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

Takeyuki Saito, Masamitsu Hara, Hiromi Kumamaru, Kazu Kobayakawa, Kazuya Yokota, Ken Kijima, Shingo Yoshizaki, Katsumi Harimaya, Yoshihiro Matsumoto, Kenichi Kawaguchi, Mitsumasa Hayashida, Yutaka Inagaki, Keiichiro Shiba, Yasuharu Nakashima, Seiji Okada

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2831-2840
Number of pages10
JournalAmerican Journal of Pathology
Volume187
Issue number12
DOIs
Publication statusPublished - Dec 2017

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Ligamentum Flavum
Hypertrophy
Collagen
Fibroblasts
Macrophages
Microdissection
Lasers
Clodronic Acid
Spinal Stenosis
Spinal Canal
Collagen Type II
Activities of Daily Living
Green Fluorescent Proteins
Liposomes
Transgenic Mice
Leg

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Macrophage Infiltration Is a Causative Factor for Ligamentum Flavum Hypertrophy through the Activation of Collagen Production in Fibroblasts. / Saito, Takeyuki; Hara, Masamitsu; Kumamaru, Hiromi; Kobayakawa, Kazu; Yokota, Kazuya; Kijima, Ken; Yoshizaki, Shingo; Harimaya, Katsumi; Matsumoto, Yoshihiro; Kawaguchi, Kenichi; Hayashida, Mitsumasa; Inagaki, Yutaka; Shiba, Keiichiro; Nakashima, Yasuharu; Okada, Seiji.

In: American Journal of Pathology, Vol. 187, No. 12, 12.2017, p. 2831-2840.

Research output: Contribution to journalArticle

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