title: Increased bone volume and correction of HYP mouse hypophosphatemia in the Klotho/HYP mouse.
abstract: 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's 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 +/- 6.3%; Klotho, 32.5 +/- 10.3%; HYP, 8.6 +/- 7.7%; and wild type, 21.4 +/- 3.4%; P < 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.
authors: Department of Genetics, Yale University School of Medicine, 333 Cedar Street, SHM I-308, New Haven, Connecticut 06510, USA.
authors: Catherine A
authors: CA
authors: Brownstein
authors: Junhui
authors: J
authors: Zhang
authors: Althea
authors: A
authors: Stillman
authors: Bruce
authors: B
authors: Ellis
authors: Nancy
authors: N
authors: Troiano
authors: Douglas J
authors: DJ
authors: Adams
authors: Caren M
authors: CM
authors: Gundberg
authors: Richard P
authors: RP
authors: Lifton
authors: Thomas O
authors: TO
authors: Carpenter
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood; D003433:Crosses, Genetic; D017931:DNA Primers; D004268:DNA-Binding Proteins; D053098:Familial Hypophosphatemic Rickets / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000000981:diagnostic imaging*; D000089703:Fibroblast Growth Factor-23; D040181:Genetic Diseases, X-Linked; D005838:Genotype; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013977:Tibia / Q000033:anatomy & histology / Q000473:pathology*; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D009687:Nuclear Proteins; C497703:PHF19 protein, human; D014157:Transcription Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium