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.