5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression

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• 作者：Ju-Hee Kang^a ; Zheng Ting^a ; Mi-ran Moon^a ; Jung-Seon Sim^a ; Jung-Min Lee^a ; Kyung-Eun Doh^c ; Sunhye Hong^c ; Minghua Cui^c ; Sun Choi^c ; Hyeun Wook Chang^b ; Hea-Young Park Choo^c ; ^{hypark@ewha.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Mijung Yim^a ; ^{myim@soomyung.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：5-LO ; 5-lipoxygenase ; LTs ; leukotrienes ; BMMs ; bone marrow-derived macrophages ; BMMCs ; bone marrow-derived mast cells ; LPS ; lipopolysaccharide ; M-CSF ; macrophage-colony stimulating factor ; RANK ; a receptor of RANKL ; RANKL ; receptor activator of nuclear factor-κB ligand ; ERK ; extracellular signal-regulated kinases ; MAPKs ; mitogen-activated protein kinases ; NFATc1 ; nuclear factor of activated T cells c1 ; TRAP ; tartrate-resistant acid phosphatase ; TRAP+ ; tartrate-resistant acid phosphatase positive
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：23
• 期：21
• 页码：7069-7078
• 全文大小：1289 K

文摘

5-Lipoxygenase synthesizes leukotrienes from arachidonic acid. We developed three novel 5-LO inhibitors having a benzoxazole scaffold as a potential anti-osteoclastogenics. They significantly suppressed RANKL-induced osteoclast formation in mouse bone marrow-derived macrophages. Furthermore, one compound, K7, inhibited the bone resorptive activity of osteoclasts. The anti-osteoclastogenic effect of K7 was mainly attributable to reduction in the expression of NFATc1, an essential transcription factor for osteoclast differentiation. K7 inhibited osteoclast formation via ERK and p38 MAPK, as well as NF-κB signaling pathways. K7 reduced lipopolysaccharide (LPS)-induced osteoclast formation in vivo, corroborating the in vitro data. Thus, K7 exerted an inhibitory effect on osteoclast formation in vitro and in vivo, properties that make it a potential candidate for the treatment of bone diseases associated with excessive bone resorption.