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Bioactive Iron Oxide Nanoparticles Suppress Osteoclastogenesis and Ovariectomy-induced Bone Loss through Regulating the TRAF6-p62-CYLD Signaling Complex

Liu L1Jin R2Duan J1Yang L1Cai Z1Zhu W3Nie Y1He J1Xia C4Gong Q4Song B4Anderson JM5Ai H6.

Acta Biomater. 2019 Dec 19. pii: S1742-7061(19)30851-7. doi: 10.1016/j.actbio.2019.12.022. [Epub ahead of print]



Iron oxide nanoparticles (IONPs) have been widely used as contrast agents for magnetic resonance imaging (MRI) and other biomedical applications in both clinical and preclinical cases. In the present study, we show that two clinically used IONPs, ferumoxytol and ferucarbotran, have an intrinsic inhibitory effect on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis of bone marrow-derived monocytes/macrophages (BMMs). IONPs significantly inhibited the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear osteoclasts and functional actin ring structures. More importantly, the inhibitory effect was also verified in vivo by its capacity to rescue the bone loss of ovariectomized (OVX) mice after intravenous injection with IONPs. Mechanistically, we found that IONPs trigger the upregulation of p62 which result in recruitment of CYLD and enhanced deubiquitination of TRAF6, a master controller of RANKL signaling. The downstream activation of NF-κB and MAPK signals was accordingly attenuated, ultimately leading to reduced expression of osteoclatogenesis-related genes. Taken together, clinically used IONPs can inhibit osteoclastogenesis through regulating TRAF6-p62-CYLD signaling complex, and they may be considered as alternative options for treatment of osteoporosis.