{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:05:34Z","timestamp":1784552734002,"version":"3.55.0"},"posted":{"date-parts":[[2026,7,16]]},"group-title":"Pharmacology and Toxicology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"NIH NIAMS","award":["R01AR082460"],"award-info":[{"award-number":["R01AR082460"]}]},{"name":"NIH NIAMS","award":["R21AR083597"],"award-info":[{"award-number":["R21AR083597"]}]},{"name":"PXE International"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,16]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Pseudoxanthoma elasticum (PXE) is a rare inherited disorder characterized by progressive ectopic calcification of soft connective tissues, including skin, arteries, and eyes, leading to significant morbidity. PXE results from loss of functional ABCC6, a liver specific ATP efflux conduit. Reduced ATP release into the circulation limits its conversion into AMP and the mineralization inhibitor pyrophosphate (PPi). Consequently, low plasma PPi levels drive ectopic calcification in PXE. Although oral PPi supplementation can inhibit ectopic calcification in Abcc6\u207b\/\u207b mice, impractically high doses are needed, due to its rapid hydrolysis in the gastrointestinal tract.<\/jats:p>\n                <jats:p>Here, we evaluated phosphocitrate, an exceedingly more potent mineralization inhibitor, in vitro and in Abcc6\u207b\/\u207b mice. In ATDC5 cells, 1 \u00b5M phosphocitrate significantly inhibited mineralization following induction, comparable to approximately tenfold higher concentrations of PPi. In vivo, daily intraperitoneal administration of phosphocitrate (4.7 \u00b5mol\/kg bw) markedly reduced calcification in muzzle skin and kidneys, whereas an at least fivefold higher dose of PPi was needed to achieve a similar effect. Oral administration required substantially higher doses of both compounds (\u223c2.4 mmol\/kg bw), but PC remained more effective than PPi at inhibiting soft tissue calcification in Abcc6\u207b\/\u207b mice.<\/jats:p>\n                <jats:p>Importantly, unlike PPi, oral phosphocitrate did not adversely affect skeletal strength or stiffness, even at supraphysiological doses.<\/jats:p>\n                <jats:p>In summary, phosphocitrate is a more potent inhibitor of ectopic calcification than PPi in Abcc6\u207b\/\u207b mice. While optimization of oral delivery remains necessary, its increased potency supports the potential of alternative administration routes, including subcutaneous delivery, as a practical therapeutic strategy for PXE.<\/jats:p>","DOI":"10.64898\/2026.07.10.737791","type":"posted-content","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:35:12Z","timestamp":1784266512000},"source":"Crossref","is-referenced-by-count":0,"title":["Phosphocitrate Is Superior to Pyrophosphate in Preventing Soft Connective Tissue Calcification in a Mouse Model of Pseudoxanthoma Elasticum"],"prefix":"10.64898","author":[{"given":"Ibtesam","family":"Rajpar","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celina","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Niaziorimi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob","family":"Beiriger","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petri","family":"Turhanen","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University of Eastern Finland, Biocenter Kuopio, Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen","family":"van de Wetering","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072005350457000_2026.07.10.737791v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14498"},{"key":"2026072005350457000_2026.07.10.737791v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2018.10.005"},{"key":"2026072005350457000_2026.07.10.737791v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejvs.2022.08.009"},{"key":"2026072005350457000_2026.07.10.737791v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242015041"},{"key":"2026072005350457000_2026.07.10.737791v1.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1319582110"},{"key":"2026072005350457000_2026.07.10.737791v1.6","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14587"},{"key":"2026072005350457000_2026.07.10.737791v1.7","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201707532"},{"key":"2026072005350457000_2026.07.10.737791v1.8","doi-asserted-by":"crossref","unstructured":"Rajparo, I. , et al. 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