Delayed Administration of IGFBP7 Improved Bone Defect Healing via ZO-1 Dependent Vessel Stabilization

The vascular response following injury is pivotal for successful bone-defect repair but constitutes a major hurdle in the field of regenerative medicine. Throughout this process, vessel stabilization is crucial to provide an adequate nutrient supply and facilitate efficient waste removal. Therefore, this study investigated whether promoting vascular stabilization improves bone defect repair outcomes. The findings show that insulin-like growth factor-binding protein (IGFBP) 7 exhibits a novel biological function in attenuating vascular permeability and enhancing vascular wall integrity. The potential underlying mechanism involves the up-regulation of insulin-like growth factor 1 receptor (IGF1R) expression by IGFBP7 on endothelial cell membrane, followed by activation of the downstream PI3K/Akt signaling pathway and upregulated expression of the tight junction protein zonula occludens-1 (ZO-1). IGFBP7 delayed administration in mice with cranial defects significantly improved bone defect healing by increasing ZO-1 and CD31 co-localization within vessel walls and optimizing the perfusion function of the final vascular network. Furthermore, the application of the typical tight junction regulator AT1001 effectively promoted ZO-1-dependent vascular stabilization and facilitated bone defect repair. This study presents a new approach to enhance bone defect healing via vascular stabilization-targeted interventions and significantly advances the understanding of the complex interplay between osteogenesis and angiogenesis in bone defect healing.

AT1001; IGFBP7; Zonula Occluden‐1; bone defect repair; endothelial tight junctions; vessel stabilization.