ID | 61785 |
フルテキストURL | |
著者 |
Okui, Tatsuo
Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
Hiasa, Masahiro
Department of Biomaterials and Bioengineerings, University of Tokushima Graduate School of Dentistry
Ryumon, Shoji
Ono, Kisho
Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
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Kunisada, Yuki
Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
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Ibaragi, Soichiro
Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
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Sasaki, Akira
Department of Oral and Maxillofacial Surgery and Biopathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science
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Roodman, G. David
Department of Medicine, Hematology Oncology, Indiana University School of Medicine
White, Fletcher A.
Department of Anesthesia, Paul and Carole Stark Neurosciences Research Institute
Yoneda, Toshiyuki
Department of Cellular and Molecular Biochemistry, Osaka University Graduate School of Dentistry
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抄録 | Bone pain is a common complication of breast cancer (BC) bone metastasis and is a major cause of increased morbidity and mortality. Although the mechanism of BC-associated bone pain (BCABP) remains poorly understood, involvement of BC products in the pathophysiology of BCABP has been proposed. Aggressive cancers secrete damage-associated molecular patterns (DAMPs) that bind to specific DAMP receptors and modulate cancer microenvironment. A prototypic DAMP, high mobility group box 1 (HMGB1), which acts as a ligand for the receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), is increased in its expression in BC patients with poor outcomes. Here we show that 4T1 mouse BC cells colonizing bone up-regulate the expression of molecular pain markers, phosphorylated ERK1/2 (pERK) and pCREB, in the dorsal root ganglia (DRGs) innervating bone and induced BCABP as evaluated by hind-paw mechanical hypersensitivity. Importantly, silencing HMGB1 in 4T1 BC cells by shRNA reduced pERK and pCREB and BCABP with decreased HMGB1 levels in bone. Further, administration of a neutralizing antibody to HMGB1 or an antagonist for RAGE, FPS-ZM1, ameliorated pERK, pCREB and BCABP, while a TLR4 antagonist, TAK242, showed no effects. Consistent with these in vivo results, co-cultures of F11 sensory neuron-like cells with 4T1 BC cells in microfluidic culture platforms increased neurite outgrowth of F11 cells, which was blocked by HMGB1 antibody. Our results show that HMGB1 secreted by BC cells induces BCABP via binding to RAGE of sensory neurons and suggest that the HMGB1/RAGE axis may be a potential novel therapeutic target for BCABP.
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キーワード | Breast cancer
Bone pain
Sensory neurons
HMGB1
RAGE
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発行日 | 2021-02-28
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出版物タイトル |
Journal of Bone Oncology
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巻 | 26巻
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出版者 | Elsevier
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開始ページ | 100330
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ISSN | 22121374
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資料タイプ |
学術雑誌論文
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言語 |
英語
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OAI-PMH Set |
岡山大学
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著作権者 | © 2020 The Authors.
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論文のバージョン | publisher
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PubMed ID | |
DOI | |
Web of Science KeyUT | |
関連URL | isVersionOf https://doi.org/10.1016/j.jbo.2020.100330
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ライセンス | http://creativecommons.org/licenses/by-nc-nd/4.0/
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Citation | Tatsuo Okui, Masahiro Hiasa, Shoji Ryumon, Kisho Ono, Yuki Kunisada, Soichiro Ibaragi, Akira Sasaki, G. David Roodman, Fletcher A. White, Toshiyuki Yoneda, The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone, Journal of Bone Oncology, Volume 26, 2021, 100330, ISSN 2212-1374, https://doi.org/10.1016/j.jbo.2020.100330.
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助成機関名 |
日本学術振興会
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助成番号 | 18K17225
17H04377
20H03859
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オープンアクセス(出版社) |
OA
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オープンアーカイブ(出版社) |
非OpenArchive
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