title: Peptide drugs accelerate BMP-2-induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling.
abstract: Both W9 and OP3-4 were known to bind the receptor activator of NF-κB ligand (RANKL), inhibiting osteoclastogenesis. Recently, both peptides were shown to stimulate osteoblast differentiation; however, the mechanism underlying the activity of these peptides remains to be clarified. A primary osteoblast culture showed that rapamycin, an mTORC1 inhibitor, which was recently demonstrated to be an important serine/threonine kinase for bone formation, inhibited the peptide-induced alkaline phosphatase activity. Furthermore, both peptides promoted the phosphorylation of Akt and S6K1, an upstream molecule of mTORC1 and the effector molecule of mTORC1, respectively. In the in vivo calvarial defect model, W9 and OP3-4 accelerated BMP-2-induced bone formation to a similar extent, which was confirmed by histomorphometric analyses using fluorescence images of undecalcified sections. Our data suggest that these RANKL-binding peptides could stimulate the mTORC1 activity, which might play a role in the acceleration of BMP-2-induced bone regeneration by the RANKL-binding peptides.
authors.affiliation: Department of Bio-Matrix (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Sugamori
authors.affiliation: Department of Bio-Matrix (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Setsuko
authors.initials: S
authors.lastname: Mise-Omata
authors.affiliation: Department of Bio-Matrix (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Chizuko
authors.initials: C
authors.lastname: Maeda
authors.affiliation: Faculty of Medicine, Department of Pharmacy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Aoki
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
authors.affiliation: Nagahama Institute for Biochemical Science, Oriental Yeast Co. Ltd., Shiga, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Department of Biochemistry, Matsumoto Dental University, Nagano, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.affiliation: Faculty of Medicine, Department of Pharmacy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Faculty of Medicine, Department of Pharmacy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan.|Faculty of Medicine, Department of Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Honma
authors.affiliation: Department of Bio-Matrix (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Aoki
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D001861:Bone Regeneration / Q000187:drug effects*; D002454:Cell Differentiation; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D046912:Multiprotein Complexes; D009842:Oligopeptides; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: BMP-2; bone regeneration; histomorphometry; mTORC1; osteoblast differentiation; peptide therapeutics; rapamycin