Parathyroid hormone-related protein is a positive regulator of keratinocyte growth factor expression by normal dermal fibroblasts

Abstract

Parathyroid hormone-related protein (PTHrP), an important factor in the pathogenesis of humoral hypercalcemia of malignancy, is produced by many normal tissues, including the skin, where it regulates keratinocyte growth and differentiation and dermal fibroblast function. Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is a secretory product of stromal cells and functions as a mediator of epithelial cell growth and differentiation. Phenotypes of the skin in several transgenic mouse models, in which the KGF and PTHrP genes have been overexpressed or disrupted, suggest that these two factors interact in vivo to regulate homeostasis of the skin. In this study, we investigated the effects of KGF on PTHrP secretion and expression by normal human foreskin keratinocytes (NHFK) and the effects of PTHrP on KGF secretion and expression by normal human dermal fibroblasts (NHDF) in vitro. N-terminal PTHrP(1-36) increased KGF secretion, protein expression and mRNA expression by NHDF in a dose-dependent manner, however, KGF did not regulate PTHrP expression and secretion by NHFK. By flow cytometry, PTHrP also increased the percentage of NHDF producing KGF. Our results indicate that PTHrP produced by keratinocytes is a potential paracrine regulator of KGF expression by dermal fibroblasts in vivo. This paracrine regulation may explain, in part, the epidermal atrophy seen in the PTHrP null mice and epidermal hyperplasia seen in transgenic mice overexpressing PTHrP in their basal keratinocytes. Our results also suggest that PTHrP is an important mediator for the healing of skin wounds and growth of neoplasms of squamous origin.