Pip5k1a regulates mandibular homeostasis by orchestrating osteogenesis in mice

Mandibular homeostasis depends on mesenchymal stromal cells (MSCs), whose site-specific characteristics critically influence osteogenesis. While phosphoinositide signaling has been extensively studied in limb osteogenesis, its role in mandibular homeostasis remains poorly understood. Despite shared mechanisms underlying hard tissue homeostasis, this study uncovers a distinct regulatory function for Pip5k1a in mandibular osteogenesis, contrasting the previously established role of Pip5k1c in limb osteogenesis. Single-cell transcriptomic analysis revealed unique transcriptional profiles between mandibular MSCs (MdMSCs) and limb MSCs (LbMSCs), with Pip5k1a being highly expressed in MdMSCs and their osteo-lineages. Functional assays demonstrated that Pip5k1a inhibition significantly reduced osteoblastic differentiation while promoting adipogenesis in MdMSCs, underscoring its essential role in osteogenic fate determination. Enrichment of Pip5k1a expression in the mandibular periosteum and endosteum further supports its specialized role in mandibular biology. These findings highlight site-specific molecular mechanisms in bone remodeling and position Pip5k1a as a promising therapeutic target for mandibular bone diseases, such as periodontitis and fractures.