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 journalArticle

6 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 1 2018

Fingerprint

Osteogenesis
Bone Morphogenetic Proteins
Bone
Peptides
Osteoblasts
Chondrogenesis
Bone Regeneration
Genetic Promoter Regions
Transcriptional Activation
Phosphorylation
Transcription Factors
Amino Acids
Bone and Bones
Protein Domains
DNA
Chemical activation
Association reactions
Molecules

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis. / Urata, Mariko; Kokabu, Shoichiro; Matsubara, Takuma; Sugiyama, Goro; Nakatomi, Chihiro; Takeuchi, Hiroshi; Hirata-Tsuchiya, Shizu; Aoki, Kazuhiro; Tamura, Yukihiko; Moriyama, Yasuko; Ayukawa, Yasunori; Matsuda, Miho; Zhang, Min; Koyano, Kiyoshi; Kitamura, Chiaki; Jimi, Eijiro.

In: Journal of cellular physiology, Vol. 233, No. 9, 01.09.2018, p. 7356-7366.

Research output: Contribution to journalArticle

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 2018, 'A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis', Journal of cellular physiology, vol. 233, no. 9, pp. 7356-7366. https://doi.org/10.1002/jcp.26571
Urata, Mariko ; Kokabu, Shoichiro ; Matsubara, Takuma ; Sugiyama, Goro ; Nakatomi, Chihiro ; Takeuchi, Hiroshi ; Hirata-Tsuchiya, Shizu ; Aoki, Kazuhiro ; Tamura, Yukihiko ; Moriyama, Yasuko ; Ayukawa, Yasunori ; Matsuda, Miho ; Zhang, Min ; Koyano, Kiyoshi ; Kitamura, Chiaki ; Jimi, Eijiro. / A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis. In: Journal of cellular physiology. 2018 ; Vol. 233, No. 9. pp. 7356-7366.
@article{ad76ce3fb04f4b638f2567358e4a71ca,
title = "A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis",
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.",
author = "Mariko Urata and Shoichiro Kokabu and Takuma Matsubara and Goro Sugiyama and Chihiro Nakatomi and Hiroshi Takeuchi and Shizu Hirata-Tsuchiya and Kazuhiro Aoki and Yukihiko Tamura and Yasuko Moriyama and Yasunori Ayukawa and Miho Matsuda and Min Zhang and Kiyoshi Koyano and Chiaki Kitamura and Eijiro Jimi",
year = "2018",
month = "9",
day = "1",
doi = "10.1002/jcp.26571",
language = "English",
volume = "233",
pages = "7356--7366",
journal = "Journal of Cellular Physiology",
issn = "0021-9541",
publisher = "Wiley-Liss Inc.",
number = "9",

}

TY - JOUR

T1 - A peptide that blocks the interaction of NF-κB p65 subunit with Smad4 enhances BMP2-induced osteogenesis

AU - Urata, Mariko

AU - Kokabu, Shoichiro

AU - Matsubara, Takuma

AU - Sugiyama, Goro

AU - Nakatomi, Chihiro

AU - Takeuchi, Hiroshi

AU - Hirata-Tsuchiya, Shizu

AU - Aoki, Kazuhiro

AU - Tamura, Yukihiko

AU - Moriyama, Yasuko

AU - Ayukawa, Yasunori

AU - Matsuda, Miho

AU - Zhang, Min

AU - Koyano, Kiyoshi

AU - Kitamura, Chiaki

AU - Jimi, Eijiro

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85045837814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85045837814&partnerID=8YFLogxK

U2 - 10.1002/jcp.26571

DO - 10.1002/jcp.26571

M3 - Article

AN - SCOPUS:85045837814

VL - 233

SP - 7356

EP - 7366

JO - Journal of Cellular Physiology

JF - Journal of Cellular Physiology

SN - 0021-9541

IS - 9

ER -