Osteoclastic ATP6AP2 maintains β-catenin levels to prevent hyper-osteoclastic activation and trabecular bone-loss.

Osteoclast (OC) formation and bone resorption are regulated by several factors, including V-ATPase, Wnt/β-Catenin, and RANKL/RANK signaling. ATP6AP2, also known as the prorenin receptor (PRR), is an accessory subunit of V-ATPase and a regulator of Wnt/β-Catenin signaling. While the V-ATPase subunit ATP6AP1 is essential for osteoclast formation and function, the role of ATP6AP2 in OC-lineage cells is less clear. Here, we provide evidence that ATP6AP2 plays a negative role in osteoclastogenesis and function, contrasting with the positive role of ATP6AP1. Mice with conditional knockout (cKO) of ATP6AP2 in OCs (Atp6ap2LysM) exhibit trabecular bone loss, likely due to the increased osteoclastogenesis and activity, since bone formation rates are comparable to control mice. In vitro assays using bone marrow macrophages (BMMs) show that Atp6ap2LysM cultures have more RANKL-induced TRAP+ OC-like cells and increased bone resorptive activity. Further studies reveal that while RANKL signaling and V-ATPase activity are normal, in ATP6AP2 KO OCs, but not BMMs, have reduced basal levels of Wnt/β-Catenin pathway proteins, such as LRP5/6 and β-Catenin, compared to controls. Wnt3A treatment induces β-Catenin and suppresses osteoclast formation in both control and ATP6AP2 KO OC-lineage cells, indicating that Wnt/β-Catenin signaling negatively regulates OC-formation and operates independently of ATP6AP2. Overall, these results suggest that ATP6AP2 is critical for maintaining basal levels of LRP5/6 receptors and β-Catenin in osteoclasts, thus acting as a negative regulator of osteoclastogenesis and activation.