RRC ID 61210
Author Urata M, Kokabu S, Matsubara T, Sugiyama G, Nakatomi C, Takeuchi H, Hirata-Tsuchiya S, Aoki K, Tamura Y, Moriyama Y, Ayukawa Y, Matsuda M, Zhang M, Koyano K, Kitamura C, Jimi E.
Title A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis.
Journal J Cell Physiol
Abstract Bone morphogenetic protein (BMP) potentiates bone formation through the Smad signaling pathway in vitro and in vivo. The transcription factor nuclear factor κB (NF-κB) suppresses BMP-induced osteoblast differentiation. Recently, we identified that the transactivation (TA) 2 domain of p65, a main subunit of NF-κB, interacts with the mad homology (MH) 1 domain of Smad4 to inhibit BMP signaling. Therefore, we further attempted to identify the interacting regions of these two molecules at the amino acid level. We identified a region that we term the Smad4-binding domain (SBD), an amino-terminal region of TA2 that associates with the MH1 domain of Smad4. Cell-permeable SBD peptide blocked the association of p65 with Smad4 and enhanced BMP2-induced osteoblast differentiation and mineralization without affecting the phosphorylation of Smad1/5 or the activation of NF-κB signaling. SBD peptide enhanced the binding of the BMP2-inudced phosphorylated Smad1/5 on the promoter region of inhibitor of DNA binding 1 (Id-1) compared with control peptide. Although SBD peptide did not affect BMP2-induced chondrogenesis during ectopic bone formation, the peptide enhanced BMP2-induced ectopic bone formation in subcortical bone. Thus, the SBD peptide is useful for enabling BMP2-induced bone regeneration without inhibiting NF-κB activity.
Volume 233(9)
Pages 7356-7366
Published 2018-9-1
DOI 10.1002/jcp.26571
PMID 29663368
MeSH Animals Bone Morphogenetic Protein 2 / pharmacology* COS Cells Cell Differentiation / drug effects Cell Line Cell-Penetrating Peptides Chlorocebus aethiops Chondrogenesis / drug effects Choristoma / pathology Cortical Bone / drug effects Cortical Bone / metabolism Mice Osteoblasts / cytology Osteoblasts / drug effects Osteoblasts / metabolism Osteogenesis / drug effects* Peptides / pharmacology* Protein Binding / drug effects Protein Domains Protein Subunits / metabolism* Recombinant Proteins / pharmacology Smad4 Protein / chemistry Smad4 Protein / metabolism* Transcription Factor RelA / chemistry Transcription Factor RelA / metabolism* Transcription, Genetic / drug effects Transforming Growth Factor beta / pharmacology*
IF 5.546
Human and Animal Cells MC3T3-E1(RCB1126)