Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway

Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-kappa B (NF-kappa B) during anti-osteoclastogenic effects by ISL in vitro and in vivo. We observed that ISL inhibited the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-kappa B expression and nuclear translocation, whereas the NF-kappa B inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K, autophagic LC3, and NF-kappa B expression to protect against inflammatory calvarial bone erosion in vivo. Our findings highlight the inhibition of NF-kappa B-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity. (C) 2016 Elsevier Inc. All rights reserved.