PUBLICATION
Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β
- Authors
- Cook, B., Rafiq, R., Lee, H., Banks, K.M., El-Debs, M., Chiaravalli, J., Glickman, J.F., Das, B.C., Chen, S., Evans, T.
- ID
- ZDB-PUB-190430-3
- Date
- 2019
- Source
- Cell chemical biology 26(7): 926-935.e6 (Journal)
- Registered Authors
- Das, Bhaskar C., Evans, Todd, Rafiq, Ruhina
- Keywords
- differentiation, osteogenesis, signaling, zebrafish
- MeSH Terms
-
- Alkaline Phosphatase/metabolism
- Animals
- Cell Differentiation/drug effects
- Cell Differentiation/physiology*
- Cell Proliferation/drug effects
- Core Binding Factor Alpha 1 Subunit
- Humans
- MAP Kinase Signaling System/drug effects
- Mesenchymal Stem Cells/metabolism
- Mice
- Mitogen-Activated Protein Kinase 11/metabolism*
- Mitogen-Activated Protein Kinase 11/physiology
- Osteoblasts/metabolism*
- Osteoblasts/physiology
- Osteogenesis
- RAW 264.7 Cells
- Signal Transduction/drug effects
- Zebrafish
- p38 Mitogen-Activated Protein Kinases
- PubMed
- 31031140 Full text @ Cell Chem Biol
Citation
Cook, B., Rafiq, R., Lee, H., Banks, K.M., El-Debs, M., Chiaravalli, J., Glickman, J.F., Das, B.C., Chen, S., Evans, T. (2019) Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β. Cell chemical biology. 26(7):926-935.e6.
Abstract
Disorders of bone healing and remodeling are indications with an unmet need for effective pharmacological modulators. We used a high-throughput screen to identify activators of the bone marker alkaline phosphatase (ALP), and discovered 6,8-dimethyl-3-(4-phenyl-1H-imidazol-5-yl)quinolin-2(1H)-one (DIPQUO). DIPQUO markedly promotes osteoblast differentiation, including expression of Runx2, Osterix, and Osteocalcin. Treatment of human mesenchymal stem cells with DIPQUO results in osteogenic differentiation including a significant increase in calcium matrix deposition. DIPQUO stimulates ossification of emerging vertebral primordia in developing zebrafish larvae, and increases caudal fin osteogenic differentiation during adult zebrafish fin regeneration. The stimulatory effect of DIPQUO on osteoblast differentiation and maturation was shown to be dependent on the p38 MAPK pathway. Inhibition of p38 MAPK signaling or specific knockdown of the p38-β isoform attenuates DIPQUO induction of ALP, suggesting that DIPQUO mediates osteogenesis through activation of p38-β, and is a promising lead candidate for development of bone therapeutics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping