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

Parathyroid hormone-related protein (PTHrP), an important factor in the pat hogenesis of humoral hypercalcemia of malignancy, is produced by many norma l tissues, including the skin, where it regulates keratinocyte growth and d ifferentiation 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 gr owth and differentiation. Phenotypes of the skin in several transgenic mous e models, in which the KGF and PTHrP genes have been overexpressed or disru pted, suggest that these two factors interact in vivo to regulate homeostas is 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 secretio n, protein expression and mRNA expression by NHDF in a dose-dependent manne r, 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 p aracrine regulator of KGF expression by dermal fibroblasts in vivo. This pa racrine regulation may explain, in part, the epidermal atrophy seen in the PTHrP null mice and epidermal hyperplasia seen in transgenic mice overexpre ssing PTHrP in their basal keratinocytes. Our results also suggest that PTH rP is an important mediator for the healing of skin wounds and growth of ne oplasms of squamous origin. (C) 1999 Elsevier Science Ireland Ltd. All righ ts reserved.