title: Aminothiazoles inhibit RANKL- and LPS-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells.
abstract: Periodontitis is characterized by chronic inflammation and osteoclast-mediated bone loss regulated by the receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). The aim of this study was to investigate the effect of aminothiazoles targeting prostaglandin E synthase-1 (mPGES-1) on RANKL- and lipopolysaccharide (LPS)-mediated osteoclastogenesis and prostaglandin E2 (PGE2 ) production in vitro using the osteoclast precursor RAW 264.7 cells. RAW 264.7 cells were treated with RANKL or LPS alone or in combination with the aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) or 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644). Aminothiazoles significantly decreased the number of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclast-like cells in cultures of RANKL- and LPS-stimulated RAW 264.7 cells, as well as reduced the production of PGE2 in culture supernatants. LPS-treatment induced mPGES-1 mRNA expression at 16 hrs and the subsequent PGE2 production at 72 hrs. Conversely, RANKL did not affect PGE2 secretion but markedly reduced mPGES-1 at mRNA level. Furthermore, mRNA expression of TRAP and cathepsin K (CTSK) was reduced by aminothiazoles in RAW 264.7 cells activated by LPS, whereas RANK, OPG or tumour necrosis factor α mRNA expression was not significantly affected. In RANKL-activated RAW 264.7 cells, TH-848 and TH-644 down-regulated CTSK but not TRAP mRNA expression. Moreover, the inhibitory effect of aminothiazoles on PGE2 production was also confirmed in LPS-stimulated human peripheral blood mononuclear cell cultures. In conclusion, the aminothiazoles reduced both LPS- and RANKL-mediated osteoclastogenesis and PGE2 production in RAW 264.7 cells, suggesting these compounds as potential inhibitors for treatment of chronic inflammatory bone resorption, such as periodontitis.
authors.affiliation: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Anna
authors.identifier: 0000-0003-3650-2195
authors.initials: A
authors.lastname: Kats
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Norgård
authors.affiliation: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Zenebech
authors.initials: Z
authors.lastname: Wondimu
authors.affiliation: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Catalin
authors.initials: C
authors.lastname: Koro
authors.affiliation: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Hernán
authors.initials: H
authors.lastname: Concha Quezada
authors.affiliation: Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Andersson
authors.affiliation: Division of Periodontology, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Tülay
authors.initials: T
authors.lastname: Yucel-Lindberg
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology*; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D008070:Lipopolysaccharides; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: RAW 264.7 cells; aminothiazole; lipopolysaccharides; prostaglandin E synthase; prostaglandin E2; receptor activator of nuclear factor-κB ligand