{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:15:57Z","timestamp":1791483357980,"version":"4.3.4"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2009,12]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            <jats:italic>Klotho<\/jats:italic>\n            -knockout mice (\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            ) have increased renal expression of sodium\/phosphate cotransporters (NaPi2a), associated with severe hyperphosphatemia. Such serum biochemical changes in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice lead to extensive soft-tissue anomalies and vascular calcification. To determine the significance of increased renal expression of the NaPi2a protein and concomitant hyperphosphatemia and vascular calcification in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, we generated\n            <jats:italic>klotho<\/jats:italic>\n            and\n            <jats:italic>NaPi2a<\/jats:italic>\n            double-knockout (\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            <jats:italic>\/NaPi2a<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            ) mice.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            Genetic inactivation of NaPi2a activity from\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice reversed the severe hyperphosphatemia to mild hypophosphatemia or normophosphatemia. Importantly, despite significantly higher serum calcium and 1,25-dihydroxyvitamin D levels in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            <jats:italic>\/NaPi2a<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, the vascular and soft-tissue calcifications were reduced. Extensive soft-tissue anomalies and cardiovascular calcification were consistently noted in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice by 6 weeks of age; however, these vascular and soft-tissue abnormalities were absent even in 12-week-old double-knockout mice.\n            <jats:italic>Klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            <jats:italic>\/NaPi2a<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice also regained body weight and did not develop the generalized tissue atrophy often noted in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            single-knockout mice.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusion\u2014<\/jats:italic>\n            <\/jats:bold>\n            Our in vivo genetic manipulation studies have provided compelling evidence for a pathological role of increased NaPi2a activities in regulating abnormal mineral ion metabolism and soft-tissue anomalies in\n            <jats:italic>klotho<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice. Notably, our results suggest that serum phosphate levels are the important in vivo determinant of calcification and that lowering serum phosphate levels can reduce or eliminate soft-tissue and vascular calcification, even in presence of extremely high serum calcium and 1,25-dihydroxyvitamin D levels. These in vivo observations have significant clinical importance and therapeutic implications for patients with chronic kidney disease with cardiovascular calcification.\n          <\/jats:p>","DOI":"10.1161\/circgenetics.108.847814","type":"journal-article","created":{"date-parts":[[2009,9,22]],"date-time":"2009-09-22T01:31:55Z","timestamp":1253583115000},"page":"583-590","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":100,"title":["In Vivo Genetic Evidence for Suppressing Vascular and Soft-Tissue Calcification Through the Reduction of Serum Phosphate Levels, Even in the Presence of High Serum Calcium and 1,25-Dihydroxyvitamin D Levels"],"prefix":"10.1161","volume":"2","author":[{"given":"Mutsuko","family":"Ohnishi","sequence":"first","affiliation":[{"name":"From the Departments of Oral Medicine, Infection, and Immunity (M.O., T.N., M.S.R.) and Developmental Biology (B.L.), Harvard School of Dental Medicine, Boston, Mass; and Department of Pathology (M.S.R.), Nagasaki University School of Medicine, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruyo","family":"Nakatani","sequence":"additional","affiliation":[{"name":"From the Departments of Oral Medicine, Infection, and Immunity (M.O., T.N., M.S.R.) and Developmental Biology (B.L.), Harvard School of Dental Medicine, Boston, Mass; and Department of Pathology (M.S.R.), Nagasaki University School of Medicine, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Lanske","sequence":"additional","affiliation":[{"name":"From the Departments of Oral Medicine, Infection, and Immunity (M.O., T.N., M.S.R.) and Developmental Biology (B.L.), Harvard School of Dental Medicine, Boston, Mass; and Department of Pathology (M.S.R.), Nagasaki University School of Medicine, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Shawkat","family":"Razzaque","sequence":"additional","affiliation":[{"name":"From the Departments of Oral Medicine, Infection, and Immunity (M.O., T.N., M.S.R.) and Developmental Biology (B.L.), Harvard School of Dental Medicine, Boston, Mass; and Department of Pathology (M.S.R.), Nagasaki University School of Medicine, Nagasaki, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2005.02.014"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfh991"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.218"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114245"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1159\/000112824"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1210\/me.2003-0048"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","unstructured":"Nakatani T Ohnishi M Razzaque MS. Inactivation of klotho function induces hyperphosphatemia even in presence of high serum fibroblast growth factor 23 levels in a genetically engineered hypophosphatemic (Hyp) mouse model. FASEB J. doi: 10.1096\/fj.08-123992.","DOI":"10.1096\/fj.08-123992"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/36285"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-114397"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000154"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.9.5372"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-5432fje"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1159\/000115290"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000128607"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1870"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199709)183:1<24::AID-PATH1106>3.0.CO;2-B"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-0302"},{"key":"e_1_3_2_18_2","first-page":"1183","volume":"11","year":"1998","unstructured":"Razzaque MS, Nazneen A, Taguchi T. Immunolocalization of collagen and collagen-binding heat shock protein 47 in fibrotic lung diseases. Mod Pathol. 1998; 11: 1183\u20131188.","journal-title":"Mod Pathol"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.05.002"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1159\/000107069"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.25.050304.092642"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.24"},{"key":"e_1_3_2_23_2","first-page":"4","volume":"24","year":"2009","unstructured":"Razzaque MS. Does FGF23 toxicity influence the outcome of chronic kidney disease? Nephrol Dial Transplant. 2009; 24: 4\u20137.","journal-title":"Nephrol Dial Transplant"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000133041.27682.A2"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa041031"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.743161"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0015"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","unstructured":"Razzaque MS. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis. Nat Rev Endocrinol. doi: 10.1038\/nrendo.2009.196.","DOI":"10.1038\/nrendo.2009.196"},{"key":"e_1_3_2_29_2","doi-asserted-by":"crossref","first-page":"F470","DOI":"10.1152\/ajprenal.90538.2008","volume":"296","year":"2009","unstructured":"Razzaque MS. FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player? Am J Physiol Renal Physiol. 2009; 296: F470\u2013F476.","journal-title":"Am J Physiol Renal Physiol"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0667"}],"container-title":["Circulation: Cardiovascular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCGENETICS.108.847814","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T01:35:08Z","timestamp":1715564108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCGENETICS.108.847814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,12]]},"references-count":30,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["10.1161\/CIRCGENETICS.108.847814"],"URL":"https:\/\/doi.org\/10.1161\/circgenetics.108.847814","relation":{},"ISSN":["1942-325X","1942-3268"],"issn-type":[{"value":"1942-325X","type":"print"},{"value":"1942-3268","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,12]]}}}