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

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 Cancers 2020, 12, 929 2 of 16 treatment disadvantageously impacts bone, and that febuxostat can prevent the ROS-mediated osteoclastic bone damage.

GPR120 Inhibits RANKL-Induced Osteoclast Formation and Resorption by Attenuating Reactive Oxygen Species Production in RAW264.7 Murine Macrophages

“…ROS are known to play an important role in RANKL-induced osteoclast formation [ 4 , 5 ]. ROS may be crucial for TRAF6 mediated activation of NF-κB and MAPK signalling pathways in osteoclasts [ 6 ].…”

“…Studies have shown that reactive oxygen species (ROS) production is crucial for RANKL-mediated osteoclast formation [ 4 , 5 ]. RANK, a member of the tumour necrosis factor (TNF) family, shares many features with other TNF receptors such as the increased ROS production upon receptor binding [ 6 ].…”

Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death

“…As noted in previous studies, one-electron DOX reduction, a key process in oxidative stress development, is catalysed by xanthine oxidases, and its inhibitor febuxostat has been demonstrated to effectively inhibit the formation of ROS, thereby blocking cardiotoxicity associated with DOX (Figure 1A). However, it has not been used in clinical practice [49,50].…”

Recent Advances on the Pathobiology and Treatment of Multiple Myeloma

“…Ashtar et al reported that febuxostat, a xanthine oxidase inhibitor used for prevention of tumor lysis syndrome, antagonized RANKL-dependent osteoclastogenesis through inhibition of RANKL-induced ROS production and OC formation in vitro and in ovariectomized mice. Interestingly, doxorubicin further enhanced RANKL-induced osteoclastogenesis through up-regulation of ROS production, which was abolished by febuxostat [6]. Tibullo et al also focused on MMBD, demonstrating that ixazomib, a third-generation proteasome inhibitor (PI), was able to reduce differentiation of human monocytes into OCs and to inhibit the expression of OC markers in vitro; moreover, ixazomib was able to stimulate osteogenic differentiation of human mesenchymal stromal cells (MSCs), increasing osteogenic markers.…”