A peptide that blocks the interaction of NF‐κB p65 subunit with Smad4 enhances BMP2‐induced osteogenesis

Autor: Shizu Hirata-Tsuchiya, Eijiro Jimi, Miho Matsuda, Kiyoshi Koyano, Shoichiro Kokabu, Chiaki Kitamura, Yasunori Ayukawa, Min Zhang, Yukihiko Tamura, Yasuko Moriyama, Hiroshi Takeuchi, Goro Sugiyama, Takuma Matsubara, Kazuhiro Aoki, Chihiro Nakatomi, Mariko Urata
Rok vydání: 2018
Předmět:
0301 basic medicine
animal structures
Transcription
Genetic
Physiology
Clinical Biochemistry
Bone Morphogenetic Protein 2
Peptide
Cell-Penetrating Peptides
SMAD
Choristoma
Bone morphogenetic protein
Bone morphogenetic protein 2
Cell Line
Mice
03 medical and health sciences
Transactivation
0302 clinical medicine
Protein Domains
Osteogenesis
Transforming Growth Factor beta
Chlorocebus aethiops
Cortical Bone
medicine
Animals
Bone regeneration
Transcription factor
Smad4 Protein
chemistry.chemical_classification
Osteoblasts
Chemistry
Transcription Factor RelA
Cell Differentiation
Osteoblast
Cell Biology
Recombinant Proteins
biological factors
Cell biology
Protein Subunits
030104 developmental biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
COS Cells
embryonic structures
Peptides
Chondrogenesis
Protein Binding
Zdroj: Journal of Cellular Physiology. 233:7356-7366
ISSN: 1097-4652
0021-9541
DOI: 10.1002/jcp.26571
Popis: 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.
Databáze: OpenAIRE
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