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 Lee & 1 others Yun Soo Bae

Research output: Contribution to journalArticle

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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
Publication statusPublished - 2016 Mar 15

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NADPH Oxidase
Ovariectomy
Osteoporosis
Osteoclasts
Isoenzymes
Cell Differentiation
Macrophages
Therapeutics
Macrophage Activation
Cytoplasmic and Nuclear Receptors
Mitogen-Activated Protein Kinases
Bone Density
Oral Administration
Interleukin-6
Reactive Oxygen Species
Estrogens
pyrazole
Ligands
Bone and Bones
Cancellous Bone

ASJC Scopus subject areas

  • General

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

In: Scientific Reports, Vol. 6, 22389, 15.03.2016.

Research output: Contribution to journalArticle

Joo, JH, Huh, JE, Lee, JH, Park, DR, Lee, Y, Lee, SG, Choi, S, Lee, HJ, Song, SW, Jeong, Y, Goo, JI, Choi, Y, Baek, HK, Yi, SS, Park, SJ, Lee, JE, Ku, SK, Lee, WJ, Lee, KI, Lee, SY & Bae, YS 2016, 'A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase', Scientific Reports, vol. 6, 22389. https://doi.org/10.1038/srep22389
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. / A novel pyrazole derivative protects from ovariectomy-induced osteoporosis through the inhibition of NADPH oxidase. In: Scientific Reports. 2016 ; Vol. 6.
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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.",
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AU - Lee, Seul Gee

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AU - Goo, Ja Il

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AU - Baek, Hye Kyung

AU - Yi, Sun Shin

AU - Park, Soo Jin

AU - Lee, Ji Eun

AU - Ku, Sae Kwang

AU - Lee, Won Jae

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AU - Lee, Soo Young

AU - Bae, Yun Soo

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N2 - 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.

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