title: Epoxyeicosanoids suppress osteoclastogenesis and prevent ovariectomy-induced bone loss.
abstract: Epoxyeicosatrienoic acids (EETs) are products of arachidonic acid metabolism catalyzed by cytochrome P450 epoxygenases. 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 in vitro and in vivo 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-κB ligand (RANKL):osteoprotegerin ratio and serum levels of TNF-α and IL-1β. At the molecular level, EETs abrogated RANKL-induced activation of NF-κB, activator protein-1 (AP-1), 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-specific gene expression, including tartrate resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, and receptor activator of NF-κB (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-related disorders, such as rheumatoid arthritis and postmenopausal osteoporosis.
authors.affiliation: *Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Translational Medicine Research & Development Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Guan
authors.affiliation: *Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Translational Medicine Research & Development Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Zhao
authors.affiliation: *Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Translational Medicine Research & Development Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Cao
authors.affiliation: *Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Translational Medicine Research & Development Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
authors.forename: Anmin
authors.initials: A
authors.lastname: Chen
authors.affiliation: *Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; and Translational Medicine Research & Development Center, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China xiaojun301@sina.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010052:Ovariectomy / Q000009:adverse effects*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014665:Vasodilator Agents; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D015126:8,11,14-Eicosatrienoic Acid
keywords: NF-κB; RANK; osteoclast; osteoporosis