Gingival fibrosis is a side effect of certain drugs. Fibrosis is characterized by excess extracellular matrix which is not resorbed. This condition, therefore, is treated by periodontal surgery. The biochemical composition of the fibrotic lesions varies, and depends on the drug that induced the pathology. Thus, cyclosporine A leads to collagen-rich fibrotic gingiva, whereas phenytoin and nifedipine lead to increased non- collagenous proteins. Histologic characterization of phenytoin- and nifedipine-induced lesions reveals increased group substance and oxytalan fibers. These fibers contain elastin. I hypothesize that drug induced gingival fibrosis is characterized by increased lysyl oxidase phenytoin and nifedipine-dependent lesions are likely to be elastin-rich. Lysyl oxidase catalyzes the oxidative deamination of lysine residues in collagen and elastin. This ultimately leads to crosslinking and insolubilization of both proteins, rendering them rendering them resistant to proteolysis and resorption. I propose to characterize the regulation of lysyl oxidase, collagen, and elastin mRNA and protein in gingival fibroblasts cultured from normal and drug-treated subjects. This will be accomplished by culturing early passage gingival fibroblasts in the presence and absence of fibrogenic drugs under optimized conditions. The changes in steady state levels of the mRNA's will be compared to changes in mRNA stability, rates of transcription, and rates of protein synthesis for all three gene products. Changes in lysyl oxidase enzyme activity will be measured. The role of prostaglandins in mediating the drug-dependent changes will be established. The ability of retinoic acid and vitamin D3 to restore normal regulation of lysyl oxidase, collagen and elastin will be evaluated. The content of lysyl oxidase, elastin, and collagen in the tissues of normal and drug-treated subjects will be determined to establish the link between in vitro studies and the in vivo pathology.
|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|