Acute Parathyroid Hormone Injection Increases C-Terminal but Not Intact Fibroblast Growth Factor 23 Levels.
The acute effects of parathyroid hormone (PTH) on fibroblast growth factor 23 (FGF23) in vivo are not well understood. After a single subcutaneous PTH (1-34) injection (50 nmol/kg) in mice, FGF23 levels were assessed in plasma using assays that measure either intact alone (iFGF23) or intact/C-terminal FGF23 (cFGF23). Furthermore, FGF23 messenger RNA (mRNA) and protein levels were assessed in bone. In addition, we examined the effects of PTH treatment on FGF23 production in vitro using differentiated calvarial osteocyte-like cells. cFGF23 levels increased by three- to fivefold within 2 hours following PTH injection, which returned to baseline by 4 hours. In contrast, iFGF23 levels remained unchanged for the first 2 hours, yet declined to ∼60% by 6 hours and remained suppressed before returning to baseline after 24 hours. Using homozygous mice for an autosomal dominant hypophosphatemic rickets-FGF23 mutation or animals treated with a furin inhibitor, we showed that cFGF23 and iFGF23 levels increased equivalently after PTH injection. These findings are consistent with increased FGF23 production in bone, yet rapid cleavage of the secreted intact protein. Using primary osteocyte-like cell cultures, we showed that PTH increased FGF23 mRNA expression through cyclic adenosine monophosphate/protein kinase A, but not inositol triphosphate/protein kinase C signaling; PTH also increased furin protein levels. In conclusion, PTH injection rapidly increases FGF23 production in bone in vivo and in vitro. However, iFGF23 is rapidly degraded. At later time points through an unidentified mechanism, a sustained decrease in FGF23 production occurs.
Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.|Department of Biomedical Sciences, University of Veterinary Medicine, A-1210 Vienna, Austria.
Vanessa M
VM
Knab
Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Braden
B
Corbin
Department of Biomedical Sciences, University of Veterinary Medicine, A-1210 Vienna, Austria.
Olena
O
Andrukhova
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Julia M
JM
Hum
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Pu
P
Ni
Department of Medicine, New York Medical College, Valhalla, New York 10595.
Seham
S
Rabadi
Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Akira
A
Maeda
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
Kenneth E
KE
White
Department of Biomedical Sciences, University of Veterinary Medicine, A-1210 Vienna, Austria.
Reinhold G
RG
Erben
Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.
Harald
H
Jüppner
Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts 02114.|Department of Medicine, New York Medical College, Valhalla, New York 10595.
Marta
M
Christov
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D007267:Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000494:pharmacology; D010446:Peptide Fragments / Q000097:blood; D000072417:Protein Domains
C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23