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

Animals
Animals, Genetically Modified
Bone Morphogenetic Proteins/genetics
Bone Morphogenetic Proteins/metabolism*
Cell Differentiation/drug effects*
Cell Differentiation/genetics
Cell Line
Cell Nucleus/drug effects
Cell Nucleus/metabolism
Gene Expression/drug effects
Larva/genetics
Larva/metabolism
Luminescent Proteins/metabolism
Mice
Microscopy, Fluorescence
Molecular Structure
Osteoblasts/cytology
Osteoblasts/metabolism*
Osteogenesis/drug effects*
Osteogenesis/genetics
Pyrimidines/pharmacology*
Signal Transduction/drug effects
Signal Transduction/genetics
Small Molecule Libraries/chemistry
Small Molecule Libraries/pharmacology*
Wnt Proteins/genetics
Wnt Proteins/metabolism*
Zebrafish/genetics
Zebrafish/metabolism
beta Catenin/genetics
beta Catenin/metabolism

(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

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Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: osteogenesis regulator	Protruding-mouth	splanchnocranium ab1-smad labeling increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: osteogenesis regulator	Protruding-mouth	splanchnocranium Ab3-ctnnb1 labeling increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: osteogenesis regulator	Protruding-mouth	whole organism ab1-smad labeling increased amount, abnormal	Fig. 6
WT	chemical treatment by environment: osteogenesis regulator	Protruding-mouth	whole organism Ab3-ctnnb1 labeling increased amount, abnormal	Fig. 6
gz15Tg	chemical treatment by environment: osteogenesis regulator	Days 7-13	cleithrum bone mineralization increased occurrence, abnormal	Fig. 6
gz15Tg	chemical treatment by environment: osteogenesis regulator	Days 7-13	Meckel's cartilage bone mineralization increased occurrence, abnormal	Fig. 6
gz15Tg	chemical treatment by environment: osteogenesis regulator	Days 7-13	palatoquadrate arch bone mineralization increased occurrence, abnormal	Fig. 6
gz15Tg	chemical treatment by environment: osteogenesis regulator	Days 7-13	vertebra bone mineralization increased occurrence, abnormal	Fig. 6

1 - 8 of 8

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
osteoporosis			TAS

Sequence Targeting Reagents

Fish

Fish
gz15Tg
WT

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-smad	polyclonal	smad1 smad5 smad9	IgG	Rabbit
Ab3-ctnnb1	monoclonal	ctnnb1	IgG1	Mouse

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP

Mapping

Bae et al., 2017 ZDB-PUB-170818-14 PMID:28814721

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

Bae et al., 2017

ZDB-PUB-170818-14
PMID:28814721