Abstract
Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.
Highlights
Lumbar spinal canal stenosis (LSCS) is a common spinal disorder in elder people
To establish a ligamentum flavum (LF) hypertrophy mouse model, we initially developed a loading device by which the mouse LF was subjected to consecutive mechanical stress for the present experiment (Fig 1C)
By applying consecutive mechanical bending stress to the mouse LF, we demonstrated that mechanical stress was one of the direct causes of LF hypertrophy
Summary
Lumbar spinal canal stenosis (LSCS) is a common spinal disorder in elder people. There are approximately 250,000 to 500,000 LSCS patients in the United States, with the number increasing due to the aging of the population [1]. LSCS causes lower back pain, leg pain, and claudication, leading to severe disability in the activities of daily living [2]. These symptoms primarily result from the hypertrophy of the ligamentum flavum (LF). The LF is a spinal ligament that covers most of the posterior and lateral parts of the spinal canal. Hypertrophy of LF directly compresses the nerve roots and/or cauda equine, resulting in spinal disorders [3]. There have been several studies about LF hypertrophy, its pathomechanism remains unclear
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