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HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl\u2212\/\u2212, aka Akp2\u2212\/\u2212) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl\u2212\/\u2212 mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl\u2212\/\u2212 mice, histological, \u00b5CT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP at 8.2\u2009mg\/kg\/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP. \u00a9 2012 American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbmr.1619","type":"journal-article","created":{"date-parts":[[2012,3,31]],"date-time":"2012-03-31T00:41:13Z","timestamp":1333154473000},"page":"1722-1734","source":"Crossref","is-referenced-by-count":87,"title":["Enzyme replacement prevents enamel defects in hypophosphatasia mice"],"prefix":"10.1093","volume":"27","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":"Rodrigo Cardoso","family":"de Oliveira","sequence":"additional","affiliation":[{"name":"University of S\u00e3o Paulo, Bauru Dental School, Department of Biological Sciences, Bauru-SP, Brazil"},{"name":"Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L","family":"Foster","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanson","family":"Fong","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Cory","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, 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":"Robert L","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Somerman","sequence":"additional","affiliation":[{"name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P","family":"Whyte","sequence":"additional","affiliation":[{"name":"Shriners Hospital for Children and Washington University, St. Louis, MO, USA"}],"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":[[2012,3,28]]},"reference":[{"key":"2024020318281384300_bib1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1111\/j.1601-6343.2005.00345.x","article-title":"Inducers and inhibitors of biomineralization: lessons from pathological calcification","volume":"8","author":"Giachelli","year":"2005","journal-title":"Orthod Craniofac Res."},{"key":"2024020318281384300_bib2","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1101\/gad.1276205","article-title":"Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone","volume":"19","author":"Murshed","year":"2005","journal-title":"Genes Dev."},{"key":"2024020318281384300_bib3","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1017\/CBO9780511545795.005","volume-title":"The osteoporosis primer","author":"McKee","year":"2000"},{"key":"2024020318281384300_bib4","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1016\/S0021-9258(18)43458-8","article-title":"Properties of dissociatively extracted fetal tooth matrix proteins. 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