Gingival overgrowth is a side effect of specific medications, and occurs as inherited and idiopathic forms (HGF). The condition impairs mastication, and predisposes affected individuals to systemic complications. Although gingival overgrowth lesions appear clinically similar, our studies have shown that the molecular and cellular features of gingival overgrowth vary as a function of the cause. Phenytoin-induced gingival overgrowth and HGF lesions are highly fibrotic and contain high levels of connective tissue growth factor (CTGF); whereas cyclosporin A induced overgrowth is less fibrotic, and contains low amounts of CTGF; and nifedipine-induced gingival overgrowth is intermediated in all respects. Recent studies have identified tissue specific pathways that provide the mechanism for elevated CTGF expression in fibrotic gingival tissues, and potential therapeutic strategies. In addition, we have published evidence that CTGF promotes extracellular matrix deposition via alpha-6 and beta-1 integrins. Preliminary data suggest that the process of epithelial- mesenchymal transition (EMT) contributes to all forms of gingival overgrowth; and that a critically important matrix metalloproteinase (MMP-13) is down regulated in fibrotic forms of gingival overgrowth. Thus, two aims are proposed.
In Aim 1 we will establish that EMT occurs in all forms of human gingival overgrowth in vivo, and we will evaluate the mechanism of inhibitors of EMT to block progression of abnormalities in in vitro studies of primary gingival epithelial cells and fibroblasts.
Aim 2 proposes to evaluate the hypothesis that CTGF regulates extracellular collagen processing enzymes and a matrix metalloproteinase (MMP-13), thereby increasing net extracellular matrix accumulation. Proposed studies will determine CTGF stimulated signal transduction pathways and regulated downstream genes that lead to increased extracellular matrix deposition. These studies take advantage of a peptide that inhibits CTGF-dependent extracellular matrix deposition that we have recently identified. The proposed experimental approach utilizes in situ analyses of human gingival overgrowth tissues, and primary cultured human gingival epithelial cells grown in monolayer and three dimensional configurations. Studies will identify novel cellular and molecular pathways that contribute to gingival overgrowth. Findings will have relevance to fibrosis in both oral and non-oral tissues in which CTGF is a contributing factor, thus potentially identifying new therapeutic strategies in various tissues. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE011004-11A1
Application #
7320134
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Shirazi, Yasaman
Project Start
1994-04-01
Project End
2012-06-30
Budget Start
2007-08-01
Budget End
2008-06-30
Support Year
11
Fiscal Year
2007
Total Cost
$363,750
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Saxena, D; Mahjour, F; Findlay, A D et al. (2018) Multiple Functions of Lysyl Oxidase Like-2 in Oral Fibroproliferative Processes. J Dent Res 97:1277-1284
de Santana, Ronaldo Barcellos; Trackman, Phillip C (2015) Effect of targeted delivery of bone morphogenetic protein-2 on bone formation in type 1 diabetes. Int J Oral Maxillofac Implants 30:707-14
Assaggaf, Mohammad A; Kantarci, Alpdogan; Sume, Siddika S et al. (2015) Prevention of phenytoin-induced gingival overgrowth by lovastatin in mice. Am J Pathol 185:1588-99
Trackman, P C; Kantarci, A (2015) Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 94:540-6
Khosravi, Roozbeh; Sodek, Katharine L; Faibish, Michael et al. (2014) Collagen advanced glycation inhibits its Discoidin Domain Receptor 2 (DDR2)-mediated induction of lysyl oxidase in osteoblasts. Bone 58:33-41
Khosravi, Roozbeh; Sodek, Katharine L; Xu, Wan-Peng et al. (2014) A novel function for lysyl oxidase in pluripotent mesenchymal cell proliferation and relevance to inflammation-associated osteopenia. PLoS One 9:e100669
Bahammam, Maha; Black Jr, Samuel A; Sume, Siddika Selva et al. (2013) Requirement for active glycogen synthase kinase-3? in TGF-?1 upregulation of connective tissue growth factor (CCN2/CTGF) levels in human gingival fibroblasts. Am J Physiol Cell Physiol 305:C581-90
Beerlage, Christiane; Greb, Jessica; Kretschmer, Dorothee et al. (2013) Hypoxia-inducible factor 1-regulated lysyl oxidase is involved in Staphylococcus aureus abscess formation. Infect Immun 81:2562-73
Kantarci, A; Nseir, Z; Kim, Y-S et al. (2011) Loss of basement membrane integrity in human gingival overgrowth. J Dent Res 90:887-93
Sume, Siddika Selva; Kantarci, Alpdogan; Lee, Alan et al. (2010) Epithelial to mesenchymal transition in gingival overgrowth. Am J Pathol 177:208-18

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