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Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in
Yi-Xin He1, Jin Liu2, Baosheng Guo1
11] Institute for Advancing Translational Medicine in Bone &Joint Diseases, School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China [2] Hong Kong Baptist University Branch of State Key Laboratory of Chemo/Biosensing and Chemometrics of Hunan University, Hong Kong SAR, China [3] Shum Yiu Foon Shum Bik Chuen Memorial Centre for Cancer and Inflammation Research, Hong Kong Baptist University, Hong Kong SAR, China [4] Institute of Integrated Bioinformedicine &Translational Science, HKBU Shenzhen Research Institute and Continuing Education, Shenzhen, China [5] Academician Chen Xinzi Workroom for Advancing Translational Medicine in Bone &Joint Diseases, Kunshan RNAi Institute, Kunshan Industrial Technology Research Institute, Kunshan, Jiangsu, China [6] Hong Kong Baptist University - Northwestern Polytechnical University Joint Research Centre for Translational Medicine on Musculoskeletal Health in Space, Shenzhen, China.
Abstract:
To examine the therapeutic effect of Src inhibitor on the VEGF mediating vascular hyperpermeability and bone destruction within steroid-associated osteonecrotic lesions in rabbits. Rabbits with high risk for progress to destructive repair in steroid-associated osteonecrosis were selected according to our published protocol. The selected rabbits were systemically administrated with either Anti-VEGF antibody (Anti-VEGF Group) or Src inhibitor (Src-Inhibition Group) or VEGF (VEGF-Supplement Group) or a combination of VEGF and Src inhibitor (Supplement &Inhibition Group) or control vehicle (Control Group) for 4 weeks. At 0, 2 and 4 weeks after administration, in vivo dynamic MRI, micro-CT based-angiography, histomorphometry and immunoblotting were employed to evaluate the vascular and skeletal events in different groups. The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group was all significantly lower than that in the Control Group. The angiogenesis was promoted in VEGF-Supplement Group, Src-Inhibition Group and Supplement &Inhibition Group, while the hyperpermeability was inhibited in Anti-VEGF Group, Src-Inhibition Group and Supplement &Inhibition Group. The trabecular structure was improved in Src-Inhibition Group and Supplement &Inhibition Group. Src inhibitor could reduce permeability without disturbing vascularization and prevent destructive repair in steroid-associated osteonecrosis.
Insights
Src inhibitor effectively treats steroid-associated osteonecrosis by reducing vascular permeability and preventing bone destruction. This study shows promising therapeutic effects for Src inhibition in managing this condition.
Area of Science:
- Orthopedics
- Vascular Biology
- Pharmacology
Background:
- Steroid-associated osteonecrosis (SAON) involves vascular hyperpermeability and bone destruction.
- Vascular Endothelial Growth Factor (VEGF) plays a role in SAON pathogenesis.
- Targeting VEGF and related pathways is a potential therapeutic strategy.
Purpose of the Study:
- To investigate the therapeutic effect of a Src inhibitor on VEGF-mediated vascular hyperpermeability and bone destruction in SAON.
- To evaluate the impact of Src inhibition on angiogenesis and vascular permeability in SAON lesions.
- To assess the potential of Src inhibitor in preventing destructive repair in SAON.
Main Methods:
- A rabbit model of SAON was established.
- Rabbits received treatments including Anti-VEGF antibody, Src inhibitor, VEGF, or combinations.
- Vascular and skeletal events were evaluated using dynamic MRI, micro-CT angiography, histomorphometry, and immunoblotting over 4 weeks.
Main Results:
- Src inhibitor significantly reduced the incidence of destructive repair compared to controls.
- Src inhibitor inhibited vascular hyperpermeability without disrupting angiogenesis.
- Improved trabecular bone structure was observed in rabbits treated with Src inhibitor.
Conclusions:
- Src inhibitor demonstrates therapeutic potential for SAON by reducing vascular permeability and preventing bone destruction.
- Src inhibition offers a promising approach to manage SAON, preserving vascularization while mitigating detrimental effects.
- Targeting Src signaling may be a viable strategy for treating steroid-associated osteonecrosis.
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