XAF1 is a promising target to regulate osteoclastogenesis

Abstract

Abstract Over-activated osteoclast (OC) is a major cause of diseases related to bone loss. Both bone resorption inhibition and apoptosis induction of osteoclast are crucial in treating these diseases. However, the mechanisms that determine osteoclast function and lifespan are limited. Here, our findings were presented indicating that the newly characterized gene X-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (Xaf1) was an important interferon-stimulated gene for termination of osteoclastogenesis via apoptosis induction. We showed that Xaf1 ablation enhanced osteoclast generation in vitro. Xaf1 knockout increased osteoclast number and bone resorption, thereby exacerbating bone loss in both OVX and osteolysis models. Activation of XAF1 with BV6 (XIAP inhibitor) suppressed osteoclast formation. Mechanistically, Xaf1 deletion decreased osteoclast apoptosis via increasing interaction between XIAP and caspase-3/7. Collectively, our data illustrated an essential role of Xaf1 in the regulation of osteoclastogenesis in both osteoporosis and osteolysis models and highlighted its underlying mechanism.