Background: It is well known that age-related fibrosis, or decreases
in the elastin-to-collagen ratio of the ligamentum flavum, along with
hypertrophy of the ligamentum flavum, are associated with lumbar spinal
stenosis. However, the molecular mechanism by which this fibrosis and
hypertrophy develop is unknown. Tissue inhibitors of matrix metalloproteinase
(TIMPs) are proteinase inhibitors that suppress extracellular matrix
degradation. Elevated TIMP-1 and TIMP-2 expression has been implicated in
various fibrotic diseases of the liver, kidney, lung, and heart. These TIMPs
can also induce cellular proliferation and inhibit apoptosis in a wide range
of cell types. These findings led us to postulate that TIMP-1 and TIMP-2 might
also be associated with hypertrophy and fibrosis of the ligamentum flavum in
lumbar spinal stenosis.
Methods: We quantified and localized TIMP expression in ligamentum
flavum tissues that had been obtained during surgery from thirty patients with
spinal stenosis and from thirty gender-matched control patients with disc
herniation. The thickness of the ligamentum flavum at the level of the facet
joint was measured on axial T1-weighted magnetic resonance images. In
addition, we examined ligamentum flavum tissues for the expression of markers
of cellular proliferation and apoptosis.
Results: The ligamentum flavum was significantly thicker in the
patients with spinal stenosis (mean, 5.68 mm) than in the patients with disc
herniation (mean, 2.70 mm) (p < 0.001). The concentration of TIMP-2 in the
ligamentum flavum was significantly higher in the patients with spinal
stenosis (mean, 12.62 ng/mL) than in those with disc herniation (mean, 8.85
ng/mL) (p = 0.028). TIMP-1 and TIMP-2 were detected in the cytoplasm of
ligamentum flavum fibroblasts. TIMP-1 and TIMP-2 concentrations were
associated with hypertrophy of the ligamentum flavum (p = 0.015 and p = 0.003,
respectively). None of the samples from the patients with stenosis had
evidence of proliferation of ligamentum flavum fibroblasts. The expression of
markers for apoptosis was significantly higher in the patients with spinal
stenosis (58.8%) than in those with disc herniation (26.6%) (p <
0.001).
Conclusions: Increased TIMP expression has been implicated in
fibrosis and hypertrophy of the extracellular matrix of several organs. Our
results suggest that increased expression of TIMP-2 in ligamentum flavum
fibroblasts is associated with fibrosis and hypertrophy of the ligamentum
flavum in patients with spinal stenosis.
Clinical Relevance: Gaining insights into the molecular pathogenesis
of hypertrophy and fibrosis of the ligamentum flavum may eventually result in
new therapeutic and potentially noninvasive alternatives to the treatment of
spinal stenosis.