Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions
The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and ant...
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MDPI AG
2023-02-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/12/5/1914 |
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| author | Haruka Kaneko Shinichiro Kuroshima Ryohei Kozutsumi Farah A. Al-Omari Hiroki Hayano Kazunori Nakajima Takashi Sawase |
| author_facet | Haruka Kaneko Shinichiro Kuroshima Ryohei Kozutsumi Farah A. Al-Omari Hiroki Hayano Kazunori Nakajima Takashi Sawase |
| author_sort | Haruka Kaneko |
| collection | DOAJ |
| description | The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169<sup>+</sup> osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80<sup>+</sup>CD38<sup>+</sup> M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions. |
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| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-11T07:20:26Z |
| publishDate | 2023-02-01 |
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| spelling | doaj.art-478c171535cc42a2921b519dbdf678152023-11-17T08:00:04ZengMDPI AGJournal of Clinical Medicine2077-03832023-02-01125191410.3390/jcm12051914Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like LesionsHaruka Kaneko0Shinichiro Kuroshima1Ryohei Kozutsumi2Farah A. Al-Omari3Hiroki Hayano4Kazunori Nakajima5Takashi Sawase6Department of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanDepartment of Applied Prosthodontics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, JapanThe pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169<sup>+</sup> osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80<sup>+</sup>CD38<sup>+</sup> M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.https://www.mdpi.com/2077-0383/12/5/1914osteal macrophageangiogenesis inhibitorzoledronatewound healingtooth extraction |
| spellingShingle | Haruka Kaneko Shinichiro Kuroshima Ryohei Kozutsumi Farah A. Al-Omari Hiroki Hayano Kazunori Nakajima Takashi Sawase Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions Journal of Clinical Medicine osteal macrophage angiogenesis inhibitor zoledronate wound healing tooth extraction |
| title | Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions |
| title_full | Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions |
| title_fullStr | Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions |
| title_full_unstemmed | Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions |
| title_short | Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions |
| title_sort | zoledronate anti vegf neutralizing antibody combination administration increases osteal macrophages in a murine model of mronj stage 0 like lesions |
| topic | osteal macrophage angiogenesis inhibitor zoledronate wound healing tooth extraction |
| url | https://www.mdpi.com/2077-0383/12/5/1914 |
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