Metabolic acidosis increases fibroblast growth factor 23 in neonatal mouse bone.
Fibroblast growth factor 23 (FGF23) significantly increases with declining renal function, leading to reduced renal tubular phosphate reabsorption, decreased 1,25-dihydroxyvitamin D, and increased left ventricular hypertrophy. Elevated FGF23 is associated with increased mortality. FGF23 is synthesized in osteoblasts and osteocytes; however, the mechanisms by which it is regulated are not clear. Patients with chronic kidney disease have decreased renal acid excretion leading to metabolic acidosis, which has a direct effect on bone cell activity. We hypothesized that metabolic acidosis would directly increase bone cell FGF23 production. Using cultured neonatal mouse calvariae, we found that metabolic acidosis increased medium FGF23 protein levels as well as FGF23 RNA expression at 24 h and 48 h compared with incubation in neutral pH medium. To exclude that the increased FGF23 was secondary to metabolic acidosis-induced release of bone mineral phosphate, we cultured primary calvarial osteoblasts. In these cells, metabolic acidosis increased FGF23 RNA expression at 6 h compared with incubation in neutral pH medium. Thus metabolic acidosis directly increases FGF23 mRNA and protein in mouse bone. If these results are confirmed in humans with chronic kidney disease, therapeutic interventions to mitigate acidosis, such as bicarbonate administration, may also lower levels of FGF23, decrease left ventricular hypertrophy, and perhaps even decrease mortality.
Dept. of Medicine, Div. of Nephrology, Univ. of Rochester School of Medicine, Box 675, 601 Elmwood Ave., Rochester, NY 14642, USA. nancy_krieger@urmc.rochester.edu
Nancy S
NS
Krieger
Christopher D
CD
Culbertson
Kelly
K
Kyker-Snowman
David A
DA
Bushinsky
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001862:Bone Resorption / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002245:Carbon Dioxide / Q000378:metabolism; D002478:Cells, Cultured; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012886:Skull / Q000187:drug effects / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D002245:Carbon Dioxide; D005346:Fibroblast Growth Factors; D012313:RNA; D000089703:Fibroblast Growth Factor-23; D002118:Calcium