number of access : ?
number of downloads : ?
ID 115041
Title Alternative
RANKLが誘導する破骨細胞分化におけるROSの役割と、Febuxostatによる破骨細胞分化抑制効果
Author
Ashtar, Mohannad Tokushima University
Bat-Erdene, Ariunzaya Mongolian National University of Medical Sciences
Oda, Asuka Tokushima University
Tanimoto, Kotaro Tokushima University
Shimizu, So Tokushima University
Higa, Yoshiki Tokushima University
Udaka, Kengo Tokushima University
Takahashi, Mamiko Tokushima University
Keywords
RANKL
ROS
doxorubicin
multiple myeloma
osteoclastogenesis
ovariectomy
Content Type
Thesis or Dissertation
Description
Receptor activator of NF-κB ligand (RANKL), a critical mediator of osteoclastogenesis, is upregulated in multiple myeloma (MM). The xanthine oxidase inhibitor febuxostat, clinically used for prevention of tumor lysis syndrome, has been demonstrated to effectively inhibit not only the generation of uric acid but also the formation of reactive oxygen species (ROS). ROS has been demonstrated to mediate RANKL-mediated osteoclastogenesis. In the present study, we therefore explored the role of cancer-treatment-induced ROS in RANKL-mediated osteoclastogenesis and the suppressive effects of febuxostat on ROS generation and osteoclastogenesis. RANKL dose-dependently induced ROS production in RAW264.7 preosteoclastic cells; however, febuxostat inhibited the RANKL-induced ROS production and osteoclast (OC) formation. Interestingly, doxorubicin (Dox) further enhanced RANKL-induced osteoclastogenesis through upregulation of ROS production, which was mostly abolished by addition of febuxostat. Febuxostat also inhibited osteoclastogenesis enhanced in cocultures of bone marrow cells with MM cells. Importantly, febuxostat rather suppressed MM cell viability and did not compromise Dox’s anti-MM activity. In addition, febuxostat was able to alleviate pathological osteoclastic activity and bone loss in ovariectomized mice. Collectively, these results suggest that excessive ROS production by aberrant RANKL overexpression and/or anticancer treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.
Journal Title
Cancers
ISSN
20726694
Publisher
MDPI
Volume
12
Issue
4
Start Page
929
Published Date
2020-04-09
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Mohannad Ashtarの学位論文として提出され,学位審査・授与の対象となっている。
Rights
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3467号
Diploma Number
甲口第466号
Granted Date
2020-12-10
Degree Name
Doctor of Dental Science
Grantor
Tokushima University
departments
Oral Sciences
University Hospital
Medical Sciences
Institute of Advanced Medical Sciences