Abstract
Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP−/− mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, β-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.
Highlights
Vascular calcification (VC) is a process of deposition of calcium phosphate crystals in the form of hydroxyapatite in the intima and media of the vessel wall[1,2]
wild type (WT) vascular smooth muscle cells (VSMCs) were cultured in medium with elevated phosphate as described before[8,32], which induced mineralisation in vitro, as observed by quantification of deposited calcium phosphate crystals (Fig. 1A)
chronic kidney disease (CKD) patients have been shown to be at an increased risk of VC5,34
Summary
Vascular calcification (VC) is a process of deposition of calcium phosphate crystals in the form of hydroxyapatite in the intima and media of the vessel wall[1,2]. In response to cellular stress VSMCs undergo VC via several mechanisms: apoptosis, release of extracellular vesicles, loss of calcification inhibitors such as matrix Gla protein MGP; reviewed in Schurgers et al.[9], ageing-related DNA damage and osteo/ chondrogenic differentiation[10,11]. When vascular injury is persistent, the phenotypic transition is dysregulated and VSMCs can undergo an unfavourable transdifferentiation into cells with characteristics of osteoblasts or chondrocytes[4,12,17,18,19,20]. Our findings indicate that Ucma/GRP reduces VC by inhibiting osteo/chondrogenic VSMC transdifferentiation through a BMP-2-regulated pathway
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