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

Mariko Urata, Shoichiro Kokabu, Takuma Matsubara, Goro Sugiyama, Chihiro Nakatomi, Hiroshi Takeuchi, Shizu Hirata-Tsuchiya, Kazuhiro Aoki, Yukihiko Tamura, Yasuko Moriyama, Yasunori Ayukawa, Miho Matsuda, Min Zhang, Kiyoshi Koyano, Chiaki Kitamura, Eijiro Jimi

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7356-7366
Number of pages11
JournalJournal of cellular physiology
Volume233
Issue number9
DOIs
Publication statusPublished - Sep 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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