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Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs

Inflammatory mediator prostaglandin E(2) (PGE (2)) contributes to bone resorption in several inflammatory conditions including periodontitis. The terminal enzyme, microsomal prostaglandin E synthase‐1 (mPGES‐1) regulating PGE (2) synthesis is a promising therapeutic target to reduce inflammatory bon...

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Autores principales: Kats, Anna, Gerasimcik, Natalija, Näreoja, Tuomas, Nederberg, Jonas, Grenlöv, Simon, Lagnöhed, Ekaterina, Desai, Suchita, Andersson, Göran, Yucel‐Lindberg, Tülay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349150/
https://www.ncbi.nlm.nih.gov/pubmed/30506812
http://dx.doi.org/10.1111/jcmm.14015
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author Kats, Anna
Gerasimcik, Natalija
Näreoja, Tuomas
Nederberg, Jonas
Grenlöv, Simon
Lagnöhed, Ekaterina
Desai, Suchita
Andersson, Göran
Yucel‐Lindberg, Tülay
author_facet Kats, Anna
Gerasimcik, Natalija
Näreoja, Tuomas
Nederberg, Jonas
Grenlöv, Simon
Lagnöhed, Ekaterina
Desai, Suchita
Andersson, Göran
Yucel‐Lindberg, Tülay
author_sort Kats, Anna
collection PubMed
description Inflammatory mediator prostaglandin E(2) (PGE (2)) contributes to bone resorption in several inflammatory conditions including periodontitis. The terminal enzyme, microsomal prostaglandin E synthase‐1 (mPGES‐1) regulating PGE (2) synthesis is a promising therapeutic target to reduce inflammatory bone loss. The aim of this study was to investigate effects of mPGES‐1 inhibitors, aminothiazoles TH‐848 and TH‐644, on PGE (2) production and osteoclastogenesis in co‐cultures of periodontal ligament (PDL) and osteoclast progenitor cells RAW 264.7, stimulated by lipopolysaccharide (LPS), and bone resorption in RANKL‐mediated peripheral blood mononuclear cells (PBMCs). PDL and RAW 264.7 cells were cultured separately or co‐cultured and treated with LPS alone or in combination with aminothiazoles. Multinucleated cells stained positively for tartrate‐resistant acid phosphatase (TRAP) were scored as osteoclast‐like cells. Levels of PGE (2), osteoprotegerin (OPG) and interleukin‐6, as well as mRNA expression of mPGES‐1, OPG and RANKL were analysed in PDL cells. PBMCs were treated with RANKL alone or in combination with aminothiazoles. TRAP‐positive multinucleated cells were analysed and bone resorption was measured by the CTX‐I assay. Aminothiazoles reduced LPS‐stimulated osteoclast‐like cell formation both in co‐cultures and in RAW 264.7 cells. Additionally, aminothiazoles inhibited PGE (2) production in LPS‐stimulated cultures, but did not affect LPS‐induced mPGES‐1, OPG or RANKL mRNA expression in PDL cells. In PBMCs, inhibitors decreased both osteoclast differentiation and bone resorption. In conclusion, aminothiazoles reduced the formation of osteoclast‐like cells and decreased the production of PGE (2) in co‐cultures as well as single‐cell cultures. Furthermore, these compounds inhibited RANKL‐induced bone resorption and differentiation of PBMCs, suggesting these inhibitors for future treatment of inflammatory bone loss such as periodontitis.
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spelling pubmed-63491502019-02-01 Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs Kats, Anna Gerasimcik, Natalija Näreoja, Tuomas Nederberg, Jonas Grenlöv, Simon Lagnöhed, Ekaterina Desai, Suchita Andersson, Göran Yucel‐Lindberg, Tülay J Cell Mol Med Original Articles Inflammatory mediator prostaglandin E(2) (PGE (2)) contributes to bone resorption in several inflammatory conditions including periodontitis. The terminal enzyme, microsomal prostaglandin E synthase‐1 (mPGES‐1) regulating PGE (2) synthesis is a promising therapeutic target to reduce inflammatory bone loss. The aim of this study was to investigate effects of mPGES‐1 inhibitors, aminothiazoles TH‐848 and TH‐644, on PGE (2) production and osteoclastogenesis in co‐cultures of periodontal ligament (PDL) and osteoclast progenitor cells RAW 264.7, stimulated by lipopolysaccharide (LPS), and bone resorption in RANKL‐mediated peripheral blood mononuclear cells (PBMCs). PDL and RAW 264.7 cells were cultured separately or co‐cultured and treated with LPS alone or in combination with aminothiazoles. Multinucleated cells stained positively for tartrate‐resistant acid phosphatase (TRAP) were scored as osteoclast‐like cells. Levels of PGE (2), osteoprotegerin (OPG) and interleukin‐6, as well as mRNA expression of mPGES‐1, OPG and RANKL were analysed in PDL cells. PBMCs were treated with RANKL alone or in combination with aminothiazoles. TRAP‐positive multinucleated cells were analysed and bone resorption was measured by the CTX‐I assay. Aminothiazoles reduced LPS‐stimulated osteoclast‐like cell formation both in co‐cultures and in RAW 264.7 cells. Additionally, aminothiazoles inhibited PGE (2) production in LPS‐stimulated cultures, but did not affect LPS‐induced mPGES‐1, OPG or RANKL mRNA expression in PDL cells. In PBMCs, inhibitors decreased both osteoclast differentiation and bone resorption. In conclusion, aminothiazoles reduced the formation of osteoclast‐like cells and decreased the production of PGE (2) in co‐cultures as well as single‐cell cultures. Furthermore, these compounds inhibited RANKL‐induced bone resorption and differentiation of PBMCs, suggesting these inhibitors for future treatment of inflammatory bone loss such as periodontitis. John Wiley and Sons Inc. 2018-12-01 2019-02 /pmc/articles/PMC6349150/ /pubmed/30506812 http://dx.doi.org/10.1111/jcmm.14015 Text en © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Kats, Anna
Gerasimcik, Natalija
Näreoja, Tuomas
Nederberg, Jonas
Grenlöv, Simon
Lagnöhed, Ekaterina
Desai, Suchita
Andersson, Göran
Yucel‐Lindberg, Tülay
Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title_full Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title_fullStr Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title_full_unstemmed Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title_short Aminothiazoles inhibit osteoclastogenesis and PGE (2) production in LPS‐stimulated co‐cultures of periodontal ligament and RAW 264.7 cells, and RANKL‐mediated osteoclastogenesis and bone resorption in PBMCs
title_sort aminothiazoles inhibit osteoclastogenesis and pge (2) production in lps‐stimulated co‐cultures of periodontal ligament and raw 264.7 cells, and rankl‐mediated osteoclastogenesis and bone resorption in pbmcs
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349150/
https://www.ncbi.nlm.nih.gov/pubmed/30506812
http://dx.doi.org/10.1111/jcmm.14015
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