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Title
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Inhibition of arterial medial calcification and bone mineralisation by extracellular nucleotides : the same functional effect mediated by differing cellular mechanisms
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Author
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Abstract
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| Arterial medial calcification (AMC) is thought to share some outward similarities to skeletal mineralisation and has been associated with the transdifferentiation of vascular smooth muscle cells (VSMCs) to an osteoblast-like phenotype. ATP and UTP have previously been shown to inhibit bone mineralisation. This investigation compared the effects of extracellular nucleotides on calcification in VSMCs with those seen in osteoblasts. ATP, UTP and the ubiquitous mineralisation inhibitor, pyrophosphate (PPi), dose dependently inhibited VSMC calcification by ≤85%. Culture of VSMCs in calcifying conditions was associated with an increase in apoptosis; treatment with ATP, UTP and PPi reduced apoptosis to levels seen in non-calcifying cells. Extracellular nucleotides had no effect on osteoblast viability. Basal alkaline phosphatase (TNAP) activity was over 100-fold higher in osteoblasts than VSMCs. ATP and UTP reduced osteoblast TNAP activity (≤50%) but stimulated VSMC TNAP activity (≤88%). The effects of extracellular nucleotides on VSMC calcification, cell viability and TNAP activity were unchanged by deletion or inhibition of the P2Y2 receptor. Conversely, the actions of ATP/UTP on bone mineralisation and TNAP activity were attenuated in osteoblasts lacking the P2Y2 receptor. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) hydrolyses ATP and UTP to produce PPi. In both VSMCs and osteoblasts, deletion of NPP1 blunted the inhibitory effects of extracellular nucleotides suggesting involvement of P2 receptor independent pathways. Our results show that although the overall functional effect of extracellular nucleotides on AMC and bone mineralisation is similar there are clear differences in the cellular mechanisms mediating these actions. |
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Language
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English
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Source (journal)
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Journal of cellular physiology. - Philadelphia, Pa
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Publication
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Philadelphia, Pa
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2018
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ISSN
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0021-9541
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DOI
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10.1002/JCP.26166
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Volume/pages
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233
:4
(2018)
, p. 3230-3243
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ISI
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000418723200053
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Pubmed ID
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28976001
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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