Fibroblast growth factor 23 production in bone is directly regulated by 1{alpha},25-dihydroxyvitamin D, but not PTH.
Fibroblast growth factor 23 (FGF23), which is primarily produced by osteocytes in bone, regulates renal phosphate excretion and 1α,25-dihydroxyvitamin D [1,25(OH)(2)D(3)] metabolism. Patients with chronic kidney disease (CKD) have increased levels of circulating serum FGF23, but the direct effect on circulating FGF23 levels in renal insufficiency is still unclear. To identify the major regulator of FGF23 synthesis in renal insufficiency, we compared the effect of parathyroid hormone (PTH) and 1,25(OH)(2)D(3) on FGF23 synthesis in the calvariae of normal rats with that of uremic rats in vitro. 1,25(OH)(2)D(3) treatment significantly increased the FGF23 concentration in the medium from both groups, but the degree of increase in the uremic group was markedly higher than in the control group. A significant increase in FGF23 mRNA expression occurred as early as 4 h after treatment and reached the maximum within 8 h in the uremic group, whereas in the normal group a significant increase in FGF23 mRNA expression was observed only at 8 h. In addition, the expression of vitamin D receptor (VDR) mRNA in the calvariae of uremic rats was markedly higher than in normal rats. However, in neither group did PTH treatment affect the medium FGF23 concentration or the FGF23 mRNA levels. These results suggest that FGF23 synthesis in bone is regulated by 1,25(OH)(2)D(3) directly, not by PTH, and that increased VDR mRNA expression induced the relatively swift and strong response in the uremic group.
Saji
Fumie
F
Div. of Nephrology and Blood Purification Medicine, Wakayama Medical Univ., 811-1 Kimiidera, Wakayama 641-8510, Japan. s-fumie@wakayama-med.ac.jp
Shigematsu
Takashi
T
Sakaguchi
Toshifumi
T
Ohya
Masaki
M
Orita
Hikari
H
Maeda
Yuka
Y
Ooura
Maki
M
Mima
Toru
T
Negi
Shigeo
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001842:Bone and Bones / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D010281:Parathyroid Hormone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D014511:Uremia / Q000378:metabolism
D002120:Calcium Channel Agonists; C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D005346:Fibroblast Growth Factors; D002117:Calcitriol