Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat

Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat:

Cancers, Vol. 12, Pages 929: The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat

Cancers doi: 10.3390/cancers12040929

Authors:
Mohannad Ashtar
Hirofumi Tenshin
Jumpei Teramachi
Ariunzaya Bat-Erdene
Masahiro Hiasa
Asuka Oda
Kotaro Tanimoto
So Shimizu
Yoshiki Higa
Takeshi Harada
Masahiro Oura
Kimiko Sogabe
Shingen Nakamura
Shiro Fujii
Ryohei Sumitani
Hirokazu Miki
Kengo Udaka
Mamiko Takahashi
Kumiko Kagawa
Itsuro Endo
Eiji Tanaka
Toshio Matsumoto
Masahiro Abe


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.