Search

Abstract: Background: Intravascular-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. Objective: The present study was to evaluate the prevention effect of the available semisynthesized small molecule Icaritin on steroid-associated ON development in a rabbit model. Methods: After 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. Results: The 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. Conclusion: Icaritin, 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. [Copyright &y& Elsevier]

Abstract: Metabolic syndrome (MetS) consists of several independent clinically recognisable features that have their own independent effects on bone metabolism, and even a single disease could have apparently contradictory effects on bone metabolism. This meta-analysis aimed to detect a relationship between MetS and osteoporosis. The PubMed, Embase, and Cochrane library databases were searched for relevant studies published before April 1, 2013. On June 22, 2013, the databases were searched again for additional studies. Studies clearly reporting a comparison of bone mineral density (BMD) in subjects with or without MetS were selected for our analysis. From these results, we analysed the crude BMD and the BMD adjusted for all covariates (age, weight, height, alcohol intake, cigarette smoking and exercise). Weighted mean differences were calculated using a random-effects model. Nine studies were included in this meta-analysis. No significant differences were found when analysing the crude lumbar spine BMD and the femoral neck BMD. However, the MetS (−) group showed a significantly higher BMD when all covariates were adjusted for femoral neck BMD (0.02, p =0.0002) and lumbar spine BMD (0.01, p =0.007). Subgroup analysis suggested a negative effect of MetS on BMD in men but not in women. These findings suggest that MetS is a risk factor for developing osteoporosis in men. [Copyright &y& Elsevier]