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

被引：36

作者：

Ashtar, Mohannad ^{[1
,2
]}

Tenshin, Hirofumi ^{[3
]}

Teramachi, Jumpei ^{[4
]}

Bat-Erdene, Ariunzaya ^{[5
]}

Hiasa, Masahiro ^{[3
]}

Oda, Asuka ^{[2
]}

Tanimoto, Kotaro ^{[1
]}

Shimizu, So ^{[1
]}

Higa, Yoshiki ^{[1
]}

Harada, Takeshi ^{[2
]}

Oura, Masahiro ^{[2
]}

Sogabe, Kimiko ^{[2
]}

Nakamura, Shingen ^{[2
]}

Fujii, Shiro ^{[2
]}

Sumitani, Ryohei ^{[2
]}

Miki, Hirokazu ^{[6
]}

Udaka, Kengo ^{[2
]}

Takahashi, Mamiko ^{[2
]}

Kagawa, Kumiko ^{[2
]}

Endo, Itsuro ^{[7
]}

Tanaka, Eiji ^{[3
]}

Matsumoto, Toshio ^{[8
]}

Abe, Masahiro ^{[2
]}

机构：

[1] Tokushima Univ, Dept Orthodont & Dentofacial Orthoped, Grad Sch Oral Sci, Tokushima 7708503, Japan

[2] Tokushima Univ, Inst Biomed Sci, Dept Hematol Endocrinol & Metab, Tokushima 7708503, Japan

[3] Tokushima Univ, Inst Biomed Sci, Dept Orthodont & Dentofacial Orthoped, Tokushima 7708503, Japan

[4] Tokushima Univ, Inst Biomed Sci, Dept Tissue Regenerat, Tokushima 7708503, Japan

[5] Mongolian Natl Univ Med Sci, Dept Immunol, Sch Biomed, Ulaanbaatar 14210, Mongolia

[6] Tokushima Univ Hosp, Div Transfus Med & Cell Therapy, Tokushima 7708503, Japan

[7] Tokushima Univ, Inst Biomed Sci, Dept Chronomed, Tokushima 7708503, Japan

[8] Tokushima Univ, Fujii Mem Inst Med Sci, Tokushima 7708503, Japan

来源：

CANCERS | 2020年 / 12卷 / 04期

关键词：

multiple myeloma; osteoclastogenesis; RANKL; ROS; doxorubicin; ovariectomy; OXIDATIVE STRESS; BONE LOSS; MYELOMA; TARGET; LIGAND; OSTEOPOROSIS; DESTRUCTION; ACTIVATION; SYSTEM; KINASE;

D O I：

10.3390/cancers12040929

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Receptor activator of NF-kappa B 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.

引用

页数：16

共 43 条

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