Angiogenic and Osteogenic Strategies for Skeletal Regeneration in Aging

Aging disrupts skeletal homeostasis, resulting in impaired fracture healing, increased risk of nonunion, and reduced regenerative capacity. These deficits are associated with dysregulated inflammation, impaired angiogenesis, and reduced osteogenesis, while current treatments remain limited in aged populations. This review examines emerging regenerative approaches that target both vascular and osteogenic dysfunction during skeletal repair.

Recent studies have emphasized the importance of angiogenic-osteogenic coupling in successful bone repair. Endothelial progenitor cells (EPCs) promote neovascularization, improve vascular function, and support osteogenesis, while EPC-derived extracellular vesicles (EV), particularly exosomes, enhance intercellular communication, angiogenesis, and tissue repair with fewer limitations than cell-based therapies. In addition, signal transducer and activator of transcription 3 (STAT3) has been identified as a key regulator of osteoblast function, angiogenesis, and bone remodeling, making it an attractive molecular target for enhancing skeletal regeneration. EPC-based therapies, exosome-mediated interventions, and modulation of STAT3 signaling are promising strategies to enhance skeletal regeneration by addressing both vascular dysfunction and impaired osteogenesis. Continued investigation into the mechanisms, safety, and translational potential of these approaches will be critical for advancing regenerative therapies for age-related skeletal disorders.