{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:45:40Z","timestamp":1792795540598,"version":"4.5.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"READYFOR","award":["JM00000141"],"award-info":[{"award-number":["JM00000141"]}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K02651"],"award-info":[{"award-number":["24K02651"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hypophosphatasia (HPP) is a rare inherited disorder caused by inactivating variants in the ALPL gene, resulting in defective mineralization of bone and teeth. Dental manifestations include early exfoliation of fully rooted primary teeth as a result of cementum dysplasia, premature loss of permanent teeth, and hypomineralization of enamel, dentin, and jawbone. However, genotype-dependent dental phenotypes and severity-based treatment strategies remain poorly defined. The aim of this study was to generate knock-in mouse models harboring clinically relevant ALPL variants and to characterize their dental and periodontal phenotypes in relation to serum tissue-nonspecific alkaline phosphatase (TNAP) activity. We analyzed mice that were compound heterozygous for a null variant and a hypomorphic variant (Alplc.1559delT\/p.F327L) and mice that were heterozygous for a dominant-negative variant (Alpl+\/p.R184W). Dental and alveolar phenotypes were assessed using micro-CT, histological analyses, and periodontal ligament traction experiments. Alplc.1559delT\/p.F327L mice exhibited reduced serum TNAP levels, mild skeletal abnormalities, and severe dental defects, including hypomineralization of enamel, dentin, and cementum, decreased alveolar BMD, and an increased distance from the cemento\u2013enamel junction to the alveolar bone crest. In contrast, Alpl+\/p.R184W mice showed isolated dental abnormalities characterized by dentin and cementum hypomineralization and decreased alveolar bone BMD without overt skeletal involvement. Periodontal tissue fragility was increased in both models. These knock-in mouse models recapitulate genotype-dependent dental manifestations of HPP and indicate that dental phenotypes are influenced not only by circulating TNAP levels but also by the functional effects of individual ALPL variants. This platform provides a valuable framework for elucidating the mechanisms underlying genotype-dependent dental manifestations and for developing dental treatment strategies tailored to disease severity.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziag147","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:34:58Z","timestamp":1787657698000},"source":"Crossref","is-referenced-by-count":1,"title":["Creation and characterization of novel knock-in mouse models of hypophosphatasia"],"prefix":"10.1093","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-209X","authenticated-orcid":false,"given":"Rena","family":"Okawa","sequence":"first","affiliation":[{"name":"Department of Pediatric Dentistry, Graduate School of Dentistry, The University of Osaka , Suita 565-0871 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