Metabolism of citrate-mediated PI3K-Akt signaling and primary cilium regulates spatiotemporal craniofacial mineralization.

The repair of craniofacial bones requires high-quality mineralization. The key regulator involved in the difference in mineralization of craniofacial bones remains unknown. As the main component of the bone, citrate regulates hydroxyapatite crystallization. We found that the regional accumulation of citrate caused differences in mineralization. Transcriptome analysis showed that the expression of the PI3K-Akt signaling pathway and primary cilia was significantly different between mineralized and unmineralized areas. Citrate specifically activated the PI3K-Akt signaling pathway to form a positive feedback loop and strengthened the metabolic activity of osteoblasts. The cooperation between citrate and primary cilia improved osteogenesis and stabilized the structure of amorphous calcium phosphate clusters. Our research reveals a new citrate-mediated metabolic-signaling-structure pattern. It explains the regional differences in mineralization of craniofacial bones and offers a theoretical basis for bone development mechanisms and regeneration strategies.