Abstract
Variations in individual TGF-β receptors (TβRs) may modify TGF-β activity and significantly alter its effects on connective tissue growth or repair. Differences in the amount of TβR type III (TβRIII) relative to signal transducing TβRI 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 TβR expression in primary osteoblast-enriched cultures. PGE2 rapidly increased TβRIII mRNA and protein expression and enhanced TβRIII 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 TβRIII gene promoter, whereas protein kinase C activators, PGF2α and phorbol myristate acetate, did not. The stimulatory effect of PGE2 on TβRIII 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 δ (C/EBPδ) binding to a half-binding site upstream of the basal TβRIII promoter region, and promoter activity was sensitive to C/EBPδ overexpression and to dominant-negative C/EBPδ competition. In parallel with their effect on TβRIII expression, activators of PKA decreased TGF-β-induced activity. In summary, high levels of PGE2 that occur with inflammation or trauma may, through PKA-activated C/EBPδ, preferentially increase TβRIII expression and in this way delay TGF-β-dependent activation of osteoblasts during the early stabilization phase of bone repair.
JUN-CCAAT/Enhancer-Binding Protein Complexes Inhibit Surfactant-Associated Protein B Promoter Activity