Suppression of miR-148a-3p Can Promote Bone Healing by Enhancing Angiogenesis-Osteogenesis Coupling Through the PI3K/Akt Pathway

Previous studies have identified miR-148a-3p as a regulator of both angiogenesis and osteogenesis. However, in vitro findings have been inconsistent. This study aimed to elucidate the role and mechanism of miR-148a-3p in bone physiology using miR-148a knockout (KO) mice. Compared to wild-type and heterozygous littermates, miR-148a KO mice demonstrated smaller body size but exhibited increased bone mass, enhanced type H vessel formation, and improved osteogenesis. In vitro experiments showed that miR-148a inhibited osteogenesis of ectomesenchymal stem cells and suppressed the proliferation, migration, as well as tube formation of bone endothelial cells. Multi-omics analyses of bone samples and primary bone endothelial cells, including bulk RNA-seq, proteomics, and scRNA-seq, indicated that Itga11 was regulated via mRNA degradation and identified as a key player in osteogenesis and a direct target of miR-148a-3p, as confirmed by dual-luciferase reporter assays, while Rcc2 was implicated in angiogenesis through Rac1. Both pathways converged to activate the PI3K/Akt pathway. In the bone defect model, antagomiR-148a facilitated bone repair by promoting angiogenesis-osteogenesis coupling, suggesting that miR-148a-3p suppression may serve as a potential therapeutic strategy for enhancing the bone healing process.