Abstract: FR-OR074

Fibroblast Growth Factor 23 (FGF23) Regulates PTH Levels through FGF Receptor Signaling In Vivo at Normal, but Not at Low, Plasma Calcium

Session Information

Category: Mineral Disease

  • 1202 Mineral Disease: Vitamin D, PTH, FGF-23

Authors

  • Mace, Maria Lerche, Herlev Hospital, Herlev, Denmark
  • Gravesen, Eva, Rigshospitalet, Copenhagen, Denmark
  • Nordholm, Anders, Herlev Hospital, Herlev, Denmark
  • Hofman-Bang, Jacob, Rigshospitalet, Copenhagen, Denmark
  • Olgaard, Klaus, Copenhagen University, Copenhagen, Denmark
  • Lewin, Ewa, Herlev Hospital, Herlev, Denmark
Background

The regulation of PTH secretion is primarily mediated by calcium. FGF23 is a bone derived phosphatonin that requires klotho as a co-receptor for binding to the FGF receptors (FGFR). Parathyroid cells express both Klotho and FGFRs, however, the physiological function of FGF23 in the parathyroid gland is not fully clarified. Parathyroid cells lose rapidly their calcium-sensing responsiveness ex vivo, and no functional parathyroid cell line has been established. Therefore the aim of the present investigation was to study FGF23’s regulation of PTH levels in vivo.

Methods

Wistar rats were randomized to FGFR inhibition by PD173074 (20-40mg) or vehicle. Acute hypocalcemia was induced by a continuous intravenuous EGTA infusion (40mM, 3ml/h) in normal rats and rats after prior FGFR inhibition. Increasing doses (0.1, 1, and 10 µg) of recombinant FGF23 were given to normal rats and rats after prior FGFR inhibition. Plasma Ca++, phosphate, FGF23 and PTH were measured.

Results

Acute inhibition of FGFR resulted in a decrease in p-FGF23 (364±22 to 154±18 pg/ml, p<0.05) and a concomitant increase in p-PTH levels (134±34 to 685±285 pg/ml, p<0.01). The PTH secretory response was challenged by acute severe hypocalcemia (p-Ca++ decreased from 1.37±0.01 to 0.98±0.03 mmol/l, p<0.01). Again at normocalcemia PTH increased in FGFR inhibited rats (85±13 to 182±10 pg/ml), while the maximal PTH secretion at low p-Ca++ was not different in FGFR inhibited rats compared to vehicle treated rats (347±61 vs. 316±22 pg/ml). Exogenous rFGF23 0.1 µg inhibited rapidly, at 20 min, PTH levels in normal rats (137±71 to 10±4 pg/ml, p<0.05). In FGFR inhibited rats 0.1 µg rFGF23 did not suppress PTH levels (270±50 vs. 347±62 pg/ml). Higher doses of rFGF23 resulted in very high levels of p-FGF23 (12,000 & 120,000 pg/ml), still these high levels had no effect on PTH levels when the FGFR was inhibited.

Conclusion

FGF23 regulates PTH tonus in vivo via the FGF receptor. The inhibitory effect of FGF23 on PTH is present at normal range of plasma Ca++, but not at low Ca++ levels, when increased PTH secretion is needed.

Funding

  • Government Support - Non-U.S.