Unconjugated
Receptor for advanced glycation end products (RAGE) is associated with inflammation and the progression of cardiovascular diseases. The current study tested the hypothesis that RAGE is involved in the pathogenesis of aortic valve (AV) calcification. Pioglitazone attenuated AV calcification in experimental hypercholesterolemic rabbits via down-regulation of RAGE. Male New Zealand rabbits weighing 2.5-3.0 kg were randomly divided into three groups: control group, high cholesterol + vitamin D(2) (HC + vitD(2)) group and HC + vitD(2) supplemented with pioglitazone group. Compared with HC + vitD(2) group, pioglitazone significantly inhibited the progression of AV calcification assessed by echocardiography. HC + vitD(2) diet markedly increased RAGE expression, oxidative stress, inflammatory cells infiltration and osteopontin expression. These changes were also significantly attenuated by administration of pioglitazone. Cultured porcine aortic valve interstitial cells (VICs) were used as in vitro model. We found that advanced glycation end products of bovine serum albumin markedly increased the expression of RAGE, induced high levels of production of pro-inflammatory cytokines and promoted osteoblastic differentiation of VICs. However, these effects were found to be remarkably suppressed by siRNA silencing of RAGE and pioglitazone as well. Our data provide evidence that RAGE activation-induced inflammation promotes AV calcification in hypercholesterolemic rabbits, which can be attenuated by pioglitazone treatment. This beneficial effect is associated with remarkable down-regulation of RAGE expression.
OBJECTIVES:
This study focuses upon the morphologic and molecular features of the layer of cells, termed the "biomembrane," which forms around methacrylate spacers in bone segmental defects. The objective of this research was to assess the biomembrane formed in a novel rodent femoral segmental defect model at 4, 8, and 16 weeks with histologic and molecular studies.
METHODS:
Following Institutional Animal Care and Use Committee approval, a segmental defect was created in the rat femur and stabilized with the AO LockingRatNail and analyzed at 4, 8, and 16 weeks postsurgery using digital radiologic imaging, morphological and immunohistochemical studies, and genomewide gene expression studies employing microarray analysis.
RESULTS:
The biomembrane formed around the methacrylate spacer was rich in vasculature, which showed vascular endothelial growth factor immunolocalization. The biomembrane supported development of foci of bone and cartilage within it. Bone morphogenetic protein 2 immunolocalization and gene expression were positive within developing osseous and chondrocyte foci. Microarray analysis showed significant expression of key genes related to bone and cartilage formation and angiogenesis.
CONCLUSIONS:
This rat bone model was effective in creation of the biomembrane. Bone and cartilage foci were formed within the vascularized biomembrane with associated expression of genes critical for bone and cartilage development/formation and vascularization. The polymethyl methacrylate-induced biomembrane offers an exciting potential solution for segmental defects; the biomembrane, may act as a receptive bed and also serve as a source for mesenchymal stem cells, which could be recruited/directed for the healing process.
