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Sci Rep. 2016 Mar 15;6:22389. doi: 10.1038/srep22389.

A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase.

Author information

1
Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
2
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
3
Bioresearch Institute, Yooyoung Pharmaceuticals Co. Ltd., Seoul 152-719, Republic of Korea.
4
College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
5
Department of Biomedical Laboratory Science, College of Medical Sciences, Asan 31538, Soonchunhyang University.
6
Department of Anatomy and Histology, College of Oriental Medicine, and The Medical Research center for Globalization of Herbal Formulation, Daegu Haany University, Gyeongsan 712-715, Republic of Korea.
7
School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
8
Green Chemistry Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Taejon 305-600, Korea.

Abstract

Osteoclast cells (OCs) are differentiated from bone marrow-derived macrophages (BMMs) by activation of receptor activator of nuclear factor κB (NF-κB) ligand (RANKL). Activation of NADPH oxidase (Nox) isozymes is involved in RANKL-dependent OC differentiation, implicating Nox isozymes as therapeutic targets for treatment of osteoporosis. Here, we show that a novel pyrazole derivative, Ewha-18278 has high inhibitory potency on Nox isozymes. Blocking the activity of Nox with Ewha-18278 inhibited the responses of BMMs to RANKL, including reactive oxygen species (ROS) generation, activation of mitogen-activated protein (MAP) kinases and NF-κB, and OC differentiation. To evaluate the anti-osteoporotic function of Ewha-18278, the derivative was applied to estrogen-deficient ovariectomized (OVX) ddY mice. Oral administration of Ewha-18278 (10 mg/kg/daily, 4 weeks) into the mice recovered bone mineral density, trabecular bone volume, trabecular bone length, number and thickness, compared to control OVX ddY mice. Moreover, treatment of OVX ddY mice with Ewha-18278 increased bone strength by increasing cortical bone thickness. We provide that Ewha-18278 displayed Nox inhibition and blocked the RANKL-dependent cell signaling cascade leading to reduced differentiation of OCs. Our results implicate Ewha-18278 as a novel therapeutic agent for the treatment of osteoporosis.

PMID:
26975635
PMCID:
PMC4792161
DOI:
10.1038/srep22389
[Indexed for MEDLINE]
Free PMC Article

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