Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783534246442303488 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7226249 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ashtarmohannad therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tenshinhirofumi therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT teramachijumpei therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT baterdeneariunzaya therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT hiasamasahiro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT odaasuka therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tanimotokotaro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT shimizuso therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT higayoshiki therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT haradatakeshi therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT ouramasahiro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT sogabekimiko therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT nakamurashingen therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT fujiishiro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT sumitaniryohei therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT mikihirokazu therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT udakakengo therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT takahashimamiko therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT kagawakumiko therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT endoitsuro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tanakaeiji therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT matsumototoshio therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT abemasahiro therolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT ashtarmohannad rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tenshinhirofumi rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT teramachijumpei rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT baterdeneariunzaya rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT hiasamasahiro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT odaasuka rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tanimotokotaro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT shimizuso rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT higayoshiki rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT haradatakeshi rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT ouramasahiro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT sogabekimiko rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT nakamurashingen rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT fujiishiro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT sumitaniryohei rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT mikihirokazu rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT udakakengo rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT takahashimamiko rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT kagawakumiko rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT endoitsuro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT tanakaeiji rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT matsumototoshio rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat AT abemasahiro rolesofrosgenerationinranklinducedosteoclastogenesissuppressiveeffectsoffebuxostat |