title: Transglutaminase 2 up-regulation is associated with RANKL/OPG pathway in cultured HPDL cells and THP-1-differentiated macrophages.
abstract: Recent evidence emphasized that transglutaminase 2 (TG2), a protein cross-linking enzyme, may play a role in the early phase of inflammation. High levels of TG2 have been associated with the constitutive activation of nuclear factor-kappa B (NF-κB) that is considered the main regulator of inflammation. In this context, the receptor activator of NF-kappa B ligand (RANKL) and receptor activator of NF-κB have extensive functions in the regulation of cytokine secretion associated with different pathological conditions. The human periodontal ligament (HPDL) cells, which express and secrete osteoprotegerin (OPG) and RANKL, represent an useful "ex vivo" model for monitoring cell response in inflammatory microenvironments, such as periodontitis-dependent tissue response. Thus, we evaluated TG2 expression and alterations in RANKL/OPG ratio occurring in cultured HPDL cells. The HPDL cells were obtained from patients with chronic periodontitis (CP) and healthy subjects. We observed the up-regulation of some inflammatory markers, such as IL-6, TNF-α, and HMGB-1, and at the same time an increase in TG2 mRNA levels in HPDL cells from CP patients compared with healthy subjects. We found a positive correlation between RANKL/OPG ratio and TG2 mRNA levels in HPDL cells from CP patients. In the parallel experiments, we demonstrated that TG2 inhibition reduced RANKL expression in both HPDL cells from CP patients and monocytes differentiated to macrophages by tetradecanoyl phorbol acetate treatment. Given the RANKL key role in NF-κB pathway and the observed up-regulation of pro-inflammatory cytokines, our data suggest that TG2 may be involved in molecular mechanisms of inflammatory response occurring in periodontal disease.
authors.affiliation: Department of Specialist Medical-Surgical Experimental Sciences and Odontostomatology, University of Messina, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Matarese
authors.affiliation: Department of Biomedical Sciences and Morpho-Functional Imaging, University of Messina, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Currò
authors.affiliation: Department of Specialist Medical-Surgical Experimental Sciences and Odontostomatology, University of Messina, Via C. Valeria, 98125, Messina, Italy.|Department of Neurosciences, Reproductive and Odontostomatological Sciences, School of Medicine University "Federico II", Via Pansini 5, 80131, Naples, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Isola
authors.affiliation: Department of Biomedical Sciences and Morpho-Functional Imaging, University of Messina, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Caccamo
authors.affiliation: Department of Biomedical Sciences and Morpho-Functional Imaging, University of Messina, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Mercurio
authors.initials: M
authors.lastname: Vecchio
authors.affiliation: Department of Biomedical Sciences and Morpho-Functional Imaging, University of Messina, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Giunta
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, School of Medicine University "Federico II", Via Pansini 5, 80131, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ramaglia
authors.affiliation: Department of Specialist Medical-Surgical Experimental Sciences and Odontostomatology, University of Messina, Via C. Valeria, 98125, Messina, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Cordasco
authors.affiliation: Dean, School of Dental Medicine, Stony Brook University, 160 Rockland Hall, Stony Brook, NY, 11794-8700, USA.
authors.forename: Ray C
authors.initials: RC
authors.lastname: Williams
authors.affiliation: Department of Biomedical Sciences and Morpho-Functional Imaging, University of Messina, Polyclinic Hospital University, Via C. Valeria, 98125, Messina, Italy. ientile@unime.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ientile
mesh_terms: D002454:Cell Differentiation; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D019204:GTP-Binding Proteins / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction; D011503:Transglutaminases / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Chronic periodontitis; Human periodontal fibroblasts; Inflammation; Monocytes/macrophages; RANKL/OPG; Transglutaminase