Parathyroid hormone-related protein is expressed by transformed and fetal human astrocytes and inhibits cell proliferation

Parathyroid hormone-related protein (PTHrP) and the PTH/PTHrP receptor are expressed in most normal tissues, including brain, where PTHrP is though to act locally in an autocrine or paracrine fashion. Previous in situ localiz ation studies in adult rodents have documented CNS PTHrP expression in neur ons but not in glial cells. However, a recent report describing immunoreact ive PTHrP in human astrocytomas suggests that PTHrP expression may be a mar ker of dedifferentiation and/or malignant transformation in glial cells. To begin to test this hypothesis, constitutive and regulated PTHrP expression were examined in cultured fetal and transformed (U-373 MG) human astrocyte s. PTHrP was expressed in untreated fetal astrocytes and U-373 MG cells, as determined by Northern analysis, immunocytochemical staining, and detectio n of PTHrP(1-84) protein in conditioned media. Epidermal growth factor and turner necrosis factor, important growth factors in astrocyte development a nd malignant transformation, stimulated PTHrP expression in both cell types . Treatment of U-373 MG cells or fetal astrocytes with PTHrP(1-34) consiste ntly inhibited cellular proliferation, as measured by [H-3]-thymidine incor poration. These findings suggest that PTHrP, a peptide whose expression is induced by mitogens in both immature and transformed human astrocytes, may feedback inhibit cellular proliferation, an effect that may be of importanc e during malignant transformation as well as CNS development. Furthermore, when combined with previous evidence of PTHrP expression by PTH/PTHrP recep tor-positive neurons, our demonstration of regulated PTHrP expression by re ceptor-positive astrocytes identifies PTHrP as a potential peptide mediator of cross-talk between glial cells and neurons. (C) 2000 Elsevier Science B .V. All rights reserved.