A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase
- Authors
- Joo, Jung Hee; Huh, Jeong-Eun; Lee, Jee Hyun; Park, Doo Ri; Lee, Yoonji; Lee, Seul Gee; Choi, Sun; Lee, Hwa Jeong; Song, Seong-Won; Jeong, Yongmi; Goo, Ja-Il; Choi, Yongseok; Baek, Hye Kyung; Yi, Sun Shin; Park, Soo Jin; Lee, Ji Eun; Ku, Sae Kwang; Lee, Won Jae; Lee, Kee-In; Lee, Soo Young; Bae, Yun Soo
- Issue Date
- 15-3월-2016
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- SCIENTIFIC REPORTS, v.6
- Indexed
- SCIE
SCOPUS
- Journal Title
- SCIENTIFIC REPORTS
- Volume
- 6
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/89205
- DOI
- 10.1038/srep22389
- ISSN
- 2045-2322
- Abstract
- Osteoclast cells (OCs) are differentiated from bone marrow-derived macrophages (BMMs) by activation of receptor activator of nuclear factor kappa B (NF-kappa B) 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-kappa B, 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.
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Collections - Graduate School > Department of Biotechnology > 1. Journal Articles
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