The roles of ROS generation in RANKL-induced osteoclastogenesis: Suppressive effects of febuxostat

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, Kumikov Kagawa, Itsuro EndoEiji Tanaka, Toshio Matsumoto, Masahiro Abe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number929
JournalCancers
Volume12
Issue number4
DOIs
Publication statusPublished - Apr 2020
Externally publishedYes

Keywords

  • Doxorubicin
  • Multiple myeloma
  • Osteoclastogenesis
  • Ovariectomy
  • RANKL
  • ROS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Ashtar, M., Tenshin, H., Teramachi, J., Bat-Erdene, A., Hiasa, M., Oda, A., Tanimoto, K., Shimizu, S., Higa, Y., Harada, T., Oura, M., Sogabe, K., Nakamura, S., Fujii, S., Sumitani, R., Miki, H., Udaka, K., Takahashi, M., Kagawa, K., ... Abe, M. (2020). The roles of ROS generation in RANKL-induced osteoclastogenesis: Suppressive effects of febuxostat. Cancers, 12(4), [929]. https://doi.org/10.3390/cancers12040929