{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T04:08:16Z","timestamp":1792382896643,"version":"4.4.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T00:00:00Z","timestamp":1622073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["K08AR067854"],"award-info":[{"award-number":["K08AR067854"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R03 AR073899"],"award-info":[{"award-number":["R03 AR073899"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R01 AR076973"],"award-info":[{"award-number":["R01 AR076973"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Osteocytes remodel the perilacunar matrix and canaliculi. X-linked hypophosphatemia (XLH) is characterized by elevated serum levels of fibroblast growth factor 23 (FGF23), leading to decreased 1,25 dihydroxyvitamin D<jats:sub>3<\/jats:sub> (1,25D) production and hypophosphatemia. Bones from mice with XLH (Hyp) have enlarged osteocyte lacunae, enhanced osteocyte expression of genes of bone remodeling, and impaired canalicular structure. The altered lacuno-canalicular (LCN) phenotype is improved with 1,25D or anti-FGF23 antibody treatment, pointing to roles for 1,25D and\/or phosphate in regulating this process. To address whether impaired 1,25D action results in LCN alterations, the LCN phenotype was characterized in mice lacking the vitamin D receptor (VDR) in osteocytes (VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup>). Mice lacking the sodium phosphate transporter NPT2a (NPT2aKO) have hypophosphatemia and high serum 1,25D levels, therefore the LCN phenotype was characterized in these mice to determine if increased 1,25D compensates for hypophosphatemia in regulating LCN remodeling. Unlike Hyp mice, neither VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup> nor NPT2aKO mice have dramatic alterations in cortical microarchitecture, allowing for dissecting 1,25D and phosphate specific effects on LCN remodeling in tibial cortices. Histomorphometric analyses demonstrate that, like Hyp mice, tibiae and calvariae in VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup> and NPT2aKO mice have enlarged osteocyte lacunae (tibiae: 0.15\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(VDR<jats:sup>f\/f;DMP1Cre-<\/jats:sup>) vs 0.19\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup>), 0.12\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(WT) vs 0.18\u00b10.0\u03bcm<jats:sup>2<\/jats:sup>(NPT2aKO), calvariae: 0.09\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(VDR<jats:sup>f\/f;DMP1Cre-<\/jats:sup>) vs 0.11\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup>), 0.08\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(WT) vs 0.13\u00b10.02\u03bcm<jats:sup>2<\/jats:sup>(NPT2aKO), p&lt;0.05 all comparisons) and increased immunoreactivity of bone resorption marker Cathepsin K (Ctsk). The osteocyte enriched RNA isolated from tibiae in VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup> and NPT2aKO mice have enhanced expression of matrix resorption genes that are classically expressed by osteoclasts (<jats:italic>Ctsk<\/jats:italic>, <jats:italic>Acp5<\/jats:italic>, <jats:italic>Atp6v0d2<\/jats:italic>, <jats:italic>Nhedc2<\/jats:italic>). Treatment of Ocy454 osteocytes with 1,25D or phosphate inhibits the expression of these genes. Like Hyp mice, VDR<jats:sup>f\/f;DMP1Cre+<\/jats:sup> and NPT2aKO mice have impaired canalicular organization in tibia and calvaria. These studies demonstrate that hypophosphatemia and osteocyte-specific 1,25D actions regulate LCN remodeling. Impaired 1,25D action and low phosphate levels contribute to the abnormal LCN phenotype observed in XLH.<\/jats:p>","DOI":"10.1371\/journal.pone.0252348","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T18:20:40Z","timestamp":1622139640000},"page":"e0252348","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Impaired 1,25 dihydroxyvitamin D3 action and hypophosphatemia underlie the altered lacuno-canalicular remodeling observed in the Hyp mouse model of XLH"],"prefix":"10.1371","volume":"16","author":[{"given":"Ye","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2915-8154","authenticated-orcid":true,"given":"Supriya","family":"Jagga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8249-7011","authenticated-orcid":true,"given":"Janaina S.","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakshya","family":"Rana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Divieti","family":"Pajevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2630-6916","authenticated-orcid":true,"given":"Eva 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