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The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat

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 u...

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Autores principales: Ashtar, Mohannad, Tenshin, Hirofumi, Teramachi, Jumpei, Bat-Erdene, Ariunzaya, Hiasa, Masahiro, Oda, Asuka, Tanimoto, Kotaro, Shimizu, So, Higa, Yoshiki, Harada, Takeshi, Oura, Masahiro, Sogabe, Kimiko, Nakamura, Shingen, Fujii, Shiro, Sumitani, Ryohei, Miki, Hirokazu, Udaka, Kengo, Takahashi, Mamiko, Kagawa, Kumiko, Endo, Itsuro, Tanaka, Eiji, Matsumoto, Toshio, Abe, Masahiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226249/
https://www.ncbi.nlm.nih.gov/pubmed/32283857
http://dx.doi.org/10.3390/cancers12040929
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author Ashtar, Mohannad
Tenshin, Hirofumi
Teramachi, Jumpei
Bat-Erdene, Ariunzaya
Hiasa, Masahiro
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Nakamura, Shingen
Fujii, Shiro
Sumitani, Ryohei
Miki, Hirokazu
Udaka, Kengo
Takahashi, Mamiko
Kagawa, Kumiko
Endo, Itsuro
Tanaka, Eiji
Matsumoto, Toshio
Abe, Masahiro
author_facet Ashtar, Mohannad
Tenshin, Hirofumi
Teramachi, Jumpei
Bat-Erdene, Ariunzaya
Hiasa, Masahiro
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Nakamura, Shingen
Fujii, Shiro
Sumitani, Ryohei
Miki, Hirokazu
Udaka, Kengo
Takahashi, Mamiko
Kagawa, Kumiko
Endo, Itsuro
Tanaka, Eiji
Matsumoto, Toshio
Abe, Masahiro
author_sort Ashtar, Mohannad
collection PubMed
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.
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spelling pubmed-72262492020-05-18 The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat Ashtar, Mohannad Tenshin, Hirofumi Teramachi, Jumpei Bat-Erdene, Ariunzaya Hiasa, Masahiro Oda, Asuka Tanimoto, Kotaro Shimizu, So Higa, Yoshiki Harada, Takeshi Oura, Masahiro Sogabe, Kimiko Nakamura, Shingen Fujii, Shiro Sumitani, Ryohei Miki, Hirokazu Udaka, Kengo Takahashi, Mamiko Kagawa, Kumiko Endo, Itsuro Tanaka, Eiji Matsumoto, Toshio Abe, Masahiro Cancers (Basel) Article 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. MDPI 2020-04-09 /pmc/articles/PMC7226249/ /pubmed/32283857 http://dx.doi.org/10.3390/cancers12040929 Text en © 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/).
spellingShingle Article
Ashtar, Mohannad
Tenshin, Hirofumi
Teramachi, Jumpei
Bat-Erdene, Ariunzaya
Hiasa, Masahiro
Oda, Asuka
Tanimoto, Kotaro
Shimizu, So
Higa, Yoshiki
Harada, Takeshi
Oura, Masahiro
Sogabe, Kimiko
Nakamura, Shingen
Fujii, Shiro
Sumitani, Ryohei
Miki, Hirokazu
Udaka, Kengo
Takahashi, Mamiko
Kagawa, Kumiko
Endo, Itsuro
Tanaka, Eiji
Matsumoto, Toshio
Abe, Masahiro
The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title_full The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title_fullStr The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title_full_unstemmed The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title_short The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat
title_sort roles of ros generation in rankl-induced osteoclastogenesis: suppressive effects of febuxostat
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226249/
https://www.ncbi.nlm.nih.gov/pubmed/32283857
http://dx.doi.org/10.3390/cancers12040929
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