In summary, our results from both loss-of-function and gain-of-function strategies revealed that F2r is a key negative regulator of osteoclastogenesis, which inhibits the Akt-GSK3β-NFATc1 and NFκB signaling pathways, suggesting that F2r can be as a novel therapeutic target for bone diseases, such as osteoporosis. This evidence concerns the gene NFKB1 and osteoporosis.