This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 21/11/2713    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McCarthy, T. L. Articles by Centrella, M. Search for Related Content PubMed PubMed Citation Articles by McCarthy, T. L. Articles by Centrella, M.

Prostaglandin E2 Increases Transforming Growth Factor-ß Type III Receptor Expression through CCAAT Enhancer-Binding Protein in Osteoblasts

Department of Surgery and Section of Plastic Surgery, Yale University School of Medicine, New Haven, Connecticut 06520

Address all correspondence and requests for reprints to Thomas L. McCarthy or Michael Centrella, 333 Cedar Street, MS 208041, New Haven, Connecticut 06520-8041. E-mail: thomas.mccarthy{at}yale.edu or michael.centrella{at}yale.edu.

Variations in individual TGF-ß receptors (TßRs) may modify TGF-ß activity and significantly alter its effects on connective tissue growth or repair. Differences in the amount of TßR type III (TßRIII) relative to signal transducing TßRI occur on bone cells during differentiation or in response to other growth regulators. Here we investigated prostaglandin (PG) E2, a potent effector during trauma, inflammation, or mechanical load, on TßR expression in primary osteoblast-enriched cultures. PGE2 rapidly increased TßRIII mRNA and protein expression and enhanced TßRIII gene promoter activity through a discrete region within 0.4 kb of the transcription start site. PGE2 alters osteoblast function through multiple signal-inducing pathways. In this regard, protein kinase A (PKA) activators, PGE1 and forskolin, also enhanced gene expression through the TßRIII gene promoter, whereas protein kinase C activators, PGF2 and phorbol myristate acetate, did not. The stimulatory effect of PGE2 on TßRIII promoter activity was suppressed by a dominant negative PKA-regulatory subunit, but not by dominant negative protein kinase C. PGE2 specifically increased nuclear factor CCAAT enhancer-binding protein (C/EBP) binding to a half-binding site upstream of the basal TßRIII promoter region, and promoter activity was sensitive to C/EBP overexpression and to dominant-negative C/EBP competition. In parallel with their effect on TßRIII expression, activators of PKA decreased TGF-ß-induced activity. In summary, high levels of PGE2 that occur with inflammation or trauma may, through PKA-activated C/EBP, preferentially increase TßRIII expression and in this way delay TGF-ß-dependent activation of osteoblasts during the early stabilization phase of bone repair.