Effect of transforming growth factor-beta1 on parathyroid hormone-related protein secretion and mRNA expression by normal human keratinocytes in vitro.
Parathyroid hormone-related protein (PTHrP) is produced by a wide range 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 keratinocytes where it regulates epidermal homeostasis. TGF-beta has been reported 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 characterized. In this study, we investigated the effects of endogenous and exogenous TGF-beta on PTHrP production by normal human foreskin keratinocytes. PTHrP secretion, mRNA expression, and mRNA transcription in vitro were determined by N-terminal radioimmunoassay, ribonuclease protection assay, and transient transfections. PTHrP production and secretion of latent TGF-beta activity were greatest in proliferating keratinocytes prior to and at confluence of monolayer cultures. TGF-beta1 increased PTHrP mRNA expression by normal keratinocytes in a dose-dependent manner with maximal stimulation at 6-1 2 h after treatment. In addition, keratinocytes treated with a monoclonal anti-TGF-beta antibody expressed decreased levels of PTHrP mRNA. The increased levels of PTHrP mRNA following TGF-beta1 treatment were owing, at least partly, to an increase in PTHrP mRNA stability. TGF-beta1 failed to activate transcription of the luciferase reporter gene driven by either the human or mouse PTHrP promoters. In conclusion, TGF-beta1 functions as a paracrine or autocrine regulator of PTHrP production in normal human keratinocytes, and this may play a role in the regulation of keratinocyte proliferation or differentiation.
Werkmeister
J R
JR
Department of Veterinary Biosciences, The Ohio State University, Columbus 43210, USA.
Blomme
E A
EA
Weckmann
M T
MT
Gröne
A
A
McCauley
L K
LK
Wade
A B
AB
O'Rourke
J
J
Capen
C C
CC
Rosol
T J
TJ
D000818:Animals; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D011863:Radioimmunoassay; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C054296:parathyroid hormone-related protein (1-34)