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Abstract
Inflammatory mediator prostaglandin E2 (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.
Highlights
In chronic inflammatory conditions including periodontitis and rheumatoid arthritis, bone loss is initiated by unresolved inflammation in the neighbouring tissues leading to pathological osteoclastogenesis.[1]
In an attempt to investigate the effect of microsomal prostaglandin E synthase‐1 (mPGES‐1) inhibitors on osteoclast formation and bone resorption, we used a co‐culture model of fibroblast‐like periodontal ligament (PDL) cells and osteoclast progenitor cells RAW 264.7 as well as peripheral blood mononuclear cells (PBMCs) stimulated by LPS or RANK ligand (RANKL)
In cell‐cell co‐cultures between PDL cells and RAW 264.7 cells, a promoted formation of osteoclast‐like cells occurred compared to co‐cultures separated by semipermeable membranes
Summary
In chronic inflammatory conditions including periodontitis and rheumatoid arthritis, bone loss is initiated by unresolved inflammation in the neighbouring tissues leading to pathological osteoclastogenesis.[1]. Controlling the production of PGE2 through COX‐inhibition, using non‐steroidal anti‐inflammatory drugs (NSAIDs) or selective COX‐2 inhibitors, have been reported to decrease the progression of alveolar bone loss and gingival inflammation in periodontitis.[11-14]. The aminothiazoles inhibited both RANKL‐ and LPS‐stimulated osteoclast formation of the osteoclast progenitor cell line RAW 264.7.23 In the present study, we aimed to further elucidate the effect of aminothiazoles on (a) osteoclastogenesis and the production of PGE2, IL‐6, OPG and mPGES‐1 in a co‐culture model using PDL and RAW 264.7 cells stimulated by LPS and (b) osteoclastogenesis and bone resorption in peripheral blood mononuclear cells (PBMCs) stimulated with RANKL
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