REGULATION OF MURINE FETAL-PLACENTAL CALCIUM-METABOLISM BY THE CALCIUM-SENSING RECEPTOR

The calcium-sensing receptor (CaSR) regulates PTH secretion to control the extracellular calcium concentration in adults, but its role in fe tal life is unknown. We used CaSR gene knockout mice to investigate th e role of the CaSR In regulating fetal calcium metabolism. The normal calcium concentration in fetal blood is raised above the maternal leve l, an increase that depends upon PTH-related peptide (PTHrP). Heterozy gous (+/-) and homozygous (-/-) disruption of the CaSR caused a furthe r increase in the fetal calcium level. This increase was modestly blun ted by concomitant disruption of the PTHrP gene and completely reverse d by disruption of the PTH/PTHrP receptor gene. Serum levels of PTH an d 1,25-dihydroxyvitamin D were substantially increased above the norma l low fetal levels by disruption of the CaSR. The free deoxypyridinoli ne level was increased in the amniotic fluid (urine) of CaSR-/- fetuse s; this result suggests that fetal bone resorption is increased. Place ntal calcium transfer was reduced, and renal calcium excretion was inc reased, by disruption of the CaSR. These studies indicate that the CaS R normally suppresses PTH secretion in the presence of the normal rais ed (and PTHrP-dependent) fetal calcium level. Disruption of the CaSR c auses fetal hyperparathyroidism and hypercalcemia, with additional eff ects on placental calcium transfer.