Human parathyroid cell proliferation in response to calcium, NPS R-467, calcitriol and phosphate

Background It remains uncertain how calcium, phosphate and calcitriol regul ate parathyroid cell growth. The present study was aimed at examining possi ble direct effects of these modulators and of the calcimimetic NPS R-467 on parathyroid cell growth in vitro. Materials and methods Cell proliferation was determined by [H-3]thymidine i ncorporation and cell cycle antigen Ki 67 expression in a parathyroid cell culture model derived from uraemic patients. The effect of NPS R-467 on par athyroid hormone (PTH) secretion and intracellular [Ca2+](i) response was a lso examined. Results Increasing the [Ca2+] in the medium from 0.5 to 1.7 mM increased DN A synthesis (P < 0.005) and the number of Ki 67-positive cells (P < 0.005). However, NPS R-467 (0.01-1 muM) inhibited (3)[H]thymidine incorporation by 35% in the presence of 0.5 mM [Ca2+](e). Exposure of cells to Ca2+ or NPS R-467 led to a rapid increase of intracellular Ca2+, although the pattern o f increase differed. Addition of calcitriol (10(-10)-10(-7) M) to the cultu re medium suppressed [H-3]thymidine incorporation dose-dependently. Finally , high levels of phosphate (3.5 mM) in the medium led to a significant (P < 0.05) increase in [H-3]thymidine incorporation. Conclusion The observed stimulatory effect of Ca2+ in the medium in vitro a ppears to be at variance with the inhibitory effect of calcimimetic NPS R-4 67 in vitro. In an attempt to solve these apparent discrepancies, and based on the notion of a reduced calcium-sensing receptor (CaR) expression in pa rathyroid tissues of uraemic patients, we hypothesize that Ca2+ may regulat e parathyroid cell proliferation via two different pathways, with predomina nt growth inhibition in cases of high CaR expression or activation, but pre vailing stimulation of proliferation in cases of low CaR expression.