Effects of high glucose concentration on migration of periodontal fibroblasts: potential regulation of Rho GTPases by micro RNAs

Abstract

Diabetes mellitus (DM) is characterized by chronic hyperglycemia (HG), in a long-term is associated mainly with complications of oxidative stress and glycation. One of the common complications of diabetes is chronic wound; addition to impairment of the vascular system, there are studies suggesting the involvement of specific functions of fibroblasts, important cells in the healing process. Another common complication of diabetes is the increased incidence of periodontal disease (gingivitis and periodontitis) and, in general, a deficiency in the healing of oral lesions. Part of the problem derives from a hypofunction of salivary glands, but it is possible that the function of fibroblasts in the oral mucosa and periodontal also be changed. In wound healing, fibroblasts proliferate, migrate, synthesize and degrade extracellular matrix (ECM). In healing / regeneration of the periodontal ligament migratory activity is especially relevant, since these cells will populate the root surface cleaned before the junctional epithelium migrates onto the surface and create a dental adhesion to form a long junctional epithelium. We recently demonstrated that oxidative stress promoted by HG negatively affects fibroblast migration on different substrates, with reduced speed and directionality phones (Lamers, et al., 2011). This effect was accompanied by increased frequency of cellular processes unproductive because they are often unstable and collapse. The HG also reduced the maturation of adhesions with the ECM and increased the activity of the GTPases Rac1 and RhoA, which respectively regulate the formation of cellular processes and cell contractility. We also observed a decrease in the distribution of different integrins on the cell surface (ALMEIDA, 2011). Rho GTPases are proteins involved in different signaling pathways and regulate cytoskeletal organization of actin and microtubules. An important and little explored in the regulation of the cytoskeleton and cell migration is the role of microRNAs (miRNAs) in signaling pathways involving Rho GTPases. It is known, however, that DM alters the expression of various miRNAs (Shen et. al., 2011). Therefore, this study has the objectives: 1) evaluate the effects of high glucose concentration on the proliferation and migration of human periodontal fibroblasts, 2) evaluate the expression regulation of miRNAs by high glucose and 3) evaluate the regulation of migration of periodontal fibroblasts by miRNAs differentially expressed in these conditions. We believe this study might reveal potential regulatory targets of migration of periodontal fibroblasts to be used in regenerative therapy in normal and diabetic patients. (AU)