Cell Chemical Biology
Volume 26, Issue 7, 18 July 2019, Pages 926-935.e6
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Article
Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β

https://doi.org/10.1016/j.chembiol.2019.03.009Get rights and content
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Highlights

  • Over 47,000 small molecules were screened for activation of ALP in C2C12 cells

  • DIPQUO was identified, also promoting osteogenesis in human MSCs and zebrafish

  • Functional activity is associated specifically with activation of p38-β

  • DIPQUO is a promising lead candidate for development of bone therapeutics

Summary

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.

Keywords

osteogenesis
differentiation
signaling
zebrafish

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