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Inhibition of MMP-13 and p38 MAPK gene expression by adenoviral-delivered shRNA in a murine model of experimentally induced periodontal disease


Inflammatory periodontal disease is characterized by extensive destruction of both mineralized and non-mineralized connective tissues. It is associated with increased expression levels of various proinflammatory genes and also of MMP-13, which is similar to what is observed in rheumatoid arthritis. Regulation of MMP-13 gene expression is very complex, but involves p38 MAPK, which represents a signaling pathway also involved in the regulation of a number of proinflammatory genes. Targeted inhibition of MMP-13 and p38 MAPK has been actively studied as a therapeutic approach to diverse inflammatory conditions, including cancer, liver disease, rheumatoid arthritis and periodontal disease, however the use of biochemical inhibitor compounds has potential serious side effects. This proposal intends to use a gene therapy approach to the inhibition of MMP-13 and p38 MAPK mediated by adenoviral-delivered shRNA. This approach yields a transient, selective and localized inhibition of the target genes, which can minimize possible side effects associated with systemic administration or with the use of viral vectors that will integrate into the host genome. Murine models of experimentally-induced periodontal disease will be used and inhibition of MMP-13 and p38 MAPK will be achieved by injecting the affected gingival tissues with the adenoviral vectors encoding shRNA for p38 MAPK and MMP-13. Injection of empty vector or vector encoding for shRNA against beta-galactosidase reporter will be used as control. The effect on bone destruction will be evaluated by histology, immunohistochemistry and micro-computed tomography. Also, the effect of inhibition of MMP-13 and p38 MAPK on inflammatory gene expression will be evaluated at the mRNA and protein levels by real time RT-PCR, Western blot and ELISA. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GUIMARAES-STABILI, MORGANA R.; DE MEDEIROS, MARCELL COSTA; ROSSI, DANUZA; CAMILLI, ANGELO CONSTANTINO; ZANELLI, CLESLEI FERNANDO; VALENTINI, SANDRO ROBERTO; SPOLIDORIO, LUIS CARLOS; KIRKWOOD, KEITH LOUGH; ROSSA, JR., CARLOS. Silencing matrix metalloproteinase-13 (Mmp-13) reduces inflammatory bone resorption associated with LPS-induced periodontal disease in vivo. CLINICAL ORAL INVESTIGATIONS, NOV 2020. Web of Science Citations: 0.

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