ATP6AP2 in osteoblasts couples cortical bone matrix remodeling to osteocyte maturation via MMP14 activation in mice

Cortical bone is a dense, lamellar structure containing osteoblast (OB)-lineage-derived osteocytes embedded within a mineralized matrix. How osteocytes differentiate and organize within lamellar bone remains incompletely understood. Here, we show that ATP6AP2 in the OB lineage is essential for osteocyte maturation and cortical bone development. Male mice with OB-lineage-specific deletion of Atp6ap2 (Atp6ap2^OCN-Cre) exhibit increased cortical bone mass composed largely of irregular woven bone, with impaired osteocyte maturation and survival, and abnormal osteocyte distribution. Mechanistic analyses identify matrix metalloproteinase-14 (MMP14) as a key downstream effector of ATP6AP2. ATP6AP2 interacts with MMP14 and promotes its surface localization largely in immature osteocytes, and expression of MMP14 in Atp6ap2-deficient OB-lineage cells diminishes cortical bone defects. These results reveal previously unrecognized roles for ATP6AP2 in regulating cortical osteocyte development and establish an ATP6AP2-MMP14 signaling axis that controls the woven-to-lamellar bone transition and osteocyte differentiation and distribution.