Osteopontin: an emerging therapeutic target in uraemic vascular disease.

The incidence of cardiovascular disease remains high in the population with renal failure and constitutes the leadingcause ofmorbidity andmortality in these patients. According to the U.S. Renal Data System 2011 Annual Data Report, the rate of death among dialysis patients attributable to cardiovascular disease was 40% and 5% to acute myocardial infarction. However, the mechanisms by which renal failure accelerates development of vascular disease and magnifies cardiovascular morbidity and mortality remain elusive. As a common component in development of atherosclerosis, calcification characterizes vasculopathy, contributes to plaque rupture and thrombosis, and predicts high mortality in hemodialysis patients. In addition to traditional risk factors, this complication is associated with nontraditional factors such as elevated serum phosphorus and serum calcium × phosphorus product in uraemia. However, recent evidence suggests that the mechanism underpinning vascular calcification in uraemia is more than passive metastatic calcification, but an active cellmediated process. Furthermore, osteopontin (OPN) has emerged as a key regulator in development of atherosclerosis-associated vasculopathy. OPN,a small integrin-binding ligand,N-linked (SIBLING)glycoprotein first identified in 1986 as a bone matrix protein in osteoblasts, is expressed in various immune and vascular cells and secreted in body fluids to carry multi-domain functions. Its expression in the healthy heart and blood vessels is very low, but consistently up-regulated following injury, and predicts poor cardiac function. In the normal human kidney, distal tubular cells manifest constitutive OPN expression that increases in glomerulonephritis. Uraemic patients have increased levels of OPN not only in the plasma, correlating with coronary calcification, but also in smooth muscle cells (SMCs) in the aorta, and macrophages surrounding atheromatous plaques were identified as the OPN mRNA-expressing cells. OPN is also associated with their migration and proliferation and regulates inflammatory cell chemotaxis. Interestingly, serum from uraemic patients increases OPN expression in bovine SMC and mineral deposition and calcification similar to that in arterial SMC of dialysis patients, whereas neutralizing antibodies directed against OPN inhibit rat carotid neointimal thickening after endothelial denudation. Furthermore, OPN deficiency has been shown to inhibit formation of atherosclerotic and inflammatory lesions in ApoE mice, whereas OPN transgenic mice fed a highcholesterol diet exhibit accelerated fatty-streak lesion formation. However, whether OPN contributes to uraemic atherogenesis remains obscure. In this issue, Pedersen et al. demonstrates a notable role of OPN in development andprogressionofplaque in uraemia achievedby fiveof six nephrectomy in an OPN/ApoE mice model. The surface area of a nephrectomy-induced plaque in the aortic arch was associated with elevations of OPN systemic levels and mRNA expression in the aorta, and positively correlated with plasma OPN levels. Notably, OPN deficiency blunted aortic plaque progression and lipid content in uraemic mice, and also lowered monocyte chemoattractant protein-1 and interleukin-6 mRNA expression in bone marrow-derived macrophages and foam cells in response to a pro-inflammatory stimulus. These observations represent an extension of their previous finding that OPN was the most significantly up-regulated gene in uraemia, accompanied with vacuolization and necrosis of SMC within the media layer. The present work reinforces the causal link between OPN and SMC dedifferentiation, a key process in atherogenesis, because OPN prevented uraemia-induced down-regulation of the transcription factor myocardin and of alpha-smooth muscle actin, indicators of a switch fromcontractile to synthetic phenotype. Therefore, these findings suggest that both systemic and local OPN may facilitate formation and progression of atherosclerotic plaques under uraemic conditions. Yet, it would have been useful if the status of phosphate and calcium × phosphate product were also reported. However, in this study transplantation of bone marrow (BMT) from OPN into uraemic mice did not prevent either formation of the atherosclerotic plaque in the aorta or SMC de-differentiation. Given that systemic OPN levels remained elevated in transplanted uraemic mice, production and excretion of OPN is possibly elaborately and adjusted by multiple factors, so that BMT may not completely deplete its production by other recipient cells. In addition, it is not clear whether OPN regulates atherogenesis remotely or indirectly, as its expression was markedly lowered in the aorta of uraemic mice following BMT. On the other hand, OPN could exert pleiotropic effects at different stages and under different conditions, so that interaction of various factors and modulators may affect its action.