期刊
JOURNAL OF CELLULAR PHYSIOLOGY
卷 233, 期 4, 页码 3230-3243出版社
WILEY
DOI: 10.1002/jcp.26166
关键词
arterial medial calcification; ATP; bone formation; NPP1; vascular smooth muscle cells
资金
- Arthritis Research UK [19205]
- British Heart Foundation [PG/15/13/31296]
- NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH [R01DE012889] Funding Source: NIH RePORTER
- Biotechnology and Biological Sciences Research Council [BBS/E/D/20221657, BBS/E/D/10002071, BB/F023928/1] Funding Source: researchfish
- Versus Arthritis [19205] Funding Source: researchfish
- BBSRC [BBS/E/D/10002071, BB/F023928/1, BBS/E/D/20221657] Funding Source: UKRI
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 P2Y(2) receptor. Conversely, the actions of ATP/UTP on bone mineralization and TNAP activity were attenuated in osteoblasts lacking the P2Y(2) 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.
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