School of Chinese Medicine
Blockage of Src by specific siRNA as a novel therapeutic strategy to prevent destructive repair in steroid-associated osteonecrosis in rabbits
© 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.Vascular hyperpermeability and highly upregulated bone resorption in the destructive repair progress of steroid-associated osteonecrosis (SAON) are associated with a high expression of VEGF and high Src activity (Src is encoded by the cellular sarcoma [c-src] gene). This study was designed to prove our hypothesis that blocking the VEGF-Src signaling pathway by specific Src siRNA is able to prevent destructive repair in a SAON rabbit model. Destructive repair in SAON was induced in rabbits. At 2, 4, and 6 weeks after SAON induction, VEGF, anti-VEGF, Src siRNA, Src siRNA+VEGF, control siRNA, and saline were introduced via intramedullary injection into proximal femora for each group, respectively. Vascularization and permeability were quantified by dynamic contrast-enhanced (DCE) MRI. At week 6 after SAON induction, proximal femurs were dissected for micro-computed tomography (μCT)-based trabecular architecture with finite element analysis (FEA), μCT-based angiography, and histological analysis. Histological evaluation revealed that VEGF enhanced destructive repair, whereas anti-VEGF prevented destructive repair and Src siRNA and Src siRNA+VEGF prevented destructive repair and enhanced reparative osteogenesis. Findings of angiography and histomorphometry were consistent with those determined by DCE MRI. Src siRNA inhibited VEGF-mediated vascular hyperpermeability but preserved VEGF-induced neovascularization. Bone resorption was enhanced in the VEGF group and inhibited in the anti-VEGF, Src siRNA, Src siRNA+VEGF groups as determined by both 3D μCT and 2D histomorphometry. FEA showed higher estimated failure load in the Src siRNA and Src siRNA+VEGF groups when compared to the vehicle control group. Blockage of VEGF-Src signaling pathway by specific Src siRNA was able to prevent steroid-associated destructive repair while improving reconstructive repair in SAON, which might become a novel therapeutic strategy.
OSTEONECROSIS, REPAIR, SIRNA, SRC
Source Publication Title
Journal of Bone and Mineral Research
American Society for Bone and Mineral Research
Link to Publisher's Edition
Zheng, Li-Zhen, Hui-Juan Cao, Shi-Hui Chen, Tao Tang, Wei-Min Fu, Le Huang, Dick Ho Kiu Chow, Yi-Xiang Wang, James Francis Griffith, Wei He, Hong Zhou, De-Wei Zhao, Ge Zhang, Xin-Luan Wang, and Ling Qin. "Blockage of Src by specific siRNA as a novel therapeutic strategy to prevent destructive repair in steroid-associated osteonecrosis in rabbits." Journal of Bone and Mineral Research 30.11 (2015): 2044-2057.