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

作者：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^*

来源：Journal of Cellular Physiology, 2018, 233(9): 7356-7366.

DOI：10.1002/jcp.26571

• BMP
• NF-kappa B
• osteoblasts

Bone morphogenetic protein (BMP) potentiates bone formation through the Smad signaling pathway in vitro and in vivo. The transcription factor nuclear factor B (NF-B) suppresses BMP-induced osteoblast differentiation. Recently, we identified that the transactivation (TA) 2 domain of p65, a main subunit of NF-B, 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-B 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-kappa B activity.

• 出版日期2018-9