Reference - Detail
| RRC ID | 38899 |
|---|---|
| Author | Mishima K, Kitoh H, Ohkawara B, Okuno T, Ito M, Masuda A, Ishiguro N, Ohno K. |
| Title | Lansoprazole Upregulates Polyubiquitination of the TNF Receptor-Associated Factor 6 and Facilitates Runx2-mediated Osteoblastogenesis. |
| Journal | EBioMedicine |
| 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. |
| Volume | 2(12) |
| Pages | 2046-61 |
| Published | 2015-12-1 |
| DOI | 10.1016/j.ebiom.2015.11.024 |
| PII | S2352-3964(15)30209-7 |
| PMID | 26844285 |
| PMC | PMC4703748 |
| MeSH | Animals Bone Morphogenetic Proteins / metabolism Cell Differentiation Cell Line Core Binding Factor Alpha 1 Subunit / genetics* Core Binding Factor Alpha 1 Subunit / metabolism Fracture Healing Fractures, Bone Humans Lansoprazole / chemistry Lansoprazole / pharmacology* MAP Kinase Kinase Kinases / metabolism Male Mice Models, Molecular Molecular Conformation Osteoblasts / cytology Osteoblasts / drug effects* Osteoblasts / metabolism* Osteogenesis / drug effects* Osteogenesis / genetics* Protein Transport Proton Pump Inhibitors / pharmacology Rats Signal Transduction / drug effects TNF Receptor-Associated Factor 6 / metabolism* Ubiquitination / drug effects Ubiquitins / chemistry Ubiquitins / metabolism p38 Mitogen-Activated Protein Kinases / metabolism |
| IF | 5.736 |
| Times Cited | 7 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | UCB408E6E7TERT-33(RCB2080) |