Saito Takeyuki, Yokota Kazuya, Kobayakawa Kazu, Hara Masamitsu, Kubota Kensuke, Harimaya Katsumi, Kawaguchi Kenichi, Hayashida Mitsumasa, Matsumoto Yoshihiro, Doi Toshio, Shiba Keiichiro, Nakashima Yasuharu, Okada Seiji
Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
PLoS One. 2017 Jan 6;12(1):e0169717. doi: 10.1371/journal.pone.0169717. eCollection 2017.
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.
腰椎管狭窄症（LSCS）是老年人中最常见的脊柱疾病之一，随着人口老龄化，LSCS患者数量不断增加。黄韧带（LF）是位于椎管内的脊柱韧带，LF肥大导致神经根和/或马尾神经直接受压，是LSCS的主要原因。尽管之前有关于LF肥大的研究，但其发病机制仍不清楚。本研究的目的是建立相关的LF肥大小鼠模型并研究疾病相关因素。首先，我们关注机械应力，开发了一种用于对小鼠LF施加连续机械屈伸应力的加载装置。在机械应力加载12周后，我们发现与对照组相比，应力组的LF厚度显著增加。此外，胶原纤维面积、LF细胞数量以及几种纤维化相关因子的基因表达均显著增加。然而，在这个机械应力模型中，没有巨噬细胞浸润、血管生成，也没有转化生长因子-β1（TGF-β1）表达增加，而这些是LSCS患者LF肥大的特征。因此，我们研究了浸润巨噬细胞对LF肥大的影响。通过对小鼠LF进行微损伤诱导巨噬细胞浸润后，我们发现在损伤后2周损伤部位胶原合成过多且TGF-β1表达增加，并在损伤后6周进一步证实了LF肥大。我们的研究结果表明机械应力是LF肥大的一个致病因素，并强烈提示巨噬细胞浸润通过刺激胶原产生在LF肥大进展中的重要性。
