TY - JOUR
T1 - The roles of ROS generation in RANKL-induced osteoclastogenesis
T2 - Suppressive effects of febuxostat
AU - Ashtar, Mohannad
AU - Tenshin, Hirofumi
AU - Teramachi, Jumpei
AU - Bat-Erdene, Ariunzaya
AU - Hiasa, Masahiro
AU - Oda, Asuka
AU - Tanimoto, Kotaro
AU - Shimizu, So
AU - Higa, Yoshiki
AU - Harada, Takeshi
AU - Oura, Masahiro
AU - Sogabe, Kimiko
AU - Nakamura, Shingen
AU - Fujii, Shiro
AU - Sumitani, Ryohei
AU - Miki, Hirokazu
AU - Udaka, Kengo
AU - Takahashi, Mamiko
AU - Kagawa, Kumikov
AU - Endo, Itsuro
AU - Tanaka, Eiji
AU - Matsumoto, Toshio
AU - Abe, Masahiro
N1 - Funding Information:
Conflicts of Interest: M.A. received research funding from Chugai Pharmaceutical, Sanofi K.K., Pfizer Seiyaku K.K., Kyowa Hakko Kirin, MSD K.K., Astellas Pharma, Takeda Pharmaceutical, Teijin Pharma, and Ono Pharmaceutical, and honoraria from the Daiichi Sankyo Company. The other authors declare no competing financial interests.
Funding Information:
Acknowledgments: Our sincere thanks to Otsuka Toshimi Scholarship Foundation for financially supporting Mohannad Ashtar throughout the time of his research.
Funding Information:
Funding: This work was supported in part by the JSPS KAKENHI Grant Numbers JP18K08329, JP16K11504, JP17H05104, JP17KK0169, JP18H06294, JP19K21382, 19K22719, and 19K08839, and the Research Clusters program of Tokushima University. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - Doxorubicin
KW - Multiple myeloma
KW - Osteoclastogenesis
KW - Ovariectomy
KW - RANKL
KW - ROS
UR - http://www.scopus.com/inward/record.url?scp=85083786103&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85083786103&partnerID=8YFLogxK
U2 - 10.3390/cancers12040929
DO - 10.3390/cancers12040929
M3 - Article
AN - SCOPUS:85083786103
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 4
M1 - 929
ER -