http://dx.doi.org/10.1002/jbmr.2542">
 

Document Type

Journal Article

Authors

Li-Zhen Zheng, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Hui-Juan Cao, Translational Medicine RandD Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Shi-Hui Chen, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Tao Tang, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Wei-Min Fu, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Le Huang, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Dick Ho Kiu Chow, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Yi-Xiang Wang, Department of Imaging and Interventional Radiology, He Chinese University of Hong Kong
James Francis Griffith, Department of Imaging and Interventional Radiology, He Chinese University of Hong Kong
Wei He, Department of Orthopaedics, First Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine
Hong Zhou, Bone Research Program, ANZAC (Australian and New Zealand Army Corps.) Research Institute, University of Sydney
De-Wei Zhao, Department of Orthopaedics, Zhongshan Hospital, Dalian University
Ge Zhang, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong KongFollow
Xin-Luan Wang, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong
Ling Qin, Musculoskeletal Research Laboratory, Department of Orthopaedics and Traumatology, Chinese University of Hong Kong

Department/Unit

School of Chinese Medicine

Title

Blockage of Src by specific siRNA as a novel therapeutic strategy to prevent destructive repair in steroid-associated osteonecrosis in rabbits

Language

English

Abstract

© 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.

Keywords

OSTEONECROSIS, REPAIR, SIRNA, SRC

Publication Date

2015

Source Publication Title

Journal of Bone and Mineral Research

Volume

30

Issue

11

Start Page

2044

End Page

2057

Publisher

American Society for Bone and Mineral Research

ISSN (print)

08840431

ISSN (electronic)

15234681

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