MgO Nanoparticles Protect against Titanium Particle-Induced Osteolysis in a Mouse Model Because of Their Positive Immunomodulatory Effect

Aseptic prosthetic loosening (APL) often leads to the failure of prostheses. It is inseparable from wear-particleinduced macrophage-mediated inflammatory responses and osteolysis. Mg2+ is a metal ion with excellent anti-inflammatory properties. Herein, Mg2+ was introduced into a nanomedicine (MgO nanoparticles (MNPs)) to protect against APL. MNPs could be phagocytized by macrophages and gradually degraded intracellularly. Following MNPs treatment, lipopolysaccharide (LPS)-activated macrophages polarized into deeper MI phenotype at 6 h but then switched to the M2 phenotype at 48 h. Furthermore, the MNPs suppressed the titanium (Ti) particle-induced osteoclasto- genesis and osteolysis in vivo. However, the MNPs exhibited no impact on the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and even inhibited osteogenesis in vitro. The contrary results between the in vitro and in vivo experiments imply that macrophages are the key factor in the inhibited osteoclastogenesis in vivo because the pathogenic process of APL is mainly attributed to macrophages, osteoblasts, and osteoclasts. Accordingly, an indirect coculture system was designed that considers the immunomodulatory effect of macrophages. RANKL-induced osteoclastogenesis was significantly inhibited under the influence of MNPs in the indirect coculture system. Taken together, the MNPs inhibited the inflammatory responses of macrophages provoked by the Ti particles and thus regulated the expressions of RANKL and OPG in osteoblasts to suppress osteoclastogenesis. The target cell of MNPs was macrophages but not osteoclasts, indicating the importance of the immunomodulatory effect of macrophages. These results collectively demonstrated that MNPs can prevent APL and other osteolysis-related diseases.