Citations

Osteoporosis is an important clinical problem, affecting more than 50% of people over age 50 yr. Estrogen signaling is critical for maintaining proper bone density, and the identification of an endogenous selective estrogen receptor (ER) modulator, 27-hydroxycholesterol (27HC), suggests a mechanism by which nutritional/metabolic status can influence bone biology. With its levels directly correlated with cholesterol, a new possibility emerges wherein 27HC links estrogen and cholesterol signaling to bone homeostasis. In these studies, we found that increasing concentrations of 27HC, both by genetic and pharmacological means, led to decreased bone mineral density that was associated with decreased bone formation and increased bone resorption. Upon manipulation of endogenous estrogen levels, many of the responses to elevated 27HC were altered in such a way as to implicate ER as a likely mediator. In a model of postmenopausal bone loss, some pathologies associated with elevated 27HC were exacerbated by the absence of endogenous estrogens, suggesting that 27HC may act both in concert with and independently from classic ER signaling. These data provide evidence for interactions between estrogen signaling, cholesterol and metabolic disease, and osteoporosis. Patients with high cholesterol likely also have higher than average 27HC, perhaps putting them at a higher risk for bone loss and fracture. More studies are warranted to fully elucidate the mechanism of action of 27HC in bone and to identify ways to modulate this pathway therapeutically.

Abstract Epidermal growth factor receptor (EGFR) vIII is a mutated EGFR that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors. In this study, we investigate the effect of ZD6474 (ZACTIMA, vandetanib), a dual inhibitor for vascular endothelial growth factor receptor 2 and EGFR on growth and angiogenesis of gliomas expressing EGFRvIII. We used two glioma xenograft models, U87MG cells overexpressing EGFRvIII and short-term cultured primary glioma GBM8 cells with EGFRvIII. ZD6474 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas. Moreover, significant inhibition of EGFRvIII-expressing U87MG and GBM8 gliomas was observed compared with their controls. Magnetic resonance imaging analysis using the apparent diffusion coefficient and three-dimensional T2*weighed measurements validated ZD6474 inhibition on tumor growth and angiogenesis in EGFRvIII-expressing GBM8 gliomas. Mechanistically, ZD6474 shows better inhibition of cell growth and survival of U87MG/EGFRvIII, GBM6, and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3, Akt, and Bcl-XL expression. Albeit in lesser extent, ZD6474 also displays suppressions of U87MG/EGFR and GBM12 cells that overexpress wild-type EGFR. Additionally, ZD6474 inhibits activation of extracellular signal-regulated kinase 1/2 in both types of cells, and expression of a constitutively active phosphoinositide 3-kinases partially rescued ZD6474 inhibition in U87MG/EGFRvIII cells. Taken together, these data show that ZD6474 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII-activated signaling mediators, suggesting a potential application of ZD6474 in treatments for glioblastomas that overexpress EGFRvIII. Mol Cancer Ther; 9(4); 929–41. ©2010 AACR.

Abstract ABSTRACT: The cellular mechanisms for bone loss in type I (postmenopausal) osteoporosis are highly controversial. We attempted to resolve this by assessing rates of formation and resorption of iliac cancellous bone by a new histomorphometric method in 89 women with osteoporosis (mean age + SD, 66 + 6 years) and in 32 carefully selected normal postmenopausal women (64 + 6 years). In the osteoporotic women, bone resorption rate was increased by 39% (P <0.05) at the cellular level and by 67% (P <0.05) at the tissue level, whereas bone formation was unchanged at the tissue level but decreased by 14% (P <0.01) at the cellular (osteoblast) level. This pronounced remodeling imbalance (P <0.001) was probably exacerbated by a 45% increase (P < 0.1) in activation frequency of new remodeling foci. These abnormalities were associated with a high rate of cancellous bone loss (median, 5.8%/year versus 0.1%/year in controls). Thus, accelerated loss of cancellous bone in type I osteoporosis results from the combination of increased bone resorption and inadequate compensation by bone formation.

Abstract Seasonal variation in physical activity, back extensor muscle strength (BES), and bone mineral density (BMD) of the lumbar spine was studied in 65 healthy postmenopausal women. Physical activity score (PAS) was assessed with an ordinal scale (0-18); this score and the BES were obtained monthly for 2 years (25 readings). BMD values were obtained semiannually (5 readings). A periodic (cosine) regression model was fit to each subject's PAS and BES data to obtain individual estimates of the annual peak day d and the average annual range due to seasonality. There was a strong (P < 0.001) seasonal pattern in physical activity; August 3 was the average peak day, and the seasonal range was 2.0 PAS units. There was modest (P = 0.047) seasonality in BES; June 6 was the estimated peak day, and the seasonal range was 8.22 pounds (about 7% of the mean). BMD averaged 0.015 g/cm2 higher in August through November than February through May (P = 0.002), and the highest monthly average BMD was in August. This seasonal range of 1.4% is larger than the average annual decline with age in BMD observed in longitudinal studies of postmenopausal women. The results of this study have important implications for the planning of longitudinal studies involving changes in physical activity or bone mass in geographic areas with diverse seasons.

Convection induced by repetitive compression of porous tissue scaffolds enhances solute transport inside the scaffold. Our previous experiments have shown that pore size, shape, and orientation with respect to strain direction greatly influence loading-induced solute transport. The objective of this study was to develop a computational model of deformation-induced solute transport in porous tissue scaffolds, which included the pore geometry of the scaffold. This geometry consisted of a cubic scaffold with single channel in the middle of the scaffold, immersed in a fluid reservoir. Cylindrical pores with circular or elliptic cross section, and spheroid pores were modeled. The scaffold was cyclically compressed from one side, causing fluid motion and dispersion of solute inside the scaffold pore. Scaffold deformation was solved using the finite element method, and fluid flow and solute transport were solved using the finite volume method. The distortion of the scaffold–fluid interface was transferred as a boundary condition to the fluid flow solver. Both convection and diffusion were included in the computations. The solute transport rates in the different scaffold pore geometries agreed well with our previous experimental results obtained with X-ray microimaging. This model will be used to explore transport properties of a spectrum of novel scaffold designs.