Reversal of mineral ion homeostasis and soft-tissue calcification of klotho knockout mice by deletion of vitamin D 1alpha-hydroxylase.
Changes in the expression of klotho, a beta-glucuronidase, contribute to the development of features that resemble those of premature aging, as well as chronic renal failure. Klotho knockout mice have increased expression of the sodium/phosphate cotransporter (NaPi2a) and 1alpha-hydroxylase in their kidneys, along with increased serum levels of phosphate and 1,25-dihydroxyvitamin D. These changes are associated with widespread soft-tissue calcifications, generalized tissue atrophy, and a shorter lifespan in the knockout mice. To determine the role of the increased vitamin D activities in klotho knockout animals, we generated klotho and 1alpha-hydroxylase double-knockout mice. These double mutants regained body weight and developed hypophosphatemia with a complete elimination of the soft-tissue and vascular calcifications that were routinely found in klotho knockout mice. The markedly increased serum fibroblast growth factor 23 and the abnormally low serum parathyroid hormone levels, typical of klotho knockout mice, were significantly reversed in the double-knockout animals. These in vivo studies suggest that vitamin D has a pathologic role in regulating abnormal mineral ion metabolism and soft-tissue anomalies of klotho-deficient mice.
Ohnishi
Mutsuko
M
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Nakatani
Teruyo
T
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Lanske
Beate
B
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Razzaque
M Shawkat
MS
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA. Electronic address: mrazzaque@hms.harvard.edu.
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001835:Body Weight; D002114:Calcinosis; D005966:Glucuronidase / Q000172:deficiency* / Q000235:genetics; D006706:Homeostasis; D017674:Hypophosphatemia / Q000209:etiology; D000090265:Klotho Proteins; D051379:Mice; D018345:Mice, Knockout; D008903:Minerals / Q000378:metabolism*; D014807:Vitamin D / Q000502:physiology
D008903:Minerals; D014807:Vitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005966:Glucuronidase; D000090265:Klotho Proteins