Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process.
Fibroblast growth factor 23 null mice (Fgf-23-/-) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Furthermore, increased vitamin D activities in homozygous mutants are associated with severe atherosclerosis and widespread soft tissue calcifications; ablation of vitamin D activity from Fgf-23-/- mice, by genetically deleting the 1alpha(OH)ase gene, eliminates atherosclerosis and ectopic calcifications and significantly rescues premature aging-like features of Fgf-23-/- mice, resulting in prolonged survival of Fgf-23-/-/1alpha(OH)ase-/- double mutants. Our results indicate a novel role of Fgf-23 in developing premature aging-like features through regulating vitamin D homeostasis. Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process.
Razzaque
Mohammed S
MS
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, USA.
Sitara
Despina
D
Taguchi
Takashi
T
St-Arnaud
René
R
Lanske
Beate
B
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D019588:Aging, Premature / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis; D049109:Cell Proliferation; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D000090265:Klotho Proteins; D008168:Lung / Q000378:metabolism; D008208:Lymphatic System / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D012867:Skin / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*
C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D005966:Glucuronidase; D000090265:Klotho Proteins