Mechanosignaling Promotes Osteogenic-Angiogenic Coupling in Bone Tissue

Osteogenesis-angiogenesis coupling is the bidirectional interaction between osteogenic and angiogenic processes. This coupling is the fundamental prerequisite for successful bone formation and post-fracture healing. While soluble biofactors are well-known mediators, mechanical stress has recently emerged as a potent driver of this coupled regeneration. However, the precise mechanotransduction cascades that translate physical forces into synchronized tissue growth remain to be fully elucidated. This review systematically summarizes the mechanisms by which mechanical stimuli activate and augment osteogenesis-angiogenesis coupling. Specifically, we detail the critical crosstalk within key mechanosensory networks. We highlight how the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation, Piezo1-mediated calcium influx, and Integrin-triggered Wnt/β-catenin signaling pathway synergistically synchronize endothelial neovascularization with osteoblast differentiation. Furthermore, we explore the clinical translation of these mechanisms. We emphasize how engineered biomaterials, particularly digitally customized 3D-printed smart scaffolds, can actively modulate these pathways in vivo. This material-driven modulation can maximize the therapeutic efficacy of osteogenesis-angiogenesis coupling. Ultimately, by linking macroscopic physical cues with microscopic biochemical cascades, this review offers highly translational perspectives for the personalized management of complex bone defects.