Abstract
BackgroundVascular calcification is an indicator of elevated cardiovascular risk. Vascular smooth muscle cells (VSMCs), the predominant cell type involved in medial vascular calcification, can undergo phenotypic transition to both osteoblastic and chondrocytic cells within a calcifying environment.Methodology/Principal FindingsIn the present study, using in vitro VSMC calcification studies in conjunction with ex vivo analyses of a mouse model of medial calcification, we show that vascular calcification is also associated with the expression of osteocyte phenotype markers. As controls, the terminal differentiation of murine calvarial osteoblasts into osteocytes was induced in vitro in the presence of calcifying medium (containing ß-glycerophosphate and ascorbic acid), as determined by increased expression of the osteocyte markers DMP-1, E11 and sclerostin. Culture of murine aortic VSMCs under identical conditions confirmed that the calcification of these cells can also be induced in similar calcifying medium. Calcified VSMCs had increased alkaline phosphatase activity and PiT-1 expression, which are recognized markers of vascular calcification. Expression of DMP-1, E11 and sclerostin was up-regulated during VSMC calcification in vitro. Increased protein expression of E11, an early osteocyte marker, and sclerostin, expressed by more mature osteocytes was also observed in the calcified media of Enpp1−/− mouse aortic tissue.Conclusions/SignificanceThis study has demonstrated the up-regulation of key osteocytic molecules during the vascular calcification process. A fuller understanding of the functional role of osteocyte formation and specifically sclerostin and E11 expression in the vascular calcification process may identify novel potential therapeutic strategies for clinical intervention.
Highlights
Vascular calcification is a marker of increased cardiovascular risk in a number of diseases, including diabetes, atherosclerosis and end-stage renal disease [1,2,3]
A number of studies have reported that vascular smooth muscle cells (VSMCs), the predominant cell type involved in vascular calcification, can undergo phenotypic transition to osteoblastic and chondrocytic cells in a calcified environment [19,20,21,22,23]
These expression studies demonstrate the terminal differentiation of calvarial osteoblasts into the osteocyte phenotype in vitro
Summary
Vascular calcification is a marker of increased cardiovascular risk in a number of diseases, including diabetes, atherosclerosis and end-stage renal disease [1,2,3]. The process of vascular calcification shares many similarities with that of bone formation [1,2]. Chondrocytes and osteoblasts calcify their extracellular matrix (ECM) during endochondral bone formation by promoting the formation of crystalline hydroxyapatite, through a series of physico-chemical and biochemical processes. Osteocytes are terminally differentiated osteoblasts and make up 90% of the cells present within bone. They are distinctive and isolated cells that are embedded within the bone matrix. Osteocytes have a reported role in mineral homeostasis. They are capable of modifying the matrix environment around them [5] and produce calcification modifying hormones and growth factors [6,7]. Vascular smooth muscle cells (VSMCs), the predominant cell type involved in medial vascular calcification, can undergo phenotypic transition to both osteoblastic and chondrocytic cells within a calcifying environment
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