{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T03:37:23Z","timestamp":1776310643207,"version":"3.50.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIDCR","award":["DE025664"],"award-info":[{"award-number":["DE025664"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Craniometaphyseal dysplasia (CMD) is a rare genetic bone disorder, characterized by progressive thickening of craniofacial bones and flared metaphyses of long bones. Craniofacial hyperostosis leads to the obstruction of neural foramina and neurological symptoms such as facial palsy, blindness, deafness, or severe headache. Mutations in ANKH (mouse ortholog ANK), a transporter of small molecules such as citrate and ATP, are responsible for autosomal dominant CMD. Knock-in (KI) mice carrying an ANKF377del mutation (AnkKI\/KI) replicate many features of human CMD. Pyrophosphate (PPi) levels in plasma are significantly reduced in AnkKI\/KI mice. PPi is a potent inhibitor of mineralization. To examine the extent to which restoration of circulating PPi levels may prevent the development of a CMD-like phenotype, we treated AnkKI\/KI mice with the recombinant human ENPP1-Fc protein IMA2a. ENPP1 hydrolyzes ATP into AMP and PPi. Male and female Ank+\/+ and AnkKI\/KI mice (n\u2009\u2265\u20096\/group) were subcutaneously injected with IMA2a or vehicle weekly for 12\u00a0wk, starting at the age of 1\u00a0wk. Plasma ENPP1 activity significantly increased in AnkKI\/KI mice injected with IMA2a (Vehicle\/IMA2a: 28.15\u2009\u00b1\u20091.65\/482.7\u2009\u00b1\u2009331.2 mOD\/min; p &amp;lt;.01), which resulted in the successful restoration of plasma PPi levels (Ank+\/+\/AnkKI\/KI vehicle treatment\/AnkKI\/KI IMA2a: 0.94\u2009\u00b1\u20090.5\/0.43\u2009\u00b1\u20090.2\/1.29\u2009\u00b1\u20090.8\u00a0\u03bcM; p &amp;lt;.01). We examined the skeletal phenotype by X-Ray imaging and \u03bcCT. IMA2a treatment of AnkKI\/KI mice did not significantly correct CMD features such as the abnormal shape of femurs, increased bone mass of mandibles, hyperostotic craniofacial bones, or the narrowed foramen magnum. However, \u03bcCT imaging showed ectopic calcification near basioccipital bones at the level of the foramen magnum and on joints of AnkKI\/KI mice. Interestingly, IMA2a treatment significantly reduced the volume of calcified nodules at both sites. Our data demonstrate that IMA2a is sufficient to restore plasma PPi levels and reduce ectopic calcification but fails to rescue skeletal abnormalities in AnkKI\/KI mice under our treatment conditions.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziae103","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T03:13:57Z","timestamp":1723086837000},"source":"Crossref","is-referenced-by-count":5,"title":["ENPP1 enzyme replacement therapy improves ectopic calcification but does not rescue skeletal phenotype in a mouse model for craniometaphyseal dysplasia"],"prefix":"10.1093","volume":"8","author":[{"given":"Ernst J","family":"Reichenberger","sequence":"first","affiliation":[{"name":"Center for Regenerative Medicine and Skeletal Development , Department of Reconstructive Sciences, School of Dental Medicine, , Farmington, CT 06030 , United States"},{"name":"University of Connecticut Health , Department of Reconstructive Sciences, School of Dental Medicine, , Farmington, CT 06030 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Research and Development, Inozyme Pharma , Boston, MA 02210 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayano","family":"Hatori","sequence":"additional","affiliation":[{"name":"Department of Endodontology , School of Dental Medicine, , Farmington, CT 06030 , United States"},{"name":"University of Connecticut Health , School of Dental Medicine, , Farmington, CT 06030 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-6768","authenticated-orcid":false,"given":"Thomas O","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (Endocrinology), Yale University School of Medicine , New Haven, CT 06520 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koen","family":"van de Wetering","sequence":"additional","affiliation":[{"name":"Department of Dermatology and Cutaneous Biology , Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, , Philadelphia, PA 19144 , United States"},{"name":"Thomas Jefferson University , Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, , Philadelphia, PA 19144 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Flaman","sequence":"additional","affiliation":[{"name":"Research and Development, Inozyme Pharma , Boston, MA 02210 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Howe","sequence":"additional","affiliation":[{"name":"Research and Development, Inozyme Pharma , Boston, MA 02210 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Research and Development, Inozyme Pharma , Boston, MA 02210 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves","family":"Sabbagh","sequence":"additional","affiliation":[{"name":"Research and Development, Inozyme Pharma , Boston, MA 02210 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7349-3091","authenticated-orcid":false,"given":"I-Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine and Skeletal Development , Department of Reconstructive Sciences, School of Dental Medicine, , Farmington, CT 06030 , United States"},{"name":"University of Connecticut Health , Department of Reconstructive Sciences, School of Dental Medicine, , Farmington, CT 06030 , United States"},{"name":"Department of Endodontology , School of Dental Medicine, , Farmington, CT 06030 , United States"},{"name":"University of Connecticut Health , School of Dental Medicine, , Farmington, CT 06030 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"issue":"6","key":"2024082013190218600_ref1","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1001\/archinte.1954.00250060005001","article-title":"Metaphyseal dysplasia, epiphyseal dysplasia, diaphyseal dysplasia, and related conditions. 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