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