PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop.
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) target the kidney to cause a phosphaturia. FGF23 also acts on the parathyroid to decrease PTH expression, but in chronic kidney disease (CKD) there are high-serum PTH and FGF23 levels and resistance of the parathyroid to FGF23. We now report that PTH acts on bone to increase FGF23 expression and characterize the signal transduction pathway whereby PTH increases FGF23 expression. Remarkably, we show that PTH is necessary for the high-FGF23 levels of early kidney failure due to an adenine high-phosphorus diet. Parathyroidectomy before the diet totally prevented the fivefold increase in FGF23 levels in kidney failure rats. Moreover, parathyroidectomy of early kidney failure rats corrected their high-FGF23 levels. Therefore, in early kidney failure, the high-FGF23 levels are dependent on the high-PTH levels. PTH infusion for 3 days to mice with normal renal function increased serum FGF23 and calvaria FGF23 mRNA levels. To demonstrate a direct effect of PTH on FGF23, we added PTH to rat osteoblast-like UMR106 cells. PTH increased FGF23 mRNA levels (4-fold) and this effect was mimicked by a PKA activator, forskolin. PTH also decreased SOST mRNA levels (3-fold). SOST codes for sclerostin, a Wnt pathway inhibitor, which is a PTH receptor (PTH1R) target. The effect of PTH was prevented by added sclerostin. Therefore, PTH increases FGF23 expression which involves the PKA and Wnt pathways. The effect of PTH on FGF23 completes a bone-parathyroid endocrine feedback loop. Importantly, secondary hyperparathyroidism is essential for the high-FGF23 levels in early CKD.
Lavi-Moshayoff
Vardit
V
Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew Univ. Medical Center, PO Box 12000, Jerusalem, Israel 91120.
Wasserman
Gilad
G
Meir
Tomer
T
Silver
Justin
J
Naveh-Many
Tally
T
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005246:Feedback; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006962:Hyperparathyroidism, Secondary / Q000150:complications / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D016105:Parathyroidectomy; D051381:Rats; D011919:Rats, Inbred Strains; D051437:Renal Insufficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism
C000717428:Fgf23 protein, mouse; C505605:Fgf23 protein, rat; D010281:Parathyroid Hormone; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D017868:Cyclic AMP-Dependent Protein Kinases