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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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Osteonecrosis Lesion Differentiation and Classification at 2 weeks and 4 weeks Post-administration.(A). Appositional bone formation (dashed arrows) with osteoblasts (OB) around the necrotic bone (ON), defined as ‘reparative osteogenesis’. (B). Eroded bone surface (solid arrows) with osteoclasts (OC) around the necrotic bone (ON) during fibrous tissue creep (dashed arrow), defined as ‘destructive repair’. (C & D). The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group was all lower than that in the Control Group, whereas it was higher in the VEGF-Supplement Group when compared to the Control Group at 2 weeks and 4 weeks Post-administration. N = 8 for 2 Weeks Post-administration, N = 15 for 4 Week Post-administration, Fisher's exact probability test, *P < 0.05 vs Control.
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f1: Osteonecrosis Lesion Differentiation and Classification at 2 weeks and 4 weeks Post-administration.(A). Appositional bone formation (dashed arrows) with osteoblasts (OB) around the necrotic bone (ON), defined as ‘reparative osteogenesis’. (B). Eroded bone surface (solid arrows) with osteoclasts (OC) around the necrotic bone (ON) during fibrous tissue creep (dashed arrow), defined as ‘destructive repair’. (C & D). The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group was all lower than that in the Control Group, whereas it was higher in the VEGF-Supplement Group when compared to the Control Group at 2 weeks and 4 weeks Post-administration. N = 8 for 2 Weeks Post-administration, N = 15 for 4 Week Post-administration, Fisher's exact probability test, *P < 0.05 vs Control.

Mentions: At 2 weeks after administration (4 weeks post-induction), the incidence of the destructive repair in the Anti-VEGF Group (1/8), Src-Inhibition Group (2/8) and Supplement & Inhibition Group (2/8) was all lower than that in the Control Group (5/8), whereas it was higher in the VEGF-Supplement Group (7/8) when compared to the Control Group. However, due to the sample size limitation, the difference was not statistically significant. At 4 weeks after administration (6 weeks post-induction), 10 of those 15 rabbits in Control group had dominant destructive repair, whereas 1 of 15, 2 of 15, 15 of 15 and 3 of 15 rabbits had dominant destructive repair in Anti-VEGF Group, Src-Inhibition Group, VEGF-Supplement Group and Supplement & Inhibition Group, respectively. 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, whereas it was significantly higher in the VEGF-Supplement Group (15/15) when compared to the Control Group. There are even 1 and 3 rabbits showed dominant reparative osteogenesis in the Src-Inhibition Group and Supplement & Inhibition Group respectively. The repair pattern in the rest of the rabbits can not be clearly identified. (Figure 1)


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)

Osteonecrosis Lesion Differentiation and Classification at 2 weeks and 4 weeks Post-administration.(A). Appositional bone formation (dashed arrows) with osteoblasts (OB) around the necrotic bone (ON), defined as ‘reparative osteogenesis’. (B). Eroded bone surface (solid arrows) with osteoclasts (OC) around the necrotic bone (ON) during fibrous tissue creep (dashed arrow), defined as ‘destructive repair’. (C & D). The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group was all lower than that in the Control Group, whereas it was higher in the VEGF-Supplement Group when compared to the Control Group at 2 weeks and 4 weeks Post-administration. N = 8 for 2 Weeks Post-administration, N = 15 for 4 Week Post-administration, Fisher's exact probability test, *P < 0.05 vs Control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Osteonecrosis Lesion Differentiation and Classification at 2 weeks and 4 weeks Post-administration.(A). Appositional bone formation (dashed arrows) with osteoblasts (OB) around the necrotic bone (ON), defined as ‘reparative osteogenesis’. (B). Eroded bone surface (solid arrows) with osteoclasts (OC) around the necrotic bone (ON) during fibrous tissue creep (dashed arrow), defined as ‘destructive repair’. (C & D). The incidence of the destructive repair in the Anti-VEGF Group, Src-Inhibition Group and Supplement & Inhibition Group was all lower than that in the Control Group, whereas it was higher in the VEGF-Supplement Group when compared to the Control Group at 2 weeks and 4 weeks Post-administration. N = 8 for 2 Weeks Post-administration, N = 15 for 4 Week Post-administration, Fisher's exact probability test, *P < 0.05 vs Control.
Mentions: At 2 weeks after administration (4 weeks post-induction), the incidence of the destructive repair in the Anti-VEGF Group (1/8), Src-Inhibition Group (2/8) and Supplement & Inhibition Group (2/8) was all lower than that in the Control Group (5/8), whereas it was higher in the VEGF-Supplement Group (7/8) when compared to the Control Group. However, due to the sample size limitation, the difference was not statistically significant. At 4 weeks after administration (6 weeks post-induction), 10 of those 15 rabbits in Control group had dominant destructive repair, whereas 1 of 15, 2 of 15, 15 of 15 and 3 of 15 rabbits had dominant destructive repair in Anti-VEGF Group, Src-Inhibition Group, VEGF-Supplement Group and Supplement & Inhibition Group, respectively. 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, whereas it was significantly higher in the VEGF-Supplement Group (15/15) when compared to the Control Group. There are even 1 and 3 rabbits showed dominant reparative osteogenesis in the Src-Inhibition Group and Supplement & Inhibition Group respectively. The repair pattern in the rest of the rabbits can not be clearly identified. (Figure 1)

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