並列タイトル等抗RANKL抗体休薬により作製した顎骨壊死様病変寛解モデルにおけるマクロファージのM１からM２への極性変化
授与機関名Nagasaki University (長崎大学)
一般注記Denosumab-related osteonecrosis of the jaw (DRONJ), which mainly occurs in cancer patients receiving anti-receptor activator NF-kappaB ligand (RANKL) antibody, reduces oral health-related quality of life. However, the exact mechanisms of and definitive treatment strategies for DRONJ remain unknown. We hypothesized that cessation of denosumab heals and/or ameliorates DRONJ, since it is a protein-based antibody agent, although stopping denosumab should be avoided in clinical situations. Therefore, the aims of this study were: 1) to create a healing and/or amelioration murine model of DRONJ-like lesions induced by chemotherapy/anti-RANKL antibody (mAb) combination therapy and tooth extraction; and 2) to investigate histopathology and immunopathology in the extraction sockets by comparing the murine model of DRONJ-like lesions with the amelioration/healing model of DRONJ-like lesions. Eight-week-old, female C57B/6J mice received chemotherapeutic drug (cyclophosphamide: CY) and mAb combination therapy (CY/mAb) with tooth extraction. Open wounds were sustained in CY/mAb-treated mice at 2 and 4 weeks post-extraction. Impaired socket healing was diagnosed as CY/mAb-related ONJ-like lesions at 3 weeks post-extraction in this study. Next, mAb was discontinued for 2 and 4 weeks after diagnosis of CY/mAb-related ONJ-like lesions. mAb cessation for 2 weeks induced partial osseous wound healing and significantly improved soft tissue wound healing of the extraction sockets. Anti-angiogenesis and normal lymphangiogenesis with CY/mAb combination therapy was not changed by mAb discontinuation. However, mAb cessation for 2 weeks significantly increased the number of CD38+F4/80+ M1 and CD163+F4/80+ M2 macrophages, which significantly increased the M2/M1 ratio in the connective tissue of extraction sockets. No direct effects of mAb on macrophages were noted both in vivo and in vitro. Therefore, the developed healing and/or amelioration murine model of CY/mAb-related ONJ-like lesions is a useful tool to investigate the histopathology and immunopathology of DRONJ in humans. Dynamic polarization shifting from M1 to M2 macrophages induced by mAb cessation may play an important role in wound healing, rather than angiogenesis and lymphangiogenesis, in DRONJ.
長崎大学学位論文 学位記番号:博(医歯薬)甲第1290号 学位授与年月日:令和2年12月2日
Author: Saki Tamaki, Shinichiro Kuroshima, Hiroki Hayano, Kazunori Nakajima, Hiroe Kakehashi, Akira Ishisaki, Takashi Sawasea
Citation: Bone, 141, 115560; 2020
identifier:Nagasaki University (長崎大学), 博士(歯学) (2020-12-02)
一次資料へのリンクURLhttps://nagasaki-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=26291&item_no=1&attribute_id=70&file_no=1 （fulltext）
著作権情報© 2020 Elsevier Inc. All rights reserved.
関連情報http://hdl.handle.net/10069/40434
関連情報（DOI）10.1016/j.bone.2020.115560
連携機関・データベース国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）