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

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

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

Authors: Joo J.H.; Huh J.-E.; Lee J.H.; Park D.R.; Lee Y.; Lee S.G.; Choi S.; Lee H.J.; Song S.-W.; Jeong Y.; Goo J.-I.; Choi Y.; Baek H.K.; Yi S.S.; Park S.J.; Lee J.E.; Ku S.K.; Lee W.J.; Lee K.-I.; Lee S.Y.; Bae Y.S.

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.