Vitamin D receptor activators can protect against vascular calcification.

An apparent conflict exists between observational studies that suggest that vitamin D receptor (VDR) activators provide a survival advantage for patients with ESRD and other studies that suggest that they cause vascular calcification. In an effort to explain this discrepancy, we studied the effects of the VDR activators calcitriol and paricalcitol on aortic calcification in a mouse model of chronic kidney disease (CKD)-stimulated atherosclerotic cardiovascular mineralization. At dosages sufficient to correct secondary hyperparathyroidism, calcitriol and paricalcitol were protective against aortic calcification, but higher dosages stimulated aortic calcification. At protective dosages, the VDR activators reduced osteoblastic gene expression in the aorta, which is normally increased in CKD, perhaps explaining this inhibition of aortic calcification. Interpreting the results obtained using this model, however, is complicated by the adynamic bone disorder; both calcitriol and paricalcitol stimulated osteoblast surfaces and rates of bone formation. Therefore, the skeletal actions of the VDR activators may have contributed to their protection against aortic calcification. We conclude that low, clinically relevant dosages of calcitriol and paricalcitol may protect against CKD-stimulated vascular calcification.

The mechanism of phosphorus as a cardiovascular risk factor in CKD.

Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima.

Kidney-bone, bone-kidney, and cell-cell communications in renal osteodystrophy.

The relationship between bone and the kidney in renal osteodystrophy is a complex interplay of kidney to bone connections, bone to kidney connections, and cell to cell connections. In addition, such interactions have a profound effect on the vasculature. In this review, we discuss the role of the bone morphogenetic proteins (BMPs) in the skeleton, kidney, and vasculature. In addition, we propose that deficiencies of these BMPs seen in chronic kidney disease (CKD) result in decreased bone remodeling and a compensatory secondary hyperparathyroidism (high turnover state). Treatment of the hyperparathyroidism blocks this compensatory arm and thus decreased bone remodeling occurs (low turnover). We review animal models of CKD in which treatment with BMP-7 resulted in normalization of both high and low turnover states. Finally, we discuss vascular calcification as it relates to bone metabolism. We discuss the roles of BMP-7 and 2 other bone regulatory proteins, osteoprotegerin (OPG) and alpha2-HS glycoprotein (AHSG, human fetuin), in the human vasculature and their implications for vascular calcification.

Inhibition of cell survival signal protein kinase B/Akt by curcumin in human prostate cancer cells.

Although curcumin has been shown to inhibit prostate tumor growth in animal models, its mechanism of action is not clear. To better understand the anti-cancer effects of curcumin, we investigated the effects of curcumin on cell survival factor Akt in human prostate cancer cell lines, LNCaP, PC-3, and DU-145. Our results demonstrated differential activation of Akt. Akt was constitutively activated in LNCaP and PC-3 cells. Curcumin inhibited completely Akt activation in both LNCaP and PC-3 cells. The presence of 10% serum decreased the inhibitory effect of curcumin in PC-3 cells whereas complete inhibition was observed in 0.5% serum. Very little or no activation of Akt was observed in serum starved DU-145 cells (0.5% serum). The presence of 10% serum activated Akt in DU-145 cells and was not inhibited by curcumin. Results suggest that one of the mechanisms of curcumin inhibition of prostate cancer may be via inhibition of Akt. To our knowledge this is the first report on the curcumin inhibition of Akt activation in LNCaP and PC-3 but not in DU-145 cells.

Proprotein convertases regulate activity of prostate epithelial cell differentiation markers and are modulated in human prostate cancer cells.

Prostate derived factor (PDF) is a member of transforming growth factor-beta (TGF-beta) superfamily proteins involved in differentiation of the prostate epithelium. Proprotein convertases (PCs) such as furin are thought to mediate the processing of TGF-beta superfamily. In the present study, we demonstrated for the first time that human prostate cancer cell lines differentially synthesize and secret prostate derived factor (PDF), and that PDF secreted by LNCaP is processed by PCs. Exposure of LNCaP cells to the decanoyl-Arg-Val-Lys-Arg-chloromethylketone (CMK), a synthetic furin-like protease inhibitor, inhibited PDF processing and resulted in the loss of luminal cell phenotype and induction of basal cell phenotype in LNCaP cells as demonstrated by alternations in the expression of cytokeratins 8, 14, 18, and 19, markers of prostate epithelial cell differentiation. These results suggest that proprotein convertases may be involved in the regulation of prostate epithelial cell differentiation, and may be an important target of prostate cancer therapy.