PUBLICATION

Acceleration of osteoblast differentiation by a novel osteogenic compound, DMP-PYT, through activation of both the BMP and Wnt pathways

Authors
Bae, S.J., Kim, H.J., Won, H.Y., Min, Y.K., Hwang, E.S.
ID
ZDB-PUB-170818-14
Date
2017
Source
Scientific Reports   7: 8455 (Journal)
Registered Authors
Keywords
Bone development, Cell signalling
MeSH Terms
  • Cell Line
  • Osteoblasts/cytology
  • Osteoblasts/metabolism*
  • Small Molecule Libraries/chemistry
  • Small Molecule Libraries/pharmacology*
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/metabolism*
  • Mice
  • Molecular Structure
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Gene Expression/drug effects
  • Animals
  • Cell Nucleus/drug effects
  • Cell Nucleus/metabolism
  • Luminescent Proteins/metabolism
  • Cell Differentiation/drug effects*
  • Cell Differentiation/genetics
  • Animals, Genetically Modified
  • beta Catenin/genetics
  • beta Catenin/metabolism
  • Microscopy, Fluorescence
  • Osteogenesis/drug effects*
  • Osteogenesis/genetics
  • Wnt Proteins/genetics
  • Wnt Proteins/metabolism*
  • Larva/genetics
  • Larva/metabolism
  • Pyrimidines/pharmacology*
  • Signal Transduction/drug effects
  • Signal Transduction/genetics
(all 31)
PubMed
28814721 Full text @ Sci. Rep.
Abstract
Osteoblast differentiation is regulated through the successive activation of signaling molecules by a complex interplay of extracellular signals such as bone morphogenetic protein (BMP) and Wnt ligands. Numerous studies have identified natural as well as synthetic compounds with osteogenic activity through the regulation of either BMP/SMADs or the Wnt/β-catenin pathway. Here, we attempted to isolate small molecules that concurrently activated both SMADs and β-catenin, which led to the discovery of a novel potent osteogenic compound, DMP-PYT. Upon BMP2 stimulation, DMP-PYT substantially increased osteoblast differentiation featured by enhanced expression of osteoblast-specific genes and accelerated calcification through activation of BMPs expression. DMP-PYT promoted BMP2-induced SMAD1/5/8 phosphorylation and β-catenin expression, the latter in a BMP2-independent manner. DMP-PYT alone enhanced nuclear localization of β-catenin to promote the DNA-binding and transcriptional activity of T-cell factor, thereby resulting in increased osteoblast differentiation in the absence of BMP2. Most importantly, DMP-PYT advanced skeletal development and bone calcification in zebrafish larvae. Conclusively, DMP-PYT strongly stimulated osteoblast differentiation and bone formation in vitro and in vivo by potentiating BMP2-induced activation of SMADs and β-catenin. These results suggest that DMP-PYT may have beneficial effects for preventing and for treating osteoporosis.
Genes / Markers
Figures
Figure Gallery (1 images)
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Expression
No data available
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gz15TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    osteoporosisTAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    No data available
    Fish
    1 - 2 of 2
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    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-smadpolyclonalIgGRabbit
    Ab3-ctnnb1monoclonalIgG1Mouse
    1 - 2 of 2
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    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    DsRedEFGDsRed
    EGFPEFGEGFP
    1 - 2 of 2
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    Mapping
    No data available