Study Design. A histologic, biologic, and immunohistochemical assessment using human samples of the lumbar ligamentum flavum.
Objective. To prove our hypothesis that hypertrophy of the ligamentum flavum is caused by accumulation of inflammation-related scar tissue.
Summary of Background Data. Lumbar spinal canal stenosis is 1 of the most common spinal disorders in elderly patients. Canal narrowing, in part, results from hypertrophy of the ligamentum flavum. The hypertrophy mechanism remains unclear. Based on our preliminary analyses, we have previously proposed that the hypertrophy may be due to accumulation of scar tissue in the ligament. Scar tissue is reported to develop after inflammation; however, there is no report, including our previous study, on inflammation in the ligamentum flavum. There is a need for an in-depth investigation of any relationship between inflammation and scar formation in the ligamentum flavum. If inflammation is related to hypertrophy, we may control/delay the hypertrophy by inhibiting the inflammation.
Methods. Twenty-one ligamentum flavum samples were obtained for the histologic study. Trichrome and Verhoeff-van Gieson stains were used to assess the degree of fibrosis (scarring) and content of elastic fibers, respectively. Two ligamentum flavum samples, hypertrophied and thin control ligaments, were used for a global genetic assessment by oligonucleotide gene array technology with gene chips. Messenger ribonucleic acid expression of cyclooxygenase (COX)-2 was quantitatively measured from 16 ligamentum flavum samples using real-time reverse transcriptase polymerase chain reaction. Immunohistochemistry evaluated the cellular location of COX-2 in ligamentum flavum.
Results. In the hypertrophied ligament, severe fibrosis (scarring) was observed in the entire area of the ligamentum flavum, and the severity of scarring showed a significant (r = 0.79; P < 0.0001) and positive linear correlation with ligamentum flavum thickness. Gene array results showed in both thin/control and hypertrophied ligaments expression of inflammation-related genes such as COX-2, tumor necrosis factor-α, and interleukin-1, 6, 8, and 15. Real-time polymerase chain reaction showed COX-2 messenger ribonucleic acid expression in all ligamentum flavum samples. Its expression showed weak positive linear correlation with the thickness of ligament. COX-2 was released from vascular endothelial cells in ligamentum flavum as per the immunohistochemical analysis.
Conclusions. 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.
Accumulation of fibrosis (scarring) causes hypertrophy of the ligamentum flavum. A sign of inflammation, which is considered to be 1 of the initial events of scarring, was found in ligamentum flavum. Our findings suggest the possibility of controlling or preventing ligamentum flavum hypertrophy through the inhibition of the tissue inflammation.
From the *Spine Research Center, Department of Bioengineering and Orthopedics, University of Toledo, Toledo, OH; †Department of Orthopedics, University of Tokushima, Tokushima, Japan; ‡Department of Biological Sciences, University of Toledo, Toledo, OH; and §Department of Pathology, University of Toledo, Toledo, OH.
Acknowledgment date: October 17, 2005. First revision date: September 2, 2006. Second revision date: November 1, 2006. Acceptance date: December 4, 2006.
The manuscript submitted does not contain information about medical device(s)/drug(s).
No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.
Address correspondence and reprint requests to Vijay K. Goel, PhD, Professor and Chairman, Department of Bioengineering, 5051C, Nitschke Hall, University of Toledo, Toledo OH 43606; E-mail: firstname.lastname@example.org