As a subunits of V-ATPase, ATP6AP2 has been reported to contribute to various pathological events/diseases, such as fibrosis, hypertension, acute kidney injury, cardiovascular disease, cancer, obesity, and various other diseases.9 Our study demonstrates a critical role of ATP6AP2 in preventing osteoporosis likely by its interaction with LRP6 and increasing LRP6 surface targeting, then promotes Wnt/LRP6/β-catenin signaling selectively in OBs at the trabecular bone region. Here, LRP6 is linked to osteoporosis.