Regulation of secretion of PTHrP by Ca2+-sensing receptor in human astrocytes, astrocytomas, and meningiomas

Parathyroid hormone-related protein (PTHrP) is the major mediator of the hu moral hypercalcemia of malignancy and of malignant osteolysis associated wi th skeletal metastases of common epithelial cancers. PTHrP secretion is reg ulated by the extracellular calcium concentration ([Ca2+](o)) in several ty pes of normal and malignant cells. Because the [Ca2+](o)-sensing receptor ( CaR) is a key mediator of [Ca2+](o)-regulated hormone secretion [e.g., of p arathyroid hormone (PTH) by parathyroid chief cells], we investigated the e xpression of the CaR and PTHrP in normal and neoplastic glial cells and stu died the effects of [Ca2+](o) on PTHrP secretion. Our results show that pri mary embryonic human astrocytes (HPA) express CaR mRNA and protein as detec ted by RT-PCR and Western analysis, respectively. Furthermore, astrocytomas and meningiomas also express the CaR at similar levels as assessed by RT-P CR and Northern and Western blot analyses. HPA and astrocytomas express tra nscripts encoding all three known isoforms of PTHrP [PTHrP(139), PTHrP(141) , and PTHrP(173), comprising 139, 141, and 173 predicted amino acid residue s, respectively] as assessed by RT-PCR, whereas meningiomas express only th e first two of these. Finally, elevated levels of [Ca2+](o) and other polyc ationic CaR agonists dose dependently stimulate PTHrP secretion from HPA, a strocytomas, and meningiomas, although both basal and high [Ca2+](o)-stimul ated rates of PTHrP secretion are similar to 2.5-fold higher in HPA than in the glial tumors studied here. Therefore, our results show that HPA, astro cytomas, and meningiomas express both the CaR and PTHrP and that CaR agonis ts stimulate PTHrP secretion.