Determinants of Periodontal/Periapical Lesion Stability and Progression.

Periodontal and periapical lesions are infectious inflammatory osteolitytic conditions in which a complex inflammatory immune response mediates bone destruction. However, the uncertainty of a lesion's progressive or stable phenotype complicates understanding of the cellular and molecular mechanisms triggering lesion activity. Evidence from clinical and preclinical studies of both periodontal and periapical lesions points to a high receptor activator of NF-κB ligand/osteoprotegerin (RANKL/OPG) ratio as the primary determinant of osteolytic activity, while a low RANKL/OPG ratio is often observed in inactive lesions. Proinflammatory cytokines directly modulate RANKL/OPG expression and consequently drive lesion progression, along with pro-osteoclastogenic support provided by Th1, Th17, and B cells. Conversely, the cooperative action between Th2 and Tregs subsets creates an anti-inflammatory and proreparative milieu associated with lesion stability. Interestingly, the trigger for lesion status switch from active to inactive can originate from an unanticipated RANKL immunoregulatory feedback, involving the induction of Tregs and a host response outcome with immunological tolerance features. In this context, dendritic cells (DCs) appear as potential determinants of host response switch, since RANKL imprint a tolerogenic phenotype in DCs, described to be involved in both Tregs and immunological tolerance generation. The tolerance state systemically and locally suppresses the development of exacerbated and pathogenic responses and contributes to lesions stability. However, immunological tolerance break by comorbidities or dysbiosis could explain lesions relapse toward activity. Therefore, this article will provide a critical review of the current knowledge concerning periodontal and periapical lesions activity and the underlying molecular mechanisms associated with the host response. Further studies are required to unravel the role of immunological responsiveness or tolerance in the determination of lesion status, as well as the potential cooperative and/or inhibitory interplay among effector cells and their impact on RANKL/OPG balance and lesion outcome.

H2 O2 activates matrix metalloproteinases through the nuclear factor kappa B pathway and Ca(2+) signals in human periodontal fibroblasts.

BACKGROUND: The mechanisms involved in reactive oxygen species and matrix metalloproteinase (MMP)-mediated periodontal tissue breakdown are unknown. OBJECTIVE: To determine the effect of H2 O2 in MMP-2 and MMP-9 activity, and the involvement of nuclear factor kappa B (NFκB) and Ca(2+) -mediated signals in human periodontal ligament fibroblasts. MATERIAL AND METHODS: Primary cultures were characterized for their phenotype and exposed for 24 h to sublethal doses (2.5-10 µm) of H2 O2 or control media. NFκB involvement was evaluated through immunofluorescence of p65 subunit, using the NFκB blocking peptide SN50 and catalase. Ca(2+) signals were analyzed by loading the cells with Fluo4-AM and recording the fluorescence changes in a confocal microscope before and after the addition of H2 O2 . 1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl was used to chelate intracellular Ca(2+) . The activity and levels of MMP-2 and MMP-9 were analyzed by gelatin zymogram and densitometric scanning, and enzyme-linked immunosorbent assay, respectively. Statistical analysis was performed with stata V11.1 software using the ANOVA test. RESULTS: H2 O2 at concentrations of 2.5-5 µm induced Ca(2+) signaling and NFκB subunit p65 nuclear translocation, whereas catalase, SN50 and BAPTA-AM prevented p65 nuclear translocation. H2 O2 at 2.5-5 µm significantly increased MMP-9 and MMP-2 activity, while SN50 resulted in lower MMP-2 and MMP-9 activity rates compared with controls. CONCLUSION: Sublethal H2 O2 induces Ca(2+) -dependent NFκB signaling with an increase in MMP gelatinolytic activity in human periodontal ligament.