Histatin-1 promotes bone regeneration by coordinating osteogenic and angiogenic responses in a sustained-release...

The regeneration of critical-sized bone defects is severely hampered by a dual challenge: insufficient vascularization and limited osteogenic activity at the injury site. Histatin-1 (Hst1), a salivary peptide with known pro-angiogenic and regenerative activities, is a hopeful candidate for bone regeneration, yet its dual function in osteogenesis and angiogenesis remains underexplored. Here, we systematically elucidated this dual function. In vitro, Hst1 was demonstrated to stimulate the osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs) through the activation of the Wnt/β-catenin signaling pathway. Concurrently, Hst1 promoted tube formation through paracrine signaling. In vivo, the hydrogel formulated from oxidized sodium alginate (OSA), gelatin (GE), and adipic acid dihydrazide (ADH) was employed to ensure the sustained delivery of Hst1. This Hst1-loaded hydrogel was applied to a 5-mm critical-sized cranial defect in rats. Compared to the Control group, Hst1-loaded hydrogel significantly enhanced bone regeneration, with the bone volume fraction (BV/TV) increasing to 20.0 % (vs. 8.2 % for Control). This was accompanied by a marked increase in vascularization, as evidenced by a 3.0-fold rise in vessel density. In conclusion, this study reveals the dual pro-regenerative function of Hst1 in simultaneously promoting osteogenesis and angiogenesis, demonstrating that harnessing Hst1 within a sustained-release hydrogel is a powerful therapeutic strategy for achieving vascularized bone regeneration.