{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:01:36Z","timestamp":1774645296787,"version":"3.50.1"},"reference-count":28,"publisher":"The Endocrine Society","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,2,1]]},"abstract":"<jats:p>Inactivating mutations of PHEX cause X-linked hypophosphatemia and result in increased circulating fibroblast growth factor 23 (FGF23). FGF23 action is dependent upon Klotho, which converts FGF receptor 1 into an FGF23-specific receptor. Disruption of Klotho results in a complex bone phenotype and hyperphosphatemia, the converse phenotype of X-linked hypophosphatemia. We examined effects of disrupting both Klotho and PHEX by creating a double-knockout (Klotho\/HYP) mouse. The combined disruption corrected the hypophosphatemia in HYP mice, indicating that Klotho is epistatic to PHEX. FGF23 levels remained elevated in all groups except wild-type, indicating that Klotho is necessary for FGF23-dependent phosphaturic activity. 1,25-Dihydroxyvitamin D levels, reduced in HYP mice, were comparably elevated in Klotho and Klotho\/HYP mice, demonstrating that Klotho is necessary for FGF23\u2019s effect on vitamin D metabolism. Serum PTH levels were reduced in both Klotho and Klotho\/HYP mice. Moreover, the Klotho null phenotype persisted in Klotho\/HYP, maintaining the runty phenotype and decreased life span of Klotho null mice. Notably, microcomputed tomography analysis demonstrated greater trabecular bone volume fraction in Klotho\/HYP mice than that in all other groups (Klotho\/HYP, 56.2 \u00b1 6.3%; Klotho, 32.5 \u00b1 10.3%; HYP, 8.6 \u00b1 7.7%; and wild type, 21.4 \u00b1 3.4%; P &amp;lt; 0.004). Histomorphometric analysis confirmed the markedly increased trabecular bone density in Klotho\/HYP mice and the well-established increase in osteoid volume in HYP mice. These observations suggest that with addition of Klotho loss of function, the overabundant osteoid typically produced in HYP mice (but fails to mineralize) is produced and mineralized in the double knockout, resulting in markedly enhanced trabecular bone density.<\/jats:p>","DOI":"10.1210\/en.2009-0564","type":"journal-article","created":{"date-parts":[[2009,12,2]],"date-time":"2009-12-02T03:06:28Z","timestamp":1259723188000},"page":"492-501","source":"Crossref","is-referenced-by-count":30,"title":["Increased Bone Volume and Correction of HYP Mouse Hypophosphatemia in the Klotho\/HYP Mouse"],"prefix":"10.1210","volume":"151","author":[{"given":"Catherine A.","family":"Brownstein","sequence":"first","affiliation":[{"name":"Departments of Genetics (C.A.B., J.Z., A.S., R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junhui","family":"Zhang","sequence":"first","affiliation":[{"name":"Departments of Genetics (C.A.B., J.Z., A.S., R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Althea","family":"Stillman","sequence":"first","affiliation":[{"name":"Departments of Genetics (C.A.B., J.Z., A.S., R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Ellis","sequence":"first","affiliation":[{"name":"Departments of Pediatrics (B.E., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Troiano","sequence":"first","affiliation":[{"name":"Departments of Orthopaedics and Rehabilitation (N.T., C.M.G., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas J.","family":"Adams","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery (D.J.A.), University of Connecticut Health Center, Farmington, Connecticut 06030"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caren M.","family":"Gundberg","sequence":"first","affiliation":[{"name":"Departments of Orthopaedics and Rehabilitation (N.T., C.M.G., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard P.","family":"Lifton","sequence":"first","affiliation":[{"name":"Departments of Genetics (C.A.B., J.Z., A.S., R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06520"},{"name":"Departments of Internal Medicine, Molecular Biophysics and Biochemistry, and the Howard Hughes Medical Institute (R.P.L.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas O.","family":"Carpenter","sequence":"first","affiliation":[{"name":"Departments of Orthopaedics and Rehabilitation (N.T., C.M.G., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520"},{"name":"Departments of Pediatrics (B.E., T.O.C.), Yale University School of Medicine, New Haven, Connecticut 06520"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071612313319900_R1","doi-asserted-by":"crossref","first-page":"4667","DOI":"10.1073\/pnas.73.12.4667","article-title":"Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets.","volume":"73","author":"Eicher","year":"1976","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612313319900_R2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/hmg\/6.2.165","article-title":"Pex gene deletions in Gy and Hyp mice provide mouse models for X-linked 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