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Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: The same functional effect mediated by different cellular mechanisms

Patel, J J; Zhu, D; Opdebeeck, B; D'Haese, P; Millán, J L; Bourne, L E; Wheeler-Jones, C P D; Arnett, T R; MacRae, V E; Orriss, I R

Authors

J J Patel

D Zhu

B Opdebeeck

P D'Haese

J L Millán

L E Bourne

C P D Wheeler-Jones

T R Arnett

V E MacRae

I R Orriss



Abstract

Arterial medial calcification (AMC) is thought to share some outward similarities to skeletal mineralization 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 mineralization. This investigation compared the effects of extracellular nucleotides on calcification in VSMCs with those seen in osteoblasts. ATP, UTP and the ubiquitous mineralization 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 mineralization 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 mineralization is similar there are clear differences in the cellular mechanisms mediating these actions.

Citation

Patel, J. J., Zhu, D., Opdebeeck, B., D'Haese, P., Millán, J. L., Bourne, L. E., …Orriss, I. R. (2018). Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: The same functional effect mediated by different cellular mechanisms. Journal of Cellular Physiology, 233(4), 3230-3243. https://doi.org/10.1002/jcp.26166

Journal Article Type Article
Acceptance Date Aug 22, 2017
Publication Date Apr 1, 2018
Deposit Date Oct 11, 2017
Publicly Available Date Mar 29, 2024
Journal Journal of Cellular Physiology
Print ISSN 0021-9541
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 233
Issue 4
Pages 3230-3243
DOI https://doi.org/10.1002/jcp.26166
Public URL https://rvc-repository.worktribe.com/output/1387829

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