Send to

Choose Destination
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

Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
Bioresearch Institute, Yooyoung Pharmaceuticals Co. Ltd., Seoul 152-719, Republic of Korea.
College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Department of Biomedical Laboratory Science, College of Medical Sciences, Asan 31538, Soonchunhyang University.
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.
School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
Green Chemistry Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Taejon 305-600, Korea.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center