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

• Project/Area Number: 16K15668
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Orthopaedic surgery
• Research Institution: Kyushu University
• Principal Investigator: Okada Seiji 九州大学, 生体防御医学研究所, 教授 (30448435)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 黄色靭帯 / 腰部脊柱管狭窄症 / 線維化 / マクロファージ

Outline of Final Research Achievements

Ligamentum flavum (LF) hypertrophy causes lumbar spinal canal stenosis, leading to leg pain and disability in activities of daily living in elderly individuals. Although there have been previous studies on LF hypertrophy, its pathomechanisms have not 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 micro-injury 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 micro-injury. These results suggested that macrophage infiltration was crucial for LF hypertrophy by stimulating collagen production in fibroblasts, providing better understanding the pathophysiology of LF hypertrophy.

Academic Significance and Societal Importance of the Research Achievements

我々の成果は、黄色靭帯肥厚の分子生物学的メカニズムにアプローチした初めての報告であり、同時に黄色靭帯肥厚研究における再現性のあるマウスモデルを確立したものである。現在、黄色靭帯肥厚による腰部脊柱管狭窄症や神経根圧迫による下肢症状に対しては、手術加療による黄色靭帯切除しかないが、将来的には１型コラーゲンの融解などで低侵襲に病態を改善できる可能性があり、本研究で確立した動物モデルが有効に活用されるものと考えている。

Research Products

• [Journal Article] Post-carbon-ion radiotherapy vertebral pathological fractures in upper cervical primary malignant spinal tumors treated by occipito-cervical fusion (2019)
  • Author(s): Baba Satoshi、Matsumoto Yoshihiro、Kawaguchi Kenichi、Iida Keiichiro、Saiwai Hirokazu、Okada Seiji、Matsunobu Akira、Shioyama Yoshiyuki、Nakashima Yasuharu
  • Journal Title: Archives of Orthopaedic and Trauma Surgery Volume: 印刷中 Issue: 11 Pages: 1525-1531
  • DOI: 10.1007/s00402-019-03183-x
  • Peer Reviewed
• [Journal Article] The acute phase serum zinc concentration is a reliable biomarker for predicting the functional outcome after spinal cord injury (2019)
  • Author(s): Kijima Ken、Kubota Kensuke、Hara Masamitsu、Kobayakawa Kazu、Yokota Kazuya、Saito Takeyuki、Yoshizaki Shingo、Maeda Takeshi、Konno Daijiro、Matsumoto Yoshihiro、Nakashima Yasuharu、Okada Seiji
  • Journal Title: EBioMedicine Volume: 41 Pages: 659-669
  • DOI: 10.1016/j.ebiom.2019.03.003
  • Peer Reviewed / Open Access
• [Journal Article] Prone position surgery for a professional sumo wrestler with thoracic ossification of the posterior longitudinal ligament resulting in intraoperative brachial plexus injury by hypertrophic pectoral muscles (2019)
  • Author(s): Saiwai Hirokazu、Okada Seiji、Kawaguchi Ken-ichi、Saito Takeyuki、Hayashida Mitsumasa、Matsushita Akinobu、Matsumoto Yoshihiro、Nakashima Yasuharu
  • Journal Title: Journal of Clinical Neuroscience Volume: 63 Pages: 227-230
  • DOI: 10.1016/j.jocn.2019.01.047
  • Peer Reviewed
• [Journal Article] Pathological changes of distal motor neurons after complete spinal cord injury (2019)
  • Author(s): Yokota Kazuya、Kubota Kensuke、Kobayakawa Kazu、Saito Takeyuki、Hara Masamitsu、Kijima Ken、Maeda Takeshi、Katoh Hiroyuki、Ohkawa Yasuyuki、Nakashima Yasuharu、Okada Seiji
  • Journal Title: Molecular Brain Volume: 12 Issue: 1
  • DOI: 10.1186/s13041-018-0422-3
  • Peer Reviewed
• [Journal Article] Cutting Edge: B cells expressing cyclic citrullinated peptide-specific antigen receptor are tolerized in normal conditions. (2018)
  • Author(s): Yamada H, Ozawa T, Kishi H, Okada S, Nakashima Y, Muraguchi A and Yoshikai Y.
  • Journal Title: J Immunol Volume: 201 Issue: 12 Pages: 3492-3496
  • DOI: 10.4049/jimmunol.1800826
  • Peer Reviewed
• [Journal Article] Periostin Promotes Fibroblast Migration and Inhibits Muscle Repair After Skeletal Muscle Injury (2018)
  • Author(s): Hara Masamitsu、Yokota Kazuya、Saito Takeyuki、Kobayakawa Kazu、Kijima Ken、Yoshizaki Shingo、Okazaki Ken、Yoshida Shigeo、Matsumoto Yoshihiro、Harimaya Katsumi、Nakashima Yasuharu、Okada Seiji
  • Journal Title: The Journal of Bone and Joint Surgery Volume: 100 Issue: 16 Pages: e108-e108
  • DOI: 10.2106/jbjs.17.01230
  • Peer Reviewed
• [Journal Article] Which Side-Bending X-ray Position is Better to Evaluate the Preoperative Curve Flexibility in Adolescent Idiopathic Scoliosis Patients, Supine or Prone? (2018)
  • Author(s): Bekki Hirofumi、Harimaya Katsumi、Matsumoto Yoshihiro、Kawaguchi Kenichi、Hayashida Mitsumasa、Okada Seiji、Doi Toshio、Nakashima Yasuharu
  • Journal Title: Asian Spine Journal Volume: 12 Issue: 4 Pages: 632-638
  • DOI: 10.31616/asj.2018.12.4.632
  • Peer Reviewed
• [Journal Article] Effect of cartilaginous endplates on extruded disc resorption in lumbar disc herniation (2018)
  • Author(s): Kawaguchi Kenichi、Harimaya Katsumi、Matsumoto Yoshihiro、Hayashida Mitsumasa、Okada Seiji、Iida Keiichiro、Kato Go、Tsuchiya Kuniyoshi、Doi Toshio、Oda Yoshinao、Iwamoto Yukihide、Nakashima Yasuharu
  • Journal Title: PLOS ONE Volume: 13 Issue: 4 Pages: e0195946-e0195946
  • DOI: 10.1371/journal.pone.0195946
  • Peer Reviewed
• [Journal Article] Histone H3.3 sub-variant H3mm7 is required for normal skeletal muscle regeneration (2018)
  • Author(s): Harada Akihito、Maehara Kazumitsu、Ono Yusuke、Taguchi Hiroyuki、Yoshioka Kiyoshi、Kitajima Yasuo、Xie Yan、Sato Yuko、Iwasaki Takeshi、Nogami Jumpei、Okada Seiji、Komatsu Tetsuro、Semba Yuichiro、Takemoto Tatsuya、Kimura Hiroshi、Kurumizaka Hitoshi、Ohkawa Yasuyuki
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1400-1400
  • DOI: 10.1038/s41467-018-03845-1
  • NAID: 120006949474
  • Peer Reviewed / Open Access
• [Journal Article] Sensitivity and specificity of the ‘knee-up test’ for estimation of the American Spinal Injury Association Impairment Scale in patients with acute motor incomplete cervical spinal cord injury (2018)
  • Author(s): Yugu? Itaru、Okada Seiji、Maeda Takeshi、Ueta Takayoshi、Shiba Keiichiro
  • Journal Title: Spinal Cord Volume: 56 Issue: 4 Pages: 347-354
  • DOI: 10.1038/s41393-017-0046-y
  • Peer Reviewed
• [Journal Article] Astrocyte reactivity and astrogliosis after spinal cord injury (2018)
  • Author(s): Okada Seiji、Hara Masamitsu、Kobayakawa Kazu、Matsumoto Yoshihiro、Nakashima Yasuharu
  • Journal Title: Neuroscience Research Volume: 126 Pages: 39-43
  • DOI: 10.1016/j.neures.2017.10.004
  • Peer Reviewed
• [Journal Article] The neurological outcome of radiotherapy versus surgery in patients with metastatic spinal cord compression presenting with myelopathy (2018)
  • Author(s): Iida Keiichiro、Matsumoto Yoshihiro、Setsu Nokitaka、Harimaya Katsumi、Kawaguchi Kenichi、Hayashida Mitsumasa、Okada Seiji、Nakashima Yasuharu
  • Journal Title: Archives of Orthopaedic and Trauma Surgery Volume: 138 Issue: 1 Pages: 7-12
  • DOI: 10.1007/s00402-017-2817-5
  • Peer Reviewed
• [Journal Article] Periostin Promotes Scar Formation through the Interaction between Pericytes and Infiltrating Monocytes/Macrophages after Spinal Cord Injury. (2017)
  • Author(s): Yokota K, Kobayakawa K, Saito T, Hara M, Kijima K, Ohkawa Y, Harada A, Okazaki K, Ishihara K, Yoshida S, Kudo A, Iwamoto Y, Okada S.
  • Journal Title: Am J Pathol. Volume: 187 Issue: 3 Pages: 639-653
  • DOI: 10.1016/j.ajpath.2016.11.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy. (2017)
  • Author(s): Saito T, Yokota K, Kobayakawa K, Hara M, Kubota K, Harimaya K, Kawaguchi K, Hayashida M, Matsumoto Y, Doi T, Shiba K, Nakashima Y, Okada S.
  • Journal Title: PLoS One Volume: 6 Issue: 1 Pages: 1-15
  • DOI: 10.1371/journal.pone.0169717
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Activation of ERK1/2 Causes Pazopanib Resistance via Downregulation of DUSP6 in Synovial Sarcoma Cells (2017)
  • Author(s): Yokoyama N, Matsunobu T, Matsumoto Y, Fukushi J, Endo M, Hatano M, Nabeshima A, Fukushima S, Okada S, and Iwamoto Y
  • Journal Title: ScイエンチフィcRえぽrts Volume: 7 Issue: 1 Pages: 45332-45332
  • DOI: 10.1038/srep45332
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin?N-cadherin pathway after spinal cord injury (2017)
  • Author(s): Hara Masamitsu、Kobayakawa Kazu、Ohkawa Yasuyuki、Kumamaru Hiromi、Yokota Kazuya、Saito Takeyuki、Kijima Ken、Yoshizaki Shingo、Harimaya Katsumi、Nakashima Yasuharu、Okada Seiji
  • Journal Title: Nature Medicine Volume: 23 Issue: 7 Pages: 818-828
  • DOI: 10.1038/nm.4354
  • Peer Reviewed / Open Access
• [Journal Article] Chd2 regulates chromatin for proper gene expression toward differentiation in mouse embryonic stem cells (2017)
  • Author(s): Semba Yuichiro、Harada Akihito、Maehara Kazumitsu、Oki Shinya、Meno Chikara、Ueda Jun、Yamagata Kazuo、Suzuki Atsushi、Onimaru Mitsuho、Nogami Jumpei、Okada Seiji、Akashi Koichi、Ohkawa Yasuyuki
  • Journal Title: Nucleic Acids Research Volume: 45 Issue: 15 Pages: 8758-8772
  • DOI: 10.1093/nar/gkx475
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of RhoA by STAT3 coordinates glial scar formation (2017)
  • Author(s): Renault-Mihara Francois、Mukaino Masahiko、Shinozaki Munehisa、Kumamaru Hiromi、Kawase Satoshi、Baudoux Matthieu、Ishibashi Toshiki、Kawabata Soya、Nishiyama Yuichiro、Sugai Keiko、Yasutake Kaori、Okada Seiji、Nakamura Masaya、Okano Hideyuki
  • Journal Title: The Journal of Cell Biology Volume: 216 Issue: 8 Pages: 2533-2550
  • DOI: 10.1083/jcb.201610102
• [Journal Article] Evaluation of Risk Factors for Vertebral Compression Fracture after Carbon-Ion Radiotherapy for Primary Spinal and Paraspinal Sarcoma (2017)
  • Author(s): Matsumoto Yoshihiro、Shinoto Makoto、Endo Makoto、Setsu Nokitaka、Iida Keiichiro、Fukushi Jun-Ichi、Kawaguchi Kenichi、Okada Seiji、Bekki Hirofumi、Imai Reiko、Kamada Tadashi、Shioyama Yoshiyuki、Nakashima Yasuharu
  • Journal Title: BioMed Research International Volume: 2017 Pages: 1-7
  • DOI: 10.1155/2017/9467402
• [Journal Article] Metabolic Tumor Volume by 18F-FDG PET/CT Can Predict the Clinical Outcome of Primary Malignant Spine/Spinal Tumors (2017)
  • Author(s): Matsumoto Yoshihiro、Baba Shingo、Endo Makoto、Setsu Nokitaka、Iida Keiichiro、Fukushi Jun-Ichi、Kawaguchi Kenichi、Okada Seiji、Bekki Hirofumi、Isoda Takuro、Kitamura Yoshiyuki、Honda Hiroshi、Nakashima Yasuharu
  • Journal Title: BioMed Research International Volume: 2017 Pages: 1-8
  • DOI: 10.1155/2017/8132676
  • Peer Reviewed
• [Journal Article] Macrophage Infiltration Is a Causative Factor for Ligamentum Flavum Hypertrophy through the Activation of Collagen Production in Fibroblasts (2017)
  • Author(s): 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
  • Journal Title: The American Journal of Pathology Volume: 187 Issue: 12 Pages: 2831-2840
  • DOI: 10.1016/j.ajpath.2017.08.020
  • Peer Reviewed / Open Access
• [Presentation] 黄色靱帯の肥厚メカニズム解明 (2018)
  • Author(s): 岡田誠司
  • Organizer: 第47回日本脊椎脊髄病学会学術集会
• [Presentation] マウスモデルを用いた黄色靱帯の肥厚メカニズム解明 (2018)
  • Author(s): 岡田誠司
  • Organizer: 第91回日本整形外科学会
• [Presentation] 血清亜鉛濃度はせき損後の予後予測に有用である (2018)
  • Author(s): 岡田誠司
  • Organizer: 第37回日本運動器移植再生医学会
• [Presentation] 脊髄損傷後のグリア瘢痕形成メカニズムの解明と治療への応用 (2018)
  • Author(s): 岡田誠司
  • Organizer: 第33回日本整形外科学会基礎学術集会（招待講演）
  • Invited
• [Presentation] Treatment for Spinal cord injury (Conservative Vs Surgery) (2018)
  • Author(s): Seiji Okada
  • Organizer: 1st international cervical symposium in Korea（招待講演）（国際学会）
  • Int'l Joint Research / Invited
• [Presentation] 黄色靭帯の肥厚メカニズム解明 (2018)
  • Author(s): 岡田誠司
  • Organizer: 第47回日本脊椎脊髄病学会
• [Presentation] 脊髄損傷後のグリア瘢痕形成メカニズムの解明と治療への応用 (2017)
  • Author(s): 岡田誠司
  • Organizer: 第46回日本脊椎脊髄病学会
• [Presentation] グリア瘢痕形成メカニズムの解明と治療への応用 (2017)
  • Author(s): 岡田誠司
  • Organizer: 第52回日本脊髄障害医学会
• [Presentation] Spinal Cord Regeneration and Astrogliosis (2017)
  • Author(s): Okada S.
  • Organizer: The 27th Hot Spring Harbor International Conference
• [Remarks] 研究室ホームページ
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/pathophysiology/index.html