Peptide drugs accelerate BMP‐2‐induced calvarial bone regeneration and stimulate osteoblast differentiation through mTORC1 signaling |
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| Authors: | Yasutaka Sugamori Setsuko Mise‐Omata Chizuko Maeda Yasuhiko Tabata Ramachandran Murali Hisataka Yasuda Nobuyuki Udagawa Hiroshi Suzuki Masashi Honma Kazuhiro Aoki |
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| Institution: | 1. Department of Bio‐Matrix (Pharmacology), Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan;2. Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;3. Research Division of Immunology, Department of Biomedical Sciences, Cedars‐Sinai Medical Center, Los Angeles, CA, USA;4. Nagahama Institute for Biochemical Science, Oriental Yeast Co. Ltd., Shiga, Japan;5. Department of Biochemistry, Matsumoto Dental University, Nagano, Japan;6. Faculty of Medicine, Department of Pharmacy, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan;7. Faculty of Medicine, Department of Pharmacology and Pharmacokinetics, The University of Tokyo Hospital, The University of Tokyo, Tokyo, Japan |
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| 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. |
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| Keywords: | BMP‐2 bone regeneration histomorphometry mTORC1 osteoblast differentiation peptide therapeutics rapamycin |
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