title: Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy.
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.
authors.affiliation: 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.
authors.forename: Takeyuki
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Orthopaedic Surgery, Spinal Injuries Center, Fukuoka, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yokota
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kazu
authors.initials: K
authors.lastname: Kobayakawa
authors.affiliation: 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.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Hara
authors.affiliation: Department of Orthopaedic Surgery, Spinal Injuries Center, Fukuoka, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Harimaya
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Hayashida
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Orthopaedic Surgery, Kyushu University Beppu Hospital, Oita, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Doi
authors.affiliation: Department of Orthopaedic Surgery, Spinal Injuries Center, Fukuoka, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nakashima
authors.affiliation: 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.
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D006984:Hypertrophy; D017843:Ligamentum Flavum / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology*; D008159:Lumbar Vertebrae; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D013314:Stress, Mechanical; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D003094:Collagen