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

Jung Hee Joo, Jeong Eun Huh, Jee Hyun Lee, Doo Ri Park, Yoonji Lee, Seul Gee Lee, Sun Choi, Hwa Jeong Lee, Seong Won Song, Yongmi Jeong, Ja Il Goo, Yongseok Choi, Hye Kyung Baek, Sun Shin Yi, Soo Jin Park, Ji Eun Lee, Sae Kwang Ku, Won Jae Lee, Kee In Lee, Soo Young LeeYun Soo Bae

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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.

Original languageEnglish
Article number22389
JournalScientific Reports
Volume6
DOIs
StatePublished - 15 Mar 2016

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grant (No. 2012R1A5A1048236, No. 2013R1A2A1A05005153, and No.2011-0028885), and by Redoxomics grant (No. 2012M3A9C5048708) funded by NRF/MEST, and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI14C0223 and HI15C2800). We thank Professors Jaesang Kim for reading the manuscript. The rights for Ewha-18278 were transferred to AptaBio Co. (Suwon, Korea), and the compound is now referred to as APX-115.

Fingerprint

Dive into the research topics of 'A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase'. Together they form a unique fingerprint.

Cite this