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Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits.

He YX, Liu J, Guo B, Wang YX, Pan X, Li D, Tang T, Chen Y, Peng S, Bian Z, Liang Z, Zhang BT, Lu A, Zhang G - Sci Rep (2015)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: 1] 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.

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Histomorphometric analyses of the bone marrow circulation.(A). Analysis procedure of edema area (region I in the left image and indicated by green color in the right enlarged image), micro vessel density (region II in the left image and indicated by arrows in the right enlarged image) and size distribution of leakage particles (region III in the left image and indicated by arrow in the right enlarged image) in different groups using Image J software. (B). Time-course change in edema area post-administration in different groups. (C). Time-course change in micro vessel density post-administration in different groups. (D). Comparison of size distribution of leakage particles in different groups. N = 8, One-way ANOVA with Student-Newman-Keuls post hoc test, *P < 0.05 vs Control at corresponding time point.
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f5: Histomorphometric analyses of the bone marrow circulation.(A). Analysis procedure of edema area (region I in the left image and indicated by green color in the right enlarged image), micro vessel density (region II in the left image and indicated by arrows in the right enlarged image) and size distribution of leakage particles (region III in the left image and indicated by arrow in the right enlarged image) in different groups using Image J software. (B). Time-course change in edema area post-administration in different groups. (C). Time-course change in micro vessel density post-administration in different groups. (D). Comparison of size distribution of leakage particles in different groups. N = 8, One-way ANOVA with Student-Newman-Keuls post hoc test, *P < 0.05 vs Control at corresponding time point.

Mentions: Figure 5 presents histomorphometry of marrow circulation at 0, 2 4 weeks post administration, including micro-vessel density (MVD), edema area (EA), and leakage particle size distribution. EA in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group decreased continuously and significantly with similar changing pattern from the baseline after administration, whereas it was almost remained in the Control Group and even increased continuously and significantly in the VEGF-Supplement Group (Figure 5B). MVD in the Anti-VEGF Group decreased continuously and significantly from the baseline after administration, whereas it was almost maintained in the Control Group, increased slightly and continuously in the Src-Inhibition Group, and even increased continuously and significantly in the VEGF-Supplement Group and Supplement & Inhibition Group (Figure 5C). In comparison with the Control Group, leakage particles were less found in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group, whereas there were a lot of leakage particles in the VEGF-Supplement Group (Figure 5D).


Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits.

He YX, Liu J, Guo B, Wang YX, Pan X, Li D, Tang T, Chen Y, Peng S, Bian Z, Liang Z, Zhang BT, Lu A, Zhang G - Sci Rep (2015)

Histomorphometric analyses of the bone marrow circulation.(A). Analysis procedure of edema area (region I in the left image and indicated by green color in the right enlarged image), micro vessel density (region II in the left image and indicated by arrows in the right enlarged image) and size distribution of leakage particles (region III in the left image and indicated by arrow in the right enlarged image) in different groups using Image J software. (B). Time-course change in edema area post-administration in different groups. (C). Time-course change in micro vessel density post-administration in different groups. (D). Comparison of size distribution of leakage particles in different groups. N = 8, One-way ANOVA with Student-Newman-Keuls post hoc test, *P < 0.05 vs Control at corresponding time point.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352921&req=5

f5: Histomorphometric analyses of the bone marrow circulation.(A). Analysis procedure of edema area (region I in the left image and indicated by green color in the right enlarged image), micro vessel density (region II in the left image and indicated by arrows in the right enlarged image) and size distribution of leakage particles (region III in the left image and indicated by arrow in the right enlarged image) in different groups using Image J software. (B). Time-course change in edema area post-administration in different groups. (C). Time-course change in micro vessel density post-administration in different groups. (D). Comparison of size distribution of leakage particles in different groups. N = 8, One-way ANOVA with Student-Newman-Keuls post hoc test, *P < 0.05 vs Control at corresponding time point.
Mentions: Figure 5 presents histomorphometry of marrow circulation at 0, 2 4 weeks post administration, including micro-vessel density (MVD), edema area (EA), and leakage particle size distribution. EA in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group decreased continuously and significantly with similar changing pattern from the baseline after administration, whereas it was almost remained in the Control Group and even increased continuously and significantly in the VEGF-Supplement Group (Figure 5B). MVD in the Anti-VEGF Group decreased continuously and significantly from the baseline after administration, whereas it was almost maintained in the Control Group, increased slightly and continuously in the Src-Inhibition Group, and even increased continuously and significantly in the VEGF-Supplement Group and Supplement & Inhibition Group (Figure 5C). In comparison with the Control Group, leakage particles were less found in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group, whereas there were a lot of leakage particles in the VEGF-Supplement Group (Figure 5D).

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: 1] 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.

Show MeSH
Related in: MedlinePlus