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Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro

Staines, Katherine A.; Myers, Katherine; Little, Kirsty; Ralston, Stuart H.; Farquharson, Colin

Authors

Katherine A. Staines

Katherine Myers

Kirsty Little

Stuart H. Ralston

Colin Farquharson



Abstract

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.

Citation

Staines, K. A., Myers, K., Little, K., Ralston, S. H., & Farquharson, C. (2021). Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro. Calcified Tissue International, 109, 696-705. https://doi.org/10.1007/s00223-021-00882-9

Journal Article Type Article
Acceptance Date Jun 19, 2021
Online Publication Date Jul 2, 2021
Publication Date 2021-12
Deposit Date Jul 12, 2021
Publicly Available Date Jul 12, 2021
Journal Calcified Tissue International
Print ISSN 0171-967X
Electronic ISSN 1432-0827
Publisher Springer
Peer Reviewed Peer Reviewed
Volume 109
Pages 696-705
DOI https://doi.org/10.1007/s00223-021-00882-9
Keywords PHOSPHO1, Proton pump inhibitors, Histamine-2 receptor antagonists, Mineralisation, TNAP
Public URL http://researchrepository.napier.ac.uk/Output/2786163

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http://creativecommons.org/licenses/by/4.0/

Copyright Statement
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/





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