title: Roles of cathelicidin-related antimicrobial peptide in murine osteoclastogenesis.
abstract: Cathelicidin-related antimicrobial peptide (CRAMP) not only kills bacteria but also binds to lipopolysaccharide (LPS) to neutralize its activity. CRAMP is highly expressed in bone marrow and its expression is reported to be up-regulated by inflammatory and infectious stimuli. Here, we examined the role of CRAMP in murine osteoclastogenesis. Osteoclasts were formed in co-cultures of osteoblasts and bone marrow cells in response to 1α,25-dihydroxyvitamin D3 [1α,25(OH)2 D3 ], prostaglandin E2 (PGE2 ), and Toll-like receptor (TLR) ligands such as LPS and flagellin through the induction of receptor activator of nuclear factor-κB ligand (RANKL) expression in osteoblasts. CRAMP inhibited the osteoclastogenesis in co-cultures treated with LPS and flagellin, but not in those treated with 1α,25(OH)2 D3 or PGE2 . Although bone marrow macrophages (BMMs) highly expressed formyl peptide receptor 2 (a receptor of CRAMP), CRAMP showed no inhibitory effect on osteoclastogenesis in BMM cultures treated with RANKL. CRAMP suppressed both LPS- and flagellin-induced RANKL expression in osteoblasts and tumour necrosis factor-α (TNF-α) expression in BMMs, suggesting that CRAMP neutralizes the actions of LPS and flagellin. LPS and flagellin enhanced the expression of CRAMP mRNA in osteoblasts. Extracellularly added CRAMP suppressed LPS- and flagellin-induced CRAMP expression. These results suggest that the production of CRAMP promoted by LPS and flagellin is inhibited by CRAMP released by osteoblasts through a feedback regulation. Even though CRAMP itself has no effect on osteoclastogenesis in mice, we propose that CRAMP is an osteoblast-derived protector in bacterial infection-induced osteoclastic bone resorption.
authors.affiliation: Graduate School of Oral Medicine, Matsumoto Dental University, Nagano, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Horibe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakamichi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Uehara
authors.forename: Midori
authors.initials: M
authors.lastname: Nakamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Koide
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
mesh_terms: D015650:24,25-Dihydroxyvitamin D 3 / Q000276:immunology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology / Q000276:immunology*; D054804:Cathelicidins / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000276:immunology; D025461:Feedback, Physiological; D005408:Flagellin / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010006:Osteoblasts / Q000187:drug effects / Q000276:immunology*; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology*; D010012:Osteogenesis / Q000187:drug effects / Q000276:immunology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008070:Lipopolysaccharides; D053245:RANK Ligand; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D005408:Flagellin; D015650:24,25-Dihydroxyvitamin D 3; D015232:Dinoprostone
keywords: cathelicidin-related antimicrobial peptide; flagellin; lipopolysaccharide; osteoclastogenesis; receptor activator of nuclear factor-κB ligand