5-Lipoxygenase inhibitors suppress RANKL-induced osteoclast formation via NFATc1 expression. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Kang, Ju-Hee; Ting, Zheng; Moon, Mi-ran; Sim, Jung-Seon; Lee, Jung-Min; Doh, Kyung-Eun; Hong, Sunhye; Cui, Minghua; Choi, Sun; Chang, Hyeun Wook; Park Choo, Hea-Young; Yim, Mijung
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 21(2015)
• Page Start: 7069
• Page End: 7078
• Publication Date: 2015-11-01
• Subjects: 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 -- MNCs multinucleated cells -- DC-STAMP dendritic cell-specific transmembrane protein -- Atp6vod2 D2 isoform of vacuolar (H+) ATPase (v-ATPase) Vo domain -- CTR calcitonin receptor; 5-Lipoxygenase -- Benzoxazole scaffold -- RANKL-induced osteoclast formation -- NFATc1 -- Lipopolysaccharide (LPS)-induced osteoclast formation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.09.025
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 ofK7 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.