{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:42:00Z","timestamp":1791276120183,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2011,1,20]],"date-time":"2011-01-20T00:00:00Z","timestamp":1295481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Alkaline phosphatase (TNAP) plays a crucial role promoting mineralization of the extracellular matrix by restricting the concentration of the calcification inhibitor inorganic pyrophosphate (PPi). Mutations in the TNAP gene cause hypophosphatasia, a heritable form of rickets and osteomalacia. Here we show that PHOSPHO1, a phosphatase with specificity for phosphoethanolamine and phosphocholine, plays a functional role in the initiation of calcification and that ablation of PHOSPHO1 and TNAP function prevents skeletal mineralization. Phospho1\u2212\/\u2212 mice display growth plate abnormalities, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis in early life. Primary cultures of Phospho1\u2212\/\u2212 tibial growth plate chondrocytes and chondrocyte-derived matrix vesicles (MVs) show reduced mineralizing ability, and plasma samples from Phospho1\u2212\/\u2212 mice show reduced levels of TNAP and elevated plasma PPi concentrations. However, transgenic overexpression of TNAP does not correct the bone phenotype in Phospho1\u2212\/\u2212 mice despite normalization of their plasma PPi levels. In contrast, double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality. We conclude that PHOSPHO1 has a nonredundant functional role during endochondral ossification, and based on these data and a review of the current literature, we propose an inclusive model of skeletal calcification that involves intravesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP, nucleotide pyrophosphatase phosphodiesterase-1, and collagen in the extravesicular progression of mineralization. \u00a9 2011 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.195","type":"journal-article","created":{"date-parts":[[2010,8,3]],"date-time":"2010-08-03T20:43:15Z","timestamp":1280868195000},"page":"286-297","source":"Crossref","is-referenced-by-count":219,"title":["Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: A unified model of the mechanisms of initiation of skeletal calcification"],"prefix":"10.1093","volume":"26","author":[{"given":"Manisha C","family":"Yadav","sequence":"first","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Maria Sper","family":"Sim\u00e3o","sequence":"additional","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonoko","family":"Narisawa","sequence":"additional","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Huesa","sequence":"additional","affiliation":[{"name":"Bone Biology Group, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D","family":"McKee","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Farquharson","sequence":"additional","affiliation":[{"name":"Bone Biology Group, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Luis","family":"Mill\u00e1n","sequence":"additional","affiliation":[{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,1,20]]},"reference":[{"key":"2024020318052740000_bib1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1083\/jcb.41.1.59","article-title":"Vesicles associated with calcification in the matrix of epiphyseal cartilage","volume":"41","author":"Anderson","year":"1969","journal-title":"J Cell Biol."},{"key":"2024020318052740000_bib2","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1073\/pnas.67.3.1513","article-title":"Isolation and characterization of calcifying matrix vesicles from epiphyseal cartilage","volume":"67","author":"Ali","year":"1970","journal-title":"Proc Natl Acad Sci USA."},{"key":"2024020318052740000_bib3","doi-asserted-by":"crossref","first-page":"9354","DOI":"10.1016\/S0021-9258(18)67662-8","article-title":"Roles of alkaline phosphatase and labile internal mineral in matrix vesicle\u2013mediated calcification: effect of selective release of membrane-bound alkaline phosphatase and treatment with isosmotic pH 6 buffer","volume":"261","author":"Register","year":"1986","journal-title":"J Biol Chem."},{"key":"2024020318052740000_bib4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.2741\/1576","article-title":"The role of matrix vesicles in growth plate development and biomineralization","volume":"10","author":"Anderson","year":"2005","journal-title":"Front Biosci."},{"key":"2024020318052740000_bib5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0003-9861(84)90356-4","article-title":"Can biological calcification occur in the presence of pyrophosphate","volume":"231","author":"Meyer","year":"1984","journal-title":"Arch. 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