title: Lansoprazole Upregulates Polyubiquitination of the TNF Receptor-Associated Factor 6 and Facilitates Runx2-mediated Osteoblastogenesis.
abstract: The transcription factor, runt-related transcription factor 2 (Runx2), plays a pivotal role in the differentiation of the mesenchymal stem cells to the osteochondroblast lineages. We found by the drug repositioning strategy that a proton pump inhibitor, lansoprazole, enhances nuclear accumulation of Runx2 and induces osteoblastogenesis of human mesenchymal stromal cells. Systemic administration of lansoprazole to a rat femoral fracture model increased osteoblastogenesis. Dissection of signaling pathways revealed that lansoprazole activates a noncanonical bone morphogenic protein (BMP)-transforming growth factor-beta (TGF-β) activated kinase-1 (TAK1)-p38 mitogen-activated protein kinase (MAPK) pathway. We found by in cellulo ubiquitination studies that lansoprazole enhances polyubiquitination of the TNF receptor-associated factor 6 (TRAF6) and by in vitro ubiquitination studies that the enhanced polyubiquitination of TRAF6 is attributed to the blocking of a deubiquitination enzyme, cylindromatosis (CYLD). Structural modeling and site-directed mutagenesis of CYLD demonstrated that lansoprazole tightly fits in a pocket of CYLD where the C-terminal tail of ubiquitin lies. Lansoprazole is a potential therapeutic agent for enhancing osteoblastic differentiation.
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan; Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Kenichi
authors: K
authors: Mishima
authors: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Hiroshi
authors: H
authors: Kitoh
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Bisei
authors: B
authors: Ohkawara
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Tatsuya
authors: T
authors: Okuno
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Mikako
authors: M
authors: Ito
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Akio
authors: A
authors: Masuda
authors: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Naoki
authors: N
authors: Ishiguro
authors: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
authors: Kinji
authors: K
authors: Ohno
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D017102:Fracture Healing; D050723:Fractures, Bone; D006801:Humans; D064747:Lansoprazole / Q000737:chemistry / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics*; D021381:Protein Transport; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D014452:Ubiquitins / Q000737:chemistry / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D019485:Bone Morphogenetic Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D064747:Lansoprazole; D020930:MAP Kinase Kinase Kinases; D054328:Proton Pump Inhibitors; D048029:TNF Receptor-Associated Factor 6; D014452:Ubiquitins; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
keywords: CYLD; Drug repositioning; Lansoprazole; Osteoblastogenesis; Runx2; TRAF6