FGF-23-Klotho signaling stimulates proliferation and prevents vitamin D-induced apoptosis.
Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism. Fgf-23(-/-) or Klotho(-/-) knockout mice exhibit several pathophysiological processes consistent with premature aging including severe atrophy of tissues. We show that the signal transduction pathways initiated by FGF-23-Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1alpha-hydroxylase expression and phosphoinositide-3 kinase-dependent inhibition of caspase activity. These data provide new insights into the physiological roles of FGF-23 and Klotho.
Medici
Damian
D
Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Razzaque
Mohammed S
MS
Deluca
Stephelynn
S
Rector
Trent L
TL
Hou
Bo
B
Kang
Kihwa
K
Goetz
Regina
R
Mohammadi
Moosa
M
Kuro-O
Makoto
M
Olsen
Bjorn R
BR
Lanske
Beate
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D005966:Glucuronidase; D000090265:Klotho Proteins