The Journal of Bone and Joint Surgery (American). 2005;87:2750-2757.
doi:10.2106/JBJS.E.00251
© 2005 The Journal of Bone and Joint Surgery, Inc.
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Hypertrophy of Ligamentum Flavum in Lumbar Spinal Stenosis Associated with Increased Proteinase Inhibitor Concentration

Jong-Beom Park, MD, PhD1, Jin-Kyung Lee, MD, PhD2, Sung-Jin Park, MD1 and K. Daniel Riew, MD3

1 Department of Orthopaedic Surgery, Uijongbu St. Mary's Hospital, The Catholic University of Korea School of Medicine, 65-1 Kumho-dong, Uijongbu-si, Kyunggi-do, 480-130, Republic of Korea. E-mail address for J.-B. Park: spinepjb{at}catholic.ac.kr
2 Department of Laboratory Medicine, Korea Institute of Radiological and Medical Science, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea
3 Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University School of Medicine, Suite 11300 West Pavilion, St. Louis, MO 63110

Investigation performed at the Catholic University of Korea School of Medicine, Seoul, Republic of Korea

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from the 2005 Research Fund of The Catholic University of Korea School of Medicine. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

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.


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