title: Liver X receptor activation inhibits osteoclastogenesis by suppressing NF-κB activity and c-Fos induction and prevents inflammatory bone loss in mice.
abstract: LXRs are nuclear receptors that function as important regulators of lipid homeostasis and inflammatory responses. LXR activation has been shown to suppress RANKL-induced osteoclast differentiation, but its underlying mechanisms and its influence on inflammatory bone destruction remain unclear. In this study, we report that the LXR agonists T0901317 and GW3965 inhibit osteoclastogenesis from primary BMMs in a dose-dependent manner. LXR activation suppressed RANKL-induced transcriptional activity of NF-κB without affecting IκBα degradation and the phosphorylation of p38. LXR agonists significantly suppressed RANKL-induced expression of c-Fos and NFATc1, which are crucial transcription factors for osteoclastogenesis. The activation of LXRs also inhibited RANKL-mediated AP-1 transcriptional activity. Furthermore, LXR activation attenuated PPARγ ligand-induced c-Fos expression, and LXR suppressed AP-1 promoter activity by PPARγ. The inhibitory effect of LXR activation on osteoclastogenesis was reversed by overexpression of c-Fos, suggesting that c-Fos is a downstream target of the antiosteoclastogenic action of LXRs. In addition to osteoclast differentiation, LXR activation accelerated apoptosis in mature osteoclasts by the induction of caspase-3 and -9 activity and Bim expression. Consistent with the in vitro effects we observed, the administration of a LXR agonist protected from bone loss induced by LPS in vivo. Together, our data provide evidence that LXRs may have potential as therapeutic targets for bone resorption-associated diseases.
authors: Kyungpook National University Hospital, 44-2 Samduk 2-ga, Jung-gu, Daegu 700-412, South Korea. biohjk@hanmail.net
authors: Hyun-Ju
authors: HJ
authors: Kim
authors: Kyung-Ae
authors: KA
authors: Yoon
authors: Hye-Jin
authors: HJ
authors: Yoon
authors: Jung Min
authors: JM
authors: Hong
authors: Min-Jung
authors: MJ
authors: Lee
authors: In-Kyu
authors: IK
authors: Lee
authors: Shin-Yoon
authors: SY
authors: Kim
mesh_terms: D016301:Alveolar Bone Loss / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D001846:Bone Development / Q000502:physiology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology* / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001565:Benzoates; D001596:Benzylamines; D006845:Hydrocarbons, Fluorinated; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: LPS; bone resorption; osteoclast; therapeutic target