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Endocrinology Vol. 138, No. 11 4672-4682
Copyright © 1997 by The Endocrine Society

ARTICLES

Transforming Growth Factor-ß1 Regulation of Prostaglandin G/H Synthase-2 Expression in Osteoblastic MC3T3-E1 Cells1

C. Pilbeam, Y. Rao, O. Voznesensky, H. Kawaguchi, C. Alander, L. Raisz and H. Herschman

Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030; and the Departments of Biological Chemistry and Molecular and Medical Pharmacology, University of California School of Medicine (H.H.), Los Angeles, California 90024

Address all correspondence and requests for reprints to: Dr. Carol C. Pilbeam, Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030. E-mail: pilbeam{at}nso.uchc.edu

Transforming growth factor-ß (TGFß) plays an important role in bone development and remodeling. TGFß stimulates PGE2 production, enhances interleukin-1-stimulated PGE2 production, and can stimulate PG-mediated bone resorption. We found that TGFß induced prostaglandin G/H synthase (PGHS-2) messenger RNA (mRNA) and PGE2 production in neonatal mouse calvarial cultures and in primary cells derived from these calvariae. We used MC3T3-E1 cells, an immortalized osteoblastic cell line derived from mouse calvariae, to examine the mechanism of PGHS-2 induction. PGHS-2 mRNA was rapidly induced by TGFß (10 ng/ml) in MC3T3-E1 cells; mRNA levels peaked at 4–8 h and were still elevated at 24 h. Induction of PGHS-2 protein and PGE2 production correlated with PGHS-2 mRNA levels. In contrast, TGFß had much less effect on PGHS-1 mRNA levels. Unlike the response to other agonists, PGHS-2 mRNA induction by TGFß was not enhanced by cycloheximide pretreatment, suggesting a requirement for new protein synthesis. To study transcriptional regulation, cells were stably transfected with a PGHS-2 promoter-luciferase reporter construct containing 371 bp of the 5'-flanking region and 70 bp of untranslated DNA from the PGHS-2 gene. TGFß-stimulated luciferase activity paralleled PGHS-2 mRNA induction. Stimulation of luciferase activity and PGHS-2 mRNA levels by other agonists, including interleukin-1, TGF{alpha}, forskolin, and phorbol 13-myristate 12-acetate, were enhanced by TGFß. A 90% drop in luciferase activity occurred with deletion of the region from -371 to -213 bp of the PGHS-2 promoter. The PG response to TGFß in MC3T3-E1 cells appears to be mediated primarily by transcriptional regulation of PGHS-2 expression through one or more cis-acting elements located between -371 and -213 bp in the 5'-flanking region of the PGHS-2 gene.




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