title: A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase.
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.
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jung Hee
authors.initials: JH
authors.lastname: Joo
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Huh
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: Park
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Seul Gee
authors.initials: SG
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.affiliation: College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Bioresearch Institute, Yooyoung Pharmaceuticals Co. Ltd., Seoul 152-719, Republic of Korea.
authors.forename: Seong-Won
authors.initials: SW
authors.lastname: Song
authors.affiliation: Bioresearch Institute, Yooyoung Pharmaceuticals Co. Ltd., Seoul 152-719, Republic of Korea.
authors.forename: Yongmi
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Ja-Il
authors.initials: JI
authors.lastname: Goo
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biomedical Laboratory Science, College of Medical Sciences, Asan 31538, Soonchunhyang University.
authors.forename: Hye Kyung
authors.initials: HK
authors.lastname: Baek
authors.affiliation: Department of Biomedical Laboratory Science, College of Medical Sciences, Asan 31538, Soonchunhyang University.
authors.forename: Sun Shin
authors.initials: SS
authors.lastname: Yi
authors.affiliation: 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.
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: School of Biological Science, Seoul National University and National Creative Research Initiative Center for Symbiosystem, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Lee
authors.affiliation: Green Chemistry Division, Korea Research Institute of Chemical Technology, P.O. Box 107, Yuseong, Taejon 305-600, Korea.
authors.forename: Kee-In
authors.initials: KI
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D015519:Bone Density / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015394:Molecular Structure; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010024:Osteoporosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D010052:Ovariectomy / Q000009:adverse effects*; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D020011:Protective Agents; D011720:Pyrazoles; D053245:RANK Ligand; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases