EFFECT OF TRANSFORMING GROWTH-FACTOR-BETA-1 ON PARATHYROID HORMONE-RELATED PROTEIN SECRETION AND MESSENGER-RNA EXPRESSION BY NORMAL HUMAN KERATINOCYTES IN-VITRO

Parathyroid hormone-related protein (PTHrP) is produced by a wide rang e of neoplastic and normal cells, including keratinocytes where it may regulate growth and differentiation. Transforming growth factor-beta (TGF-beta) is a growth factor produced by many cells, including kerati nocytes where it regulates epidermal homeostasis, TGF-beta has been re ported to be cosecreted with PTHrP in some neoplasms and to stimulate PTHrP production by neoplastic keratinocytes, However, the effects of TGF-beta on PTHrP production by normal keratinocytes are not well char acterized. In this study, we investigated the effects of endogenous an d exogenous TGF-beta on PTHrP production by normal human foreskin kera tinocytes. PTHrP secretion, mRNA expression, and mRNA transcription in vitro were determined by N-terminal radioimmunoassay, ribonuclease pr otection assay, and transient transfections. PTHrP production and secr etion of latent TGF-beta activity were greatest in proliferating kerat inocytes prior to and at confluence of monolayer cultures, TGF-beta 1 increased PTHrP mRNA expression by normal keratinocytes in a dose-depe ndent manner with maximal stimulation at 6-12 h after treatment, in ad dition, keratinocytes treated with a monoclonal anti-TGF-beta antibody expressed decreased levels of PTHrP mRNA, The increased levels of PTH rP mRNA following TGF-beta 1 treatment were owing, at least partly, to an increase in PTHrP mRNA stability, TGF-beta 1 failed to activate tr anscription of the luciferase reporter gene driven by either the human or mouse PTHrP promoters. In conclusion, TGF-beta 1 functions as a pa racrine or autocrine regulator of PTHrP production in normal human ker atinocytes, and this may play a role in the regulation of keratinocyte proliferation or differentiation.