{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:06:55Z","timestamp":1791418015680,"version":"4.3.3"},"reference-count":77,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,27]],"date-time":"2013-08-27T00:00:00Z","timestamp":1377561600000},"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":[[2014,3,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Excessive FGF23 has been identified as a pivotal phosphaturic factor leading to renal phosphate-wasting and the subsequent development of rickets and osteomalacia. In contrast, loss of FGF23 in mice (Fgf23\u2212\/\u2212) leads to high serum phosphate, calcium, and 1,25-vitamin D levels, resulting in early lethality attributable to severe ectopic soft-tissue calcifications and organ failure. Paradoxically, Fgf23\u2212\/\u2212 mice exhibit a severe defect in skeletal mineralization despite high levels of systemic mineral ions and abundant ectopic mineralization, an abnormality that remains largely unexplained. Through use of in situ hybridization, immunohistochemistry, and immunogold labeling coupled with electron microscopy of bone samples, we discovered that expression and accumulation of osteopontin (Opn\/OPN) was markedly increased in Fgf23\u2212\/\u2212 mice. These results were confirmed by qPCR analyses of Fgf23\u2212\/\u2212 bones and ELISA measurements of serum OPN. To investigate whether elevated OPN levels were contributing to the bone mineralization defect in Fgf23\u2212\/\u2212 mice, we generated Fgf23\u2212\/\u2212\/Opn\u2212\/\u2212 double-knockout mice (DKO). Biochemical analyses showed that the hypercalcemia and hyperphosphatemia observed in Fgf23\u2212\/\u2212 mice remained unchanged in DKO mice; however, micro-computed tomography (\u00b5CT) and histomorphometric analyses showed a significant improvement in total mineralized bone volume. The severe osteoidosis was markedly reduced and a normal mineral apposition rate was present in DKO mice, indicating that increased OPN levels in Fgf23\u2212\/\u2212 mice are at least in part responsible for the osteomalacia. Moreover, the increased OPN levels were significantly decreased upon lowering serum phosphate by feeding a low-phosphate diet or after deletion of NaPi2a, indicating that phosphate levels contribute in part to the high OPN levels in Fgf23\u2212\/\u2212 mice. In summary, our results suggest that increased OPN is an important pathogenic factor mediating the mineralization defect and the alterations in bone metabolism observed in Fgf23\u2212\/\u2212 bones. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2079","type":"journal-article","created":{"date-parts":[[2013,8,27]],"date-time":"2013-08-27T13:38:40Z","timestamp":1377610720000},"page":"693-704","source":"Crossref","is-referenced-by-count":93,"title":["Increased Osteopontin Contributes to Inhibition of Bone Mineralization in FGF23-Deficient Mice"],"prefix":"10.1093","volume":"29","author":[{"given":"Quan","family":"Yuan","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduPR China"},{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of EndocrinologyPeking Union Medical College HospitalBeijingPR China"},{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral Diseases, West China Hospital of StomatologySichuan UniversityChengduPR China"},{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadatoshi","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Densmore","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Sch\u00fcler","sequence":"additional","affiliation":[{"name":"Department of Biomedical SciencesUniversity of Veterinary MedicineViennaAustria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhold G","family":"Erben","sequence":"additional","affiliation":[{"name":"Department of Biomedical SciencesUniversity of Veterinary MedicineViennaAustria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc D","family":"McKee","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry, and Department of Anatomy and Cell BiologyMcGill UniversityMontrealCanada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Lanske","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Infection, and ImmunityHarvard School of Dental MedicineBostonMAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,8,27]]},"reference":[{"issue":"4","key":"2024020318564559300_jbmr2079-bib-0001","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1172\/JCI200419081","article-title":"Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism","volume":"113","author":"Shimada","year":"2004","journal-title":"J Clin Invest."},{"issue":"7","key":"2024020318564559300_jbmr2079-bib-0002","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.matbio.2004.09.007","article-title":"Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice","volume":"23","author":"Sitara","year":"2004","journal-title":"Matrix Biol."},{"key":"2024020318564559300_jbmr2079-bib-0003","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.med.051308.111339","article-title":"Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23","volume":"61","author":"Bergwitz","year":"2010","journal-title":"Annu Rev Med."},{"issue":"3","key":"2024020318564559300_jbmr2079-bib-0004","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/81664","article-title":"Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. 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