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Macrophage Infiltration Is a Causative Factor for Ligamentum Flavum Hypertrophy through the Activation of Collagen Production in Fibroblasts.

Authors
  • Saito, Takeyuki1
  • Hara, Masamitsu1
  • Kumamaru, Hiromi2
  • Kobayakawa, Kazu2
  • Yokota, Kazuya3
  • Kijima, Ken1
  • Yoshizaki, Shingo1
  • Harimaya, Katsumi2
  • Matsumoto, Yoshihiro2
  • Kawaguchi, Kenichi2
  • Hayashida, Mitsumasa2
  • Inagaki, Yutaka4
  • Shiba, Keiichiro3
  • Nakashima, Yasuharu2
  • Okada, Seiji5
  • 1 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. , (Japan)
  • 2 Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. , (Japan)
  • 3 Department of Orthopaedic Surgery, Spinal Injuries Center, Fukuoka, Japan. , (Japan)
  • 4 Center for Matrix Biology and Medicine, Graduate School of Medicine, Tokai University, Isehara, Japan; Department of Regenerative Medicine, School of Medicine, Tokai University, Isehara, Japan. , (Japan)
  • 5 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. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
American Journal Of Pathology
Publisher
Elsevier
Publication Date
Dec 01, 2017
Volume
187
Issue
12
Pages
2831–2840
Identifiers
DOI: 10.1016/j.ajpath.2017.08.020
PMID: 28935572
Source
Medline
License
Unknown

Abstract

Ligamentum flavum (LF) hypertrophy causes lumbar spinal canal stenosis, leading to leg pain and disability in activities of daily living in elderly individuals. Although previous studies have been performed on LF hypertrophy, its pathomechanisms have not been fully elucidated. In this study, we demonstrated that infiltrating macrophages were a causative factor for LF hypertrophy. Induction of macrophages into the mouse LF by applying a microinjury resulted in LF hypertrophy along with collagen accumulation and fibroblasts proliferation at the injured site, which were very similar to the characteristics observed in the severely hypertrophied LF of human. However, we found that macrophage depletion by injecting clodronate-containing liposomes counteracted LF hypertrophy even with microinjury. For identification of fibroblasts in the LF, we used collagen type I α2 linked to green fluorescent protein transgenic mice and selectively isolated green fluorescent protein-positive fibroblasts from the microinjured LF using laser microdissection. A quantitative RT-PCR on laser microdissection samples revealed that the gene expression of collagen markedly increased in the fibroblasts at the injured site with infiltrating macrophages compared with the uninjured location. These results suggested that macrophage infiltration was crucial for LF hypertrophy by stimulating collagen production in fibroblasts, providing better understanding of the pathophysiology of LF hypertrophy.

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