title: Lipoxin A4 suppresses osteoclastogenesis in RAW264.7 cells and prevents ovariectomy-induced bone loss.
abstract: Lipoxin A4 (LXA4; 5S, 6R, 15Strihydroxy- 7,9,13-trans-11-eicosatetraenoic acid) is a metabolic product of arachidonic acid under the action of lipoxidase. This lipid molecule plays important roles in several biological functions, especially inflammatory processes. In vivo, LXA4 regulates the inflammatory response through several signaling pathways. Its mechanism suggests that it might have an effect on osteoclastogenesis and bone loss. Using both in vitro and in vivo studies, it was here observed that LXA4 could significantly inhibit the formation and function of osteoclasts and these effects could be blocked by Boc-2, the specific inhibitor of FPR2/ALX (the receptor of LXA4). Meanwhile, LXA4 reduce the amount of ovariectomy-induced bone loss. These protective effects was found to be associated with inhibition of nuclear factor-κB (NF-κB), activator protein-1 (AP-1), PI3K-AKT, and p-38, ERK, and JNK in MAPKs. The expression of the receptor activator of the NF-κB ligand RANKL:osteoprotegerin ratio and serum levels of TNF-α, IL-1β, and IL-6 were decreased by LXA4. Moreover, LXA4 prevented the production of reactive oxygen species (ROS), the expression of osteoclast-specific genes, including tartrate-resistant acid phosphatase (TRAP), cathepsin K (CK), matrix metalloproteinase (MMP)-9, RANK, and osteoclastic related transcription factors of c-Fos, NFATc1 could also be significantly inhibited by LXA4 in a dose-dependent manner. Studies have demonstrated that LXA4 can inhibit the formation and function of osteoclasts through modulation of several pathways both upstream and downstream of RANKL signaling and FPR2/ALX was involved in the procedures. This shows that LXA4 may be used as a new strategy for the treatment of osteoclast-related diseases.
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China.
authors.forename: Changyu
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China.
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China. Electronic address: lifengmd@hust.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095, Wuhan 430030, China. Electronic address: jun_xiao@hust.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000517:prevention & control; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005260:Female; D006801:Humans; D044045:Lipoxins / Q000494:pharmacology* / Q000627:therapeutic use; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D010052:Ovariectomy / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase / Q000235:genetics / Q000378:metabolism
chemical_list: D044045:Lipoxins; D016328:NF-kappa B; D053245:RANK Ligand; D017382:Reactive Oxygen Species; C040527:lipoxin A4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Lipoxin A4; NF-κB; Osteoclast; RANK