{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:06:17Z","timestamp":1792785977453,"version":"4.5.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fund of Scientific Research-Flanders","award":["G045120N"],"award-info":[{"award-number":["G045120N"]}]},{"name":"Fund of Scientific Research-Flanders","award":["W000321N"],"award-info":[{"award-number":["W000321N"]}]},{"name":"Fund of Scientific Research-Flanders","award":["12Z0422N"],"award-info":[{"award-number":["12Z0422N"]}]},{"name":"Fund of Scientific Research-Flanders","award":["1S22217N"],"award-info":[{"award-number":["1S22217N"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Arterial media calcification or pathological deposition of calcium-phosphate crystals in the vessel wall contributes significantly to the high mortality rate observed in patients with CKD. Extracellular nucleotides (ie, ATP or UTP) regulate the arterial calcification process by interacting with (1) purinergic receptors and (2) breakdown via ecto-nucleotidases, such as ectonucleotide pyrophosphatase\/phosphodiesterase NPP1 or NPP3, affecting the local levels of calcification inhibitor, pyrophosphate, and stimulator inorganic phosphate (PPi\/Pi ratio). Also, it has been shown that ATP analogs (ie, \u03b2,\u03b3-methylene-ATP [\u03b2,\u03b3-meATP]) inhibit vascular smooth muscle cell calcification in vitro. In the first experiment, daily dosing of \u03b2,\u03b3-meATP (2\u00a0mg\/kg) was investigated in rats fed a warfarin diet to trigger the development of non\u2013CKD-related arterial medial calcifications. This study showed that \u03b2,\u03b3-meATP significantly lowered the calcium scores in the aorta and peripheral vessels in warfarin-exposed rats. In a second experiment, daily dosing of 4\u00a0mg\/kg \u03b2,\u03b3-meATP and its metabolite medronic acid (MDP) was analyzed in rats fed an adenine diet to promote the development of CKD-related arterial medial calcification. Administration of \u03b2,\u03b3-meATP and MDP did not significantly decrease aortic calcification scores in this model. Moreover, both compounds induced deleterious effects on physiological bone mineralization, causing an imminent risk for worsening the already compromised bone status in CKD. Due to this, it was not possible to raise the dosage of both compounds to tackle CKD-related arterial calcification. Again, this points out the difficult task of targeting solely ectopic calcifications without negatively affecting physiological bone mineralization. On the other hand, aortic mRNA expression of Enpp1 and Enpp3 was significantly and positively associated with aortic calcification scores, suggesting that normalizing the aortic NPP1\/3 activity to control values might be a possible target to treat (CKD-induced) arterial media calcifications.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziae057","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T11:05:28Z","timestamp":1713438328000},"source":"Crossref","is-referenced-by-count":4,"title":["\u03b2,\u03b3-Methylene-ATP and its metabolite medronic acid affect both arterial media calcification and bone mineralization in non-CKD and CKD rats"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9379-2718","authenticated-orcid":false,"given":"Britt","family":"Opdebeeck","sequence":"first","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6325-4997","authenticated-orcid":false,"given":"Astrid","family":"Van den Branden","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saar","family":"Adriaensen","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel R","family":"Orriss","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Science, Royal Veterinary College , London NW1 0TU , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessal J","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Comparative Biomedical Science, Royal Veterinary College , London NW1 0TU , United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Geryl","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Zwijsen","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Medicine and Pediatrics , Inflamed Center of Excellence, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Inflamed Center of Excellence, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick C","family":"D\u2019Haese","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Verhulst","sequence":"additional","affiliation":[{"name":"Laboratory of Pathophysiology , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"},{"name":"University of Antwerp , Department of Biomedical Sciences, , Antwerp 2610 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"issue":"11","key":"2024051906110244400_ref1","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1161\/CIRCULATIONAHA.120.050686","article-title":"Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options","volume":"143","author":"Jankowski","year":"2021","journal-title":"Circulation"},{"issue":"11","key":"2024051906110244400_ref2","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1093\/ndt\/gfm377","article-title":"Detection of coronary and peripheral artery calcification in patients with chronic kidney disease stages 3 and 4, with and without diabetes","volume":"22","author":"Porter","year":"2007","journal-title":"Nephrol Dialysis Transplant"},{"issue":"7","key":"2024051906110244400_ref3","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1681\/ASN.2008070692","article-title":"Vascular calcification: the killer of patients with chronic kidney disease","volume":"20","author":"Mizobuchi","year":"2009","journal-title":"J Am Soc Nephrol"},{"issue":"11","key":"2024051906110244400_ref4","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.jacc.2021.06.049","article-title":"Medial arterial calcification: JACC state-of-the-art review","volume":"78","author":"Lanzer","year":"2021","journal-title":"J Am Coll Cardiol"},{"issue":"22","key":"2024051906110244400_ref5","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1161\/CIRCULATIONAHA.107.743161","article-title":"Vascular calcification: pathobiology of a multifaceted disease","volume":"117","author":"Demer","year":"2008","journal-title":"Circulation"},{"issue":"11","key":"2024051906110244400_ref6","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/ki.2011.59","article-title":"Cell biological and physicochemical aspects of arterial calcification","volume":"79","author":"Neven","year":"2011","journal-title":"Kidney Int"},{"issue":"2","key":"2024051906110244400_ref7","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1525-139X.2007.00255.x","article-title":"The vascular biology of calcification","volume":"20","author":"Shroff","year":"2007","journal-title":"Semin Dialysis"},{"issue":"2","key":"2024051906110244400_ref8","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1530\/JOE-20-0428","article-title":"Regulation of mineralisation in bone and vascular tissue: a comparative review","volume":"248","author":"Bourne","year":"2021","journal-title":"J Endocrinol"},{"key":"2024051906110244400_ref9","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.coph.2016.03.003","article-title":"Pyrophosphate: a key inhibitor of mineralisation","volume":"28","author":"Orriss","year":"2016","journal-title":"Curr Opin Pharmacol"},{"issue":"3","key":"2024051906110244400_ref10","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.coph.2010.01.003","article-title":"Purinergic signalling and bone remodelling","volume":"10","author":"Orriss","year":"2010","journal-title":"Curr Opin Pharmacol"},{"issue":"3","key":"2024051906110244400_ref11","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.bone.2012.06.013","article-title":"The regulation of osteoblast function and bone mineralisation by extracellular nucleotides: the role of p2x receptors","volume":"51","author":"Orriss","year":"2012","journal-title":"Bone"},{"issue":"7","key":"2024051906110244400_ref12","doi-asserted-by":"crossref","first-page":"e69057","DOI":"10.1371\/journal.pone.0069057","article-title":"Extracellular ATP released by osteoblasts is a key local inhibitor of bone mineralisation","volume":"8","author":"Orriss","year":"2013","journal-title":"PLoS One"},{"issue":"9","key":"2024051906110244400_ref13","doi-asserted-by":"crossref","first-page":"4208","DOI":"10.1210\/en.2007-0066","article-title":"Extracellular nucleotides block bone mineralization in vitro: evidence for dual inhibitory mechanisms involving both P2Y2 receptors and pyrophosphate","volume":"148","author":"Orriss","year":"2007","journal-title":"Endocrinology"},{"key":"2024051906110244400_ref14","doi-asserted-by":"crossref","first-page":"114408","DOI":"10.1016\/j.bcp.2021.114408","article-title":"The P2Y\/P2X divide: how it began","volume":"187","author":"Kennedy","year":"2021","journal-title":"Biochem Pharmacol"},{"issue":"4","key":"2024051906110244400_ref15","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1002\/jcp.26166","article-title":"Inhibition of arterial medial calcification and bone mineralization by extracellular nucleotides: the same functional effect mediated by different cellular mechanisms","volume":"233","author":"Patel","year":"2018","journal-title":"J Cell Physiol"},{"issue":"3","key":"2024051906110244400_ref16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s11302-019-09672-3","article-title":"Inhibition of vascular smooth muscle cell calcification by ATP analogues","volume":"15","author":"Patel","year":"2019","journal-title":"Purinergic signalling"},{"issue":"6974","key":"2024051906110244400_ref17","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nature02254","article-title":"Identification of the gene for vitamin K epoxide reductase","volume":"427","author":"Li","year":"2004","journal-title":"Nature"},{"issue":"7","key":"2024051906110244400_ref18","doi-asserted-by":"crossref","DOI":"10.3390\/toxins11070428","article-title":"Sclerostin as regulatory molecule in vascular media calcification and the bone-vascular axis","volume":"11","author":"De Mar\u00e9","year":"2019","journal-title":"Toxins"},{"issue":"1","key":"2024051906110244400_ref19","doi-asserted-by":"crossref","DOI":"10.1002\/jcla.22168","article-title":"Evaluation and comparison of Abbott Jaffe and enzymatic creatinine methods: could the old method meet the new requirements?","volume":"32","author":"K\u00fcme","year":"2018","journal-title":"J Clin Lab Anal"},{"key":"2024051906110244400_ref20","first-page":"199","article-title":"Regulation of cellular ATP release","volume":"118","author":"Fitz","year":"2007","journal-title":"Trans Am Clin Climatol Assoc"},{"issue":"20","key":"2024051906110244400_ref21","doi-asserted-by":"crossref","DOI":"10.3390\/ijms21207636","article-title":"Extracellular nucleotides regulate arterial calcification by activating both independent and dependent purinergic receptor Signaling pathways","volume":"21","author":"Opdebeeck","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"4","key":"2024051906110244400_ref22","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1359\/jbmr.091023","article-title":"Kinetic analysis of substrate utilization by native and TNAP-, NPP1-, or PHOSPHO1-deficient matrix vesicles","volume":"25","author":"Ciancaglini","year":"2010","journal-title":"J Bone Miner Res"},{"issue":"2","key":"2024051906110244400_ref23","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s11302-022-09882-2","article-title":"NPP1 and TNAP hydrolyze ATP synergistically during biomineralization","volume":"19","author":"Andrilli","year":"2023","journal-title":"Purinergic Signalling"},{"issue":"6","key":"2024051906110244400_ref24","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1038\/sj.bjp.0705865","article-title":"Methylene ATP analogs as modulators of extracellular ATP metabolism and accumulation","volume":"142","author":"Joseph","year":"2004","journal-title":"Br J Pharmacol"},{"issue":"1","key":"2024051906110244400_ref25","doi-asserted-by":"crossref","first-page":"H61","DOI":"10.1152\/ajpheart.01020.2010","article-title":"Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle","volume":"301","author":"Villa-Bellosta","year":"2011","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"3","key":"2024051906110244400_ref26","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/BF02547219","article-title":"Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats","volume":"11","author":"Schenk","year":"1973","journal-title":"Calcif Tissue Res"},{"issue":"6","key":"2024051906110244400_ref27","doi-asserted-by":"crossref","DOI":"10.3390\/biology10060459","article-title":"Vascular calcification in rodent models-keeping track with an extented method assortment","volume":"10","author":"Herrmann","year":"2021","journal-title":"Biology"},{"issue":"6","key":"2024051906110244400_ref28","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1016\/j.kint.2017.06.019","article-title":"Identifying early pathogenic events during vascular calcification in uremic rats","volume":"92","author":"Hortells","year":"2017","journal-title":"Kidney Int"},{"issue":"1","key":"2024051906110244400_ref29","doi-asserted-by":"crossref","first-page":"e22701","DOI":"10.1096\/fj.202201044R","article-title":"Deletion of the P2Y(2) receptor aggravates internal elastic lamina calcification in chronic kidney disease mice through upregulation of alkaline phosphatase and lipocalin-2","volume":"37","author":"Opdebeeck","year":"2023","journal-title":"FASEB J"},{"issue":"1","key":"2024051906110244400_ref30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/cvr\/cvv027","article-title":"Adenosine derived from ecto-nucleotidases in calcific aortic valve disease promotes mineralization through A2a adenosine receptor","volume":"106","author":"Mahmut","year":"2015","journal-title":"Cardiovasc Res"},{"issue":"5","key":"2024051906110244400_ref31","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.yjmcc.2012.02.003","article-title":"ATP acts as a survival signal and prevents the mineralization of aortic valve","volume":"52","author":"C\u00f4t\u00e9","year":"2012","journal-title":"J Mol Cell Cardiol"},{"issue":"16","key":"2024051906110244400_ref32","doi-asserted-by":"crossref","first-page":"4189","DOI":"10.1111\/bph.13204","article-title":"Quinazoline-4-piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells","volume":"172","author":"Shayhidin","year":"2015","journal-title":"Br J Pharmacol"},{"issue":"11","key":"2024051906110244400_ref33","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.15252\/emmm.201707532","article-title":"Oral administration of pyrophosphate inhibits connective tissue calcification","volume":"9","author":"Dedinszki","year":"2017","journal-title":"EMBO Mol Med"},{"issue":"2","key":"2024051906110244400_ref34","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.kint.2015.12.004","article-title":"Changing bone patterns with progression of chronic kidney disease","volume":"89","author":"Dr\u00fceke","year":"2016","journal-title":"Kidney Int"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziae057\/57303123\/ziae057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/8\/6\/ziae057\/57727926\/ziae057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/8\/6\/ziae057\/57727926\/ziae057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,19]],"date-time":"2024-05-19T02:15:05Z","timestamp":1716084905000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziae057\/7655983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,22]]},"references-count":34,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,4,30]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziae057","relation":{},"ISSN":["2473-4039"],"issn-type":[{"value":"2473-4039","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,6,1]]},"published":{"date-parts":[[2024,4,22]]},"article-number":"ziae057"}}