Parathyroid hormone-related peptide and development of intrahepatic bile ducts in man

Abstract

Parathyroid hormone-related peptide (PTHrP) is the product of a growth factor-regulated gene that may play a role in cell growth and differentiation. Previous studies have shown a widespread, yet clearly localized, distribution in embryonic and fetal tissues. These findings are consistent with a paracrime or autocrine function of PTHrP which itself appears related to the transforming growth factor-β family of growth factors. Recently we found that reactive human bile ductules in chronic cholestatic conditions and in regenerating human liver express immunoreactive PTHrP, while normal adult human liver does not express this peptide. Because reactive bile ductules are thought to derive at least in part from ‘facultative stem cells’, the aim of this study was to investigate PTHrP immunoreactivity in human liver during fetal life and after birth. Therefore, we investigated the distribution of PTHrP in 12 human fetal liver specimens from 16 weeks of gestation until birth, 21 liver specimens from children from 1 day of age to 14 years of age and four normal adult liver biopsies. These specimens were partly needle biopsies, taken for diagnostic purposes, partly post mortem specimens. In fetal livers, we found that PTHrP was faintly expressed in the ductal plate, whereas bile ducts already incorporated in the mesenchyme of the portal tract showed stronger immunoreactivity. PTHrP immunoreactivity became more intense with gestational age, and bile ducts in neonatal livers showed strong immunoreactivity. In children from the age of 2–3 years old, PTHrP immunoreactivity progressively diminished and was no longer found after the age of 4 years. All adult biopsies were consistently negative for PTHrP. These results suggest that PTHrP plays a physiological role during normal human liver development and that this peptide may function as a growth and differentiation factor for growing and maturing bile ducts.