The clinical condition of gingival overgrowth consists of excess gingival tissues that creates disturbances in the oral environment and creates related systemic complications. For example, impaired mastication and impaired oral hygiene can result, respectively, in poor nutrition and increased microbial load in the oral cavity. There are two principal classifications of gingival overgrowth. Drug-induced gingival overgrowth is a side effect resulting from therapy with certain pharmacologic agents. Hereditary gingival fibromatosis is unrelated to pharmacological therapies. Recent studies from our laboratory show that phenytoin-induced gingival overgrowth lesions are fibrotic and contain elevated levels of connective tissue growth factor (CTGF), whereas nifedipine- and cyclosporin A-induced lesions are less fibrotic and have low levels of CTGF, and non-overgrowth tissues have no detectable CTGF. Our in vitro studies show that CTGF stimulates insoluble collagen accumulation in cultured human gingival fibroblasts. Fibrosis and CTGF levels have been associated in other pathologies. The molecular and cellular activities stimulated by CTGF that promote fibrosis are not well understood. The goals of the current proposal are (1) to identify functional domain(s) of CTGF that stimulate insoluble collagen accumulation, proliferation and apoptosis by cultured human gingival fibroblasts utilizing a series of domain-specific monoclonal CTGF antibodies; (2) determine mechanisms by which phenytoin increases CTGF itself in cultured human gingival fibroblasts focusing on prostaglandin and CAMP metabolism, and on phenytoin modulation of signal transduction pathways related to TGF-beta stimulated CTGF transcription (3) assay human drug-induced gingival overgrowth tissues and hereditary human gingival overgrowth tissues for the presence of markers related to the novel molecular mechanisms explored in vitro: prostaglandin receptors, proliferation markers, and markers for apoptosis. This experimental approach that utilizes bioassays of human gingival fibroblasts in vitro, and human gingival overgrowth tissues samples is expected to identify biologically active domains of CTGF, and mechanisms by which CTGF promotes gingival fibrosis. In addition, these findings will likely have relevance to fibrotic pathologies that occur in other tissues that also contain elevated levels of CTGF.
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