title: CXCL2 mediates lipopolysaccharide-induced osteoclastogenesis in RANKL-primed precursors.
abstract: The strong inflammatory agent lipopolysaccharide (LPS) has been shown to cause bone lysis in vivo. However, the etiology of LPS-induced bone destruction is still elusive. Here, we show that LPS stimulates the induction of CXCL2 in bone marrow macrophages (BMMs), osteoclast precursors, at the transcription level even in the absence of the synthesis of new proteins including interferon β. Reactive oxygen species were involved in the secretion of CXCL2 but not in the mRNA expression. CXCL2 mRNA induction by LPS was mediated by p38, JNK, and NFκB signaling pathways. Moreover, c-Fos and p65 were directly recruited to CXCL2 promoter. The conditioned medium from LPS-treated BMMs could enhance migration of osteoclast precursors, which was blocked by treatment with CXCL2-neutralizing antibody or CXCR2 receptor antagonist. The blockade of CXCL2 also reduced LPS-induced osteoclastogenesis. More significantly, CXCL2-neutralization prevented bone destruction in mice treated with LPS. Therefore, CXCL2 might be a useful therapeutic target for inflammatory bone destructive diseases.
authors.affiliation: Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749, Republic of Korea. haim00@snu.ac.kr
authors.forename: Jeongim
authors.initials: J
authors.lastname: Ha
authors.forename: Youngkyun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D054426:Chemokine CXCL2 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009500:Neutralization Tests; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D016328:NF-kappa B; D053245:RANK Ligand; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases