Molecular and signaling mechanisms of atherosclerosis in insulin resistance.

Although the prevalence of cardiovascular complications is increased in insulin-resistant individuals, the underlying causes of this link have been elusive. Recent work suggests that several intracellular signal transduction pathways are inappropriately activated by hyperinsulinemia, hyperglycemia, increased free fatty acids, dyslipidemia, various inflammatory cytokines and adipokines--factors that are increased in insulin resistance. Once activated, substantial cross talk occurs between these pathways, especially a self-reinforcing cascade of vascular inflammation and cell dysfunction, greatly increasing the risk and severity of atherosclerosis in the insulin-resistant individual. We review several key cell-signalling pathways, describe how they are activated in they insulin-resistant state and the damage they induce, and discusses possible therapeutic approaches to limit vascular damage.     

Pretreatment of bone with osteoclasts affects phenotypic expression of osteoblast-like cells.

Implant surface morphology regulates osteoblast phenotypic expression. Osteoblast sensitivity to non-biologic surfaces suggests that native bone surface features may also affect osteoblast response. To test this, MG63 osteoblast-like cells were grown for 7 days on bovine cortical bone wafers pretreated with rat bone marrow osteoclasts for 0, 10 or 20 days. Response to osteoclast-treated surfaces was compared to the response of MG63 cells to titanium surfaces with smooth and rough microtopographies. Cell number, differentiation (alkaline phosphatase activity and osteocalcin levels), and local factors (PGE(2) and TGF-beta1) were measured in confluent cultures. Compared to culture on plastic, cell number was reduced on all three types of bone wafers; this effect was dose-dependent with increasing resorption of the surface. Alkaline phosphatase specific activity was increased (P相似文献   

Functional and morphologic endothelial damage in rabbit external jugular veins stored in heparinized normal saline.

Previous studies have demonstrated that vein storage in normal saline leads to significant mechanical morphological, and biochemical aberrations. However, little information is available regarding the functional damage that occurs. The purpose of this study was to evaluate the effect of saline storage on venous smooth muscle and endothelial function. Segments of ten external jugular veins from male New Zealand White rabbits were placed nondistended in either modified Krebs solution at 37 degrees C (Krebs-stored, KS) or heparinized normal saline at room temperature (saline-stored, SS) for 1 h. Segments 4 mm in length were then simultaneously studied in vitro under isometric tension. There was no difference in maximum tension or sensitivity to either bradykinin or histamine. Acetylcholine-induced relaxation in KS segments was not significantly different from relaxation in a historical cohort of nonstored segments (nonstored 87.4 +/- 1.0% vs. KS 84.5 +/- 2.0%; p = NS). However, there were significant attenuations in SS segment endothelium-dependent relaxation in response to both acetylcholine (KS 84.5 +/- 2.0% vs. SS 76.4 +/- 2.7%, p less than 0.02) and adenosine diphosphate (KS 47.9 +/- 2.9% vs. SS 40.6 +/- 3.7%, p less than 0.002). Relaxant responses to sodium nitroprusside (endothelium-independent) were not significantly different in the two groups (KS 94.6 +/- 1.6% vs. SS 95.7 +/- 2.2%; p = NS). Electron microscopic evaluation of SS segments revealed endothelial cell disruption with cellular edema and loss of intact junctions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Recombinant bone morphogenetic protein (BMP)-2 regulates costochondral growth plate chondrocytes and induces expression of BMP-2 and BMP-4 in a cell maturation-dependent manner

This study examined the effect of recombinant human bone morphogenetic protein-2 on several parameters of growth, differentiation, and matrix synthesis and on the endogenous production of mRNA of bone morphogenetic proteins 2 and 4 by growth plate chondrocytes in culture. Chondrocytes from resting and growth zones were obtained from rat costochondral cartilage and cultured for 24 or 48 hours in medium containing 0.05-100 ng/ml recombinant human bone morphogenetic protein-2 and 10% fetal bovine serum. Incorporation of [³H]thymidine, cell number, alkaline phosphatase specific activity, incorporation of [³H]proline into collagenase-digestible protein and noncollagenase-digestible protein, and incorporation of [³⁵S]sulfate were assayed as indicators of cell proliferation, differentiation, and extracellular matrix synthesis. mRNA levels T for bone morphogenetic proteins 2 andv4 were determined by Northern blot analysis. Recombinant human bone morphogenetic protein-2 increased the incorporation of [³H]thymidine by quiescent resting-zone and growth-zone cells in a similar manner, whereas it had a differential effect on nonquiescent cultures. At 24 and 48 hours, 12.5-100 ng/ml recombinant human bone morphogenetic protein-2 caused a dose-dependent increase in cell number and DNA synthesis in resting-zone chondrocytes. No effect was seen in growth-zone cell Recombinant human bone morphogenetic protein-2 stimulated alkaline phosphatase specific activity in resting-zone chondrocytes in a bimodal manner, causing significant increases between 0.2 and 0.8 ng/ml and again between 25 and 100 ng/ml. In contrast, alkaline phosphatase specific activity in growth-zone chondrocytes was significantly increased only between 12.5 and 100 ng/ml. Recombinant human bone morphogenetic protein-2 increased the production of both collagenase-digestible protein and noncollagenase-digestible protein by resting-zone and growth-zone cells, but incorporation of [³⁵S]sulfate was unaffected. Administration of recombinant human bone morphogenetic protein-2 also increased incorporation of [³H]uridine in both resting-zone and growth-zone chondrocytes; these cells produced mRNA for bone morphogenetic proteins 2 and 4. Bone morphogenetic protein-2 mRNA levels in both resting-zone and growth-zone chondrocytes increased in the presence of recombinant human bone morphogenetic protein-2; however, bone morphogenetic protein-4 mRNA levels in growth-zone cells decreased under its influence, and those in resting-zone cells were upregulated only with a dose of 10 ng/ml. This indicates that recombinant human bone morphogenetic protein-2 regulates chondrocyte proliferation, differentiation, and matrix production, and the effects are dependent on the stage of cell maturation. Resting-zone chondrocytes were more sensitive, suggesting that they are targeted by bone morphogenetic protein-2 and that this growth factor may have autocrine effects on these cells.