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

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.

journal_name

Cell Chem Biol

journal_title

Cell chemical biology

authors

Cook B,Rafiq R,Lee H,Banks KM,El-Debs M,Chiaravalli J,Glickman JF,Das BC,Chen S,Evans T

doi

10.1016/j.chembiol.2019.03.009

subject

Has Abstract

pub_date

2019-07-18 00:00:00

pages

926-935.e6

issue

7

eissn

2451-9456

issn

2451-9448

pii

S2451-9456(19)30105-9

journal_volume

26

pub_type

杂志文章

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