PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop

Abstract

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.

Effect of Cinacalcet and Vitamin D Analogs on Fibroblast Growth Factor-23 during the Treatment of Secondary Hyperparathyroidism

“…Both animal and human studies have shown that PTH administration increases FGF-23 (6-10), supporting the hypothesis that PTH is an important regulator of FGF-23. Reductions in PTH after parathyroidectomy have been associated with reductions in FGF-23 in animals with experimental renal failure and patients with ESRD (7,23,24). Therefore, it is plausible that reducing PTH concentrations with medical intervention in patients with SHPT might directly result in reductions in FGF-23 concentrations.…”

The Human Response to Acute Enteral and Parenteral Phosphate Loads

“…25 Similarly, through use of a murine adenine/high PO4 diet model of CKD, it was reported that prior parathyroidectomy abrogated the CKD and hyperphosphatemia-induced increase in plasma FGF-23 concentration. 30 PTH, via PTH receptor1 (PTHR1) activation, is reported to increase murine osteocyte FGF-23 expression in vitro and to increase murine plasma FGF-23 concentration via a PTHR1 ligand (e.g., PTH) or constitutive activation of PTHR1. 31 Similarly, in humans potent PTHR1-mediated increases in plasma FGF-23 concentration have been demonstrated in Jansen metaphyseal chondroplasia, a disorder characterized by constitutive activating mutations in PTHR1.…”

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

“…19,20 FGF23 reduces the 1,25-dihydroxyvitamin level by inhibiting the renal 1-a-hydroxylase expression and promoting the 24-hydroxylase expression, thereby downregulating the amount of phosphate absorption from the gut and resorption from the bone. 21,22 Mutual regulation of FGF23 and parathyroid hormone has been reported in rodent models 23,24 and identified in clinical cases of hypophosphatemic rickets and chronic kidney disease. 25 In addition to these systemic and hormonal patterns of regulation, the FGF23 expression appears to be regulated locally by FGF23-producing cells and osteocytes through molecules such as dentin matrix protein-1 (DMP1) 26,27 and the phosphate-regulating gene with homology to endopeptidases on X chromosome (PHEX), 28 both of which are highly expressed in osteocytes.…”