Fibroblast Growth Factor (FGF) 23 Regulates the Plasma Levels of Parathyroid Hormone In Vivo Through the FGF Receptor in Normocalcemia, But Not in Hypocalcemia

Abstract

The calcium and phosphate homeostasis is regulated by a complex interplay between parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and calcitriol. Experimental studies have demonstrated an inhibitory effect of FG23 on PTH production and secretion; the physiological role of this regulation is however not well understood. Surprisingly, in uremia, concomitantly elevated FGF23 and PTH levels are observed. The parathyroid gland rapidly loses its responsiveness to extracellular calcium in vitro and a functional parathyroid cell line has currently not been established. Therefore, the aim of the present investigation was to study the impact of FGF23 on the Ca²⁺/PTH relationship in vivo under conditions of normocalcemia and hypocalcemia. Wistar rats were allocated to treatment with intravenous recombinant FGF23 and inhibition of the FGF receptor in the setting of normocalcemia and acute hypocalcemia. We demonstrated that FGF23 rapidly inhibited PTH secretion and that this effect was completely blocked by inhibition of the FGF receptor. Furthermore, inhibition of the FGF receptor by itself significantly increased PTH levels, indicating that FGF23 has a suppressive tonus on the parathyroid gland's PTH secretion. In acute hypocalcemia, there was no effect of either recombinant FGF23 or FGF receptor inhibition on the physiological response to the low ionized calcium levels. In conclusion, FGF23 has an inhibitory tonus on PTH secretion in normocalcemia and signals through the FGF receptor. In acute hypocalcemia, when increased PTH secretion is needed to restore the calcium homeostasis, this inhibitory effect of FGF23 is abolished.

Keywords: FGF23; FGFR; Hypocalcemia; PD173074; PTH.

Fig. 1

FGF23 regulates the plasma levels of PTH. a rFGF23 was administered intravenously to normal rats and resulted in a large increase in plasma intact FGF23. b The rFGF23 resulted in a significant decrease in plasma PTH levels after 10 min and the following PTH levels remained low. c Administration of the FGF receptor inhibitor (FGFRi), PD173074, resulted in a significant increase in PTH levels after 4 h. When rFGF23 was given after prior FGFRi, there was no effect of FGF23 on PTH levels. Data are expressed as mean ± SEM. *p < 0.05, **p < 0.01, n = 4 in (a and b), n = 5 in (c)

Fig. 2

FGF23’s suppressive effect on PTH secretion is abolished at low plasma Ca²⁺ levels. a Plasma Ca²⁺ was rapidly decreased by an EGTA infusion (p < 0.001). After 30 min, rFGF23 was administered intravenously. b The acute lowering of plasma Ca²⁺ resulted in a dramatic increase in PTH and a higher plateau of maximal secretion (p < 0.05). In hypocalcemia, the rFGF23 had no suppressive effect on the high PTH levels. Data are expressed as mean ± SEM, n = 6 in each group

Fig. 3

FGF receptor inhibition has no effect on PTH secretion in hypocalcemia. a FGFRi or vehicle was administered prior to induction of acute hypocalcemia by a continuous EGTA infusion that rapidly decreased plasma Ca²⁺ (p < 0.001). b FGFRi resulted again in a significant increase in PTH levels (p < 0.01). The rapid increase in PTH levels in response to acute hypocalcemia was however similar between the two groups. Data are expressed as mean ± SEM. **p < 0.01 n = 6 in each group