staining, respectively. The localization of MMP-2 (gelatinase), MMP-3 (stromelysin) and MMP-13 (collagenase) within the ligamentum flavum tissue was determined by immunohistochemistry. The expressions of the active forms of MMP-2, MMP-3 and MMP-13 were determined by western blot analysis, and the blots were quantified using an imaging densitometer. The histologic and biochemical results were compared between the two conditions.ResultsElastin degradation and fibrosis of the ligamentum flavum were significantly more severe in the spinal stenosis samples than that in the disc herniation samples (3.14 ± 0.50 vs. 0.55 ± 0.60, p < 0.001; 3.10 ± 0.57 vs. 0.76 ± 0.52, p < 0.001, respectively). The expressions of the active form of MMPs were identified in all the ligamentum flavums of the spinal stenosis and disc herniation patients. The expressions of active MMP-2 and MMP-13 were significantly higher in the spinal stenosis samples than that in the disc herniation samples (both p < 0.05). The expression of active MMP-3 was slightly higher in the spinal stenosis samples than that in the disc herniation samples, but the difference was not statistically significant (p = 0.131). MMP-2, -3, and -13 were positively stained on the ligamentum flavum fibroblasts.ConclusionsThe current results suggest that the increased expression of active MMPs by the ligamentum flavum fibroblasts might be related to the elastin degradation and fibrosis of the ligamentum flavum in the patients who suffer with lumbar spinal stenosis.

Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection

“…In addition to its role in the development of microfibrils, another important role of MFAP-4 in the suppression of MMP-12 activity is illustrated both in our in vivo and in vitro analyses. In parallel with previous studies indicating that elastin-derived peptides induce the expression of various kinds of MMPs (including MMP-12) in several types of cells5253 and that UV radiation alone is sufficient to selectively degrade many elastic fiber associated proteins54, the enhancement of MFAP-4 is thought to be in charge of the suppression of MMP-12 activity as well as the promotion of microfibril formation which is essential for the organization of functional elastic fibers, resulting in the observed photoprotection.…”

Expression of Hypoxia-inducible Factor-1α, Vascular Endothelial Growth Factor, and Matrix Metalloproteinases 1, 3, and 9 in Hypertrophied Ligamentum Flavum

“…There is some evidence that modulation of MMP activity may offer a novel therapeutic option for early LSS; our findings would be helpful in this regard. In a recent study on cultured rat Achilles tendon cells, Tsai et al 42 showed upregulated expression of MMPs 1,8,9,and 13 after incubation with ibuprofen (a common nonsteroidal anti-inflammatory drug regularly used in LSS treatment). Further studies are necessary to understand the clinical relevance of these findings, especially for LF hypertrophy.…”

Dose- and time-dependent effect of high glucose concentration on viability of notochordal cells and expression of matrix degrading and fibrotic enzymes

“…They are coexpressed with MMPs and contribute to the regulation of their activity so that increases in TIMP levels reduce MMP activity. However, contradictory results regarding the delicate balance between MMP and TIMP expression have been reported in several pathological conditions, such as abdominal aortic aneurysms, chronic liver injury, and osteoarthritis [27][28][29]. According to Won et al, the expression of MMPs and TIMPs was significantly increased in the nucleus pulposus of diabetic rats compared with non-diabetic rats of the same ages [18].…”