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These small molecules are autocrine and paracrine lipid mediators with important roles in inflammation, cardiovascular function, and angiogenesis. Recent evidence has highlighted EETs as potent promoters of organ regeneration and malignant metastasis. We speculated that EETs might impact osteoclastogenesis and bone loss. Using both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    studies, we observed that EETs significantly attenuated bone loss and inhibited osteoclast formation and activity, which were associated with a decreased receptor activator of NF\u2010\u03baB ligand (RANKL): osteoprotegerin ratio and serum levels of TNF\u2010\u03b1 and IL\u20101\u03b2. At the molecular level, EETs abrogated RANKL\u2010induced activation of NF\u2010\u03baB, activator protein\u20101 (AP\u20101), and MAPKs, including ERK and JNK, but not p38, during osteoclast formation. EETs also prevented the production of reactive oxygen species (ROS) following RANKL stimulation. As a result, EETs suppressed osteoclast\u2010specific gene expression, including tartrate resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)\u20109, and receptor activator of NF\u2010\u03baB (RANK). In conclusion, our findings demonstrate that EETs inhibit osteoclastogenesis through modulation of multiple pathways both upstream and downstream of RANKL signaling. The administration or stabilized endogenous levels of EETs could represent a novel therapeutic strategy for osteoclast\u2010related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.\u2014Guan, H., Zhao. L., Cao, H., Chen, A., Xiao, J., Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy\u2010induced bone loss. 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