Abstract:
The treatment of osteoporotic bone defects poses a challenge due to the degradation of the skeletal vascular system and the disruption of local bone metabolism within the osteoporotic microenvironment. However, it is feasible to modulate the disrupted local bone metabolism imbalance through enhanced vascularization, a theory termed \"vascularization-bone metabolic balance\". This study developed a 3D-printed polycaprolactone (PCL) scaffold modified with EPLQLKM and SVVYGLR peptides (PCL-SE). The EPLQLKM peptide attracts bone marrow-derived mesenchymal stem cells (BMSCs), while the SVVYGLR peptide enhances endothelial progenitor cells (EPCs) vascular differentiation, thus regulating bone metabolism and fostering bone regeneration through the paracrine effects of EPCs. Further mechanistic research demonstrated that PCL-SE promoted the vascularization of EPCs, activating the Notch signaling pathway in BMSCs, leading to the upregulation of osteogenesis-related genes and the downregulation of osteoclast-related genes, thereby restoring bone metabolic balance. Furthermore, PCL-SE facilitated the differentiation of EPCs into \"H\"-type vessels and the recruitment of BMSCs to synergistically enhance osteogenesis, resulting in the regeneration of normal microvessels and bone tissues in cases of femoral condylar bone defects in osteoporotic SD rats. This study suggests that PCL-SE supports in-situ vascularization, remodels bone metabolic translational balance, and offers a promising therapeutic regimen for osteoporotic bone defects.
摘要:
由于骨骼血管系统的降解和骨质疏松微环境内局部骨代谢的破坏,骨质疏松性骨缺损的治疗提出了挑战。然而,通过增强血管化调节局部骨代谢失衡是可行的,一种称为“血管化-骨代谢平衡”的理论。这项研究开发了用EPLQLKM和SVVYGLR肽(PCL-SE)修饰的3D打印聚己内酯(PCL)支架。EPLQLKM肽吸引骨髓间充质干细胞(BMSCs),而SVVYGLR肽增强内皮祖细胞(EPCs)的血管分化,从而通过EPCs的旁分泌作用调节骨代谢和促进骨再生。进一步的机制研究表明,PCL-SE促进了EPCs的血管化,激活BMSCs的Notch信号通路,导致成骨相关基因的上调和破骨细胞相关基因的下调,从而恢复骨代谢平衡。此外,PCL-SE促进EPCs向“H”型血管的分化和BMSCs的募集以协同增强成骨,导致骨质疏松SD大鼠股骨髁骨缺损病例中正常微血管和骨组织再生。这项研究表明PCL-SE支持原位血管化,重塑骨代谢平移平衡,并为骨质疏松性骨缺损提供了有希望的治疗方案。