2. Academic Validation
  3. Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β

Discovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β

  • Cell Chem Biol. 2019 Jul 18;26(7):926-935.e6. doi: 10.1016/j.chembiol.2019.03.009.
Brandoch Cook 1,  Ruhina Rafiq 2,  Heejin Lee 2,  Kelly M Banks 2,  Mohammed El-Debs 3,  Jeanne Chiaravalli 4,  J Fraser Glickman 4,  Bhaskar C Das 5,  Shuibing Chen 6,  Todd Evans 7
Affiliations

Affiliations

  • 1 Department of Surgery, 1300 York Avenue, New York, NY 10065, USA. Electronic address: [email protected].
  • 2 Department of Surgery, 1300 York Avenue, New York, NY 10065, USA; Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY 10065, USA.
  • 3 Weill Cornell Medicine-Qatar, Education City, Qatar.
  • 4 Rockefeller University High Throughput and Spectroscopy Resource Center, New York, NY 10065, USA.
  • 5 Departments of Medicine and Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 6 Department of Surgery, 1300 York Avenue, New York, NY 10065, USA. Electronic address: [email protected].
  • 7 Department of Surgery, 1300 York Avenue, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 31031140 DOI: 10.1016/j.chembiol.2019.03.009
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.

Keywords

differentiation; osteogenesis; signaling; zebrafish.

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