کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2781001 | 1153310 | 2009 | 12 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner A novel semisynthesized small molecule icaritin reduces incidence of steroid-associated osteonecrosis with inhibition of both thrombosis and lipid-deposition in a dose-dependent manner](/preview/png/2781001.png)
BackgroundIntravascular-thrombosis and extravascular-lipid-deposition are the two key pathogenic events considered to interrupt intraosseous blood supply during steroid-associated osteonecrosis (ON) development. However, there are no reported candidate agents capable of simultaneously targeting these two key pathogenic events. The authors' published experimental studies have shown that Epimedium-derived flavonoids possess an anti-ON effect. Further, the authors have recently identified a small molecule Icaritin as an intestinal metabolite of Epimedium-derived flavonoids.ObjectiveThe present study was to evaluate the prevention effect of the available semisynthesized small molecule Icaritin on steroid-associated ON development in a rabbit model.MethodsAfter receiving an established inductive protocol for inducing steroid-associated ON, eighty-four male 28-week-old New-Zealand white rabbits were divided into the following three daily oral administration groups, including low dose Icaritin group (L-ICT; n = 28; 5 mg·kg− 1·day− 1), high dose Icaritin group (H-ICT; n = 28; 10 mg·kg− 1·day− 1), and control vehicle group (CON; n = 28). Before and after induction, dynamic contrast-enhanced MRI was performed on proximal femur for intra-osseous perfusion function index. Meanwhile, blood samples were examined for coagulation, fibrinolysis, lipid-transportation, endothelium injury, oxidative stress, and hepatocyte injury index, while marrow samples were quantified for adipogenic potential index of mesenchymal stem cell by in vitro culture and proliferator-activated receptor-gamma (PPARgamma) protein expression by western blot. At baseline, week 1 and 2 post-induction, 4, 8 and 16 rabbits in each group were sacrificed, respectively. After sacrifice, femora were dissected for micro-CT-based micro-angiography, followed by histological examination of ON lesion, intravascular thrombosis, extravascular fat-cell and vascular endothelial growth factor (VEGF) localized expression.ResultsThe ON incidence in the L-ICT and H-ICT groups was both significantly lower than that in the CON group (p < 0.05 for both). The ON incidence in the H-ICT group was significantly lower than that in the L-ICT group (p < 0.05). A significant decrease in the vascularization index and a significant increase in the permeability index seen in the CON group was attenuated in the L-ICT group and almost prevented in the H-ICT group at week 1 post-induction. Reduced perfusion to vessel-like structural units was more rarely found in the H-ICT group than in the L-ICT group. Regarding intravascular thrombosis, a significant increase in the thrombotic vessel count, endothelium injury index, coagulation index, and a significant decrease in both the fibrinolysis and oxidative stress index in the CON group were attenuated in the L-ICT group and prevented in the H-ICT group. For extravascular lipid-deposition, a significant increase in the fat cell area fraction, adipogenic potential index, PPARgamma expression and lipid-transportation index in the CON group was attenuated in the L-ICT group and prevented in the H-ICT group. Increased immunoreactivity of VEGF in the CON group was attenuated in the L-ICT group and prevented in the H-ICT group. Regarding safety, the hepatocyte injury index did not show significant change from baseline in any group.ConclusionIcaritin, a novel semisynthesized small molecule with osteoprotective potential, exerts dose-dependent effect on reducing incidence of steroid-associated ON with inhibition of both intravascular thrombosis and extravascular lipid-deposition. Suppression of the up-regulated PPARgamma expression for extravascular adipogenesis of mesenchymal stem cells and protection from activated oxidative stress for intravascular endothelium injury were found to be involved in the underlying mechanisms.
Journal: Bone - Volume 44, Issue 2, February 2009, Pages 345–356