Computational modeling of tumor metastases in bone – investigation of the vicious cycle concept in osteolytic bone lesions

Abstract

The aim of this study was to examine the vasodilatory effects of parathyroid hormone-related protein (PTHrP) (1–34) and parathyroid hormone (PTH) (1–34) on the human fetal-placental circulation utilising an in vitro placental perfusion model. In all experiments, the vasculature of an isolated human placental cotyledon was pre-constricted with the throm☐ane A2 mimetic U46619. A single dose of PTHrP (1–34) or PTH (1–34) (1.7–300 n m) was then infused into the fetal-placental circulation of the cotyledon. In other experiments, cotyledons were repeatedly infused with PTHrP (1–34) or PTH (1–34) (51.3 n m). Vasodilatory responses were significantly reduced in response to repeated exposure to PTHrP (1–34) and PTH (1–34) (P<0.001), indicating that this peptide desensitizes the fetal-placental vasculature. PTHrP (1–34) and PTH (1–34) equipotently stimulated a significant vasodilatation of the fetal-placental circulation (P<0.0001). The PTHrP receptor antagonist [Asn10, Leu11]PTHrP (7–34) (102 nM) was infused in U46619-constricted placentae in the presence and absence of PTHrP (1–34) (10.2 nM). The PTHrP antagonist alone had no significant effect in the fetal-placental circulation. The antagonist significantly attenuated the response to PTHrP (1–34) (P<0.015). Based on the data obtained in this study it is suggested that locally produced PTHrP (1–34) may be involved in the regulation of normal human fetal-placental vascular tone in an autocrine and/or paracrine fashion.