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UBC Theses and Dissertations

Smad2 overexpression and the progression of periodontal disease Mazen, Alotaibi Kitab


Periodontitis is a chronic inflammatory disease, characterized by destruction of the periodontal attachment apparatus including the alveolar bone. Previous studies have provided evidence for the involvement of transforming growth factor beta (TGF-β) signaling in periodontitis progression. TGF-β signaling is responsible for a variety of cellular processes including proliferation, differentiation and apoptosis. The SMAD2 transcription factor lies at the heart of TGF-β intracellular mediators. Previous authors have reported the effect of Smad2 overexpression on multiple mouse tissues (Ito et al 2001), but did not report the role of Smad2 overexpression on the progression of periodontal disease. We hypothesized that Smad2 overexpression alters apoptosis, cell proliferation, and inflammatory cytokine secretions in the junctional epithelium (JE), leading to periodontal attachment loss. A mouse model that overexpresses Smad2 in epithelial cells driven by the cytokeratin 14 promoter (K14) was used to test the hypotheses. The K14-Smad2 mice findings were compared to those observed in wild type (WT) mice that served as controls. The results of the study showed that Smad2 overexpression reduced the histological surface area of JE when compared to WT mice. The reduction of the JE surface area in K14-Smad2 mice was attributed to an increased apoptotic index and a reduced proliferation rate. The overexpression of Smad2 increased the apoptotic index by down regulating Bcl2, an antiapoptotic molecule. Smad2 overexpression also reduced the proliferation rate of the JE cells in K14-Smad2 mice by upregulating c-Myc, which in turn upregulates phosphorylated retinoblastoma P15, and P27. The overexpression of Smad2 resulted in severe alveolar bone loss in the K14-Smad2 mice when compared to the WT controls. Smad2 overexpression resulted in a reduction in the bone density and bone volume in the K14-Smad2 mice when compared to their WT counterparts. The severe alveolar bone loss in K14-Smad2 mice was attributed to an upregulation in tumor necrosis factor alpha (TNF-α) , RANKL and increased osteoclast numbers. In summary the overexpression of Smad2 reduced the histological surface of JE and resulted in severe bone loss that follows a chronic disease pattern in K14-Smad2 mice.

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