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

TitleDiscovery of a Small Molecule Promoting Mouse and Human Osteoblast Differentiation via Activation of p38 MAPK-β.
Publication TypeJournal Article
Year of Publication2019
AuthorsCook, B, Rafiq, R, Lee, H, Banks, KM, El-Debs, M, Chiaravalli, J, J Glickman, F, Das, BC, Chen, S, Evans, T
JournalCell Chem Biol
Date Published2019 Mar 29
ISSN2451-9448
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.

DOI10.1016/j.chembiol.2019.03.009
Alternate JournalCell Chem Biol
PubMed ID31031140