Decreased mechanosensitivity and metabolic reprogramming impair bone regeneration in type II diabetes: core mechanism and targeted scaffold design

Abstract Background Bone regeneration in individuals with type 2 diabetes mellitus (T2DM) is significantly impaired, even when autologous bone grafts are used. However, previous studies have failed to elucidate the physiological mechanism, and effective treatments are lacking. This study investigated the underlying mechanisms and developed a targeted therapeutic strategy. Methods We established a femoral condyle defect model in diabetic rats and performed autologous bone grafting. Multiomics sequencing analyses revealed core events that occurred in diabetic bone tissue. Seahorse XF analysis was used to detect cellular metabolic reprogramming. Calcium ion flow cytometry and YAP nuclear localization experiments confirmed the changes in mechanosensitivity in BMSCs from diabetic rats. Targeted scaffolds to repair diabetic bone defects were developed through Si ion surface modification and structural design and validated in the diabetic rat bone defect model. Results Proteomic and targeted energy metabolomics analyses revealed an imbalance in osteogenic/adipogenic differentiation and glycolytic dysfunction. RNA sequencing of BMSCs from diabetic rats revealed that reduced mechanosensitivity may be the core mechanism responsible for the alterations in cell fate. Flow cytometry with a calcium ion probe and YAP nuclear localization experiments confirmed the decreased mechanosensitivity of BMSCs from diabetic rats. Si-CaP was developed to increase glycolysis and the TPMS microstructure was designed to promote YAP nuclear translocation, thereby redirecting BMSCs toward osteogenic differentiation. In vivo experiments in a diabetic rat femoral condyle defect model demonstrated that the structured Si-CaP TPMS scaffold effectively promoted bone regeneration. Conclusions T2DM-associated bone defect healing impairment is caused by metabolic reprogramming and reduced mechanosensitivity in BMSCs. Targeted modulation of metabolism and mechanosensitivity is an effective treatment for bone defects in T2DM rats.