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

Jessal J Patel, Dongxing Zhu, Britt Opdebeeck, Patrick D'Haese, José L Millán, Lucie E Bourne, Caroline P D Wheeler-Jones, Timothy R Arnett, Vicky E MacRae, Isabel R Orriss

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3230-3243
Number of pages14
JournalJournal of Cellular Physiology
Issue number4
Publication statusPublished - 4 Oct 2017


  • Adenosine Triphosphate/pharmacology
  • Alkaline Phosphatase/metabolism
  • Animals
  • Apoptosis/drug effects
  • Calcification, Physiologic/drug effects
  • Cell Survival/drug effects
  • Diphosphates/pharmacology
  • Extracellular Space/metabolism
  • Mice
  • Models, Biological
  • Muscle, Smooth, Vascular/drug effects
  • Myocytes, Smooth Muscle/metabolism
  • Nucleotides/pharmacology
  • Osteoblasts/drug effects
  • Phosphoric Diester Hydrolases/deficiency
  • Pyrophosphatases/deficiency
  • Receptors, Purinergic P2/metabolism
  • Tunica Media/pathology
  • Uridine Triphosphate/pharmacology
  • Vascular Calcification/pathology


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