Prostaglandin E2 increases transforming growth factor-β type III receptor expression through CCAAT enhancer-binding protein δ in osteoblasts

Variations in individual TGF-beta receptors ( T beta Rs) may modify TGF-beta activity and significantly alter its effects on connective tissue growth or repair. Differences in the amount of T beta R type III ( T beta RIII) relative to signal transducing T beta RI 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 T beta R expression in primary osteoblast-enriched cultures. PGE2 rapidly increased T beta RIII mRNA and protein expression and enhanced T beta RIII 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 T beta RIII gene promoter, whereas protein kinase C activators, PGF2 alpha and phorbol myristate acetate, did not. The stimulatory effect of PGE2 on T beta RIII 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 delta(C/EBP delta) binding to a half-binding site upstream of the basal T beta RIII promoter region, and promoter activity was sensitive to C/EBP delta overexpression and to dominant-negative C/EBP delta competition. In parallel with their effect on T beta RIII expression, activators of PKA decreased TGF-beta-induced activity. In summary, high levels of PGE2 that occur with inflammation or trauma may, through PKA-activated C/EBP delta, preferentially increase T beta RIII expression and in this way delay TGF-beta-dependent activation of osteoblasts during the early stabilization phase of bone repair.