Role of NOD and MyD88 proteins on the regulation of bacterial antigen-induced expression of RANKL and on the modulation of inflammation: a study on relevant cells of the periodontium

• Grant number: 06/00721-6
• Support Opportunities: Scholarships in Brazil - Technical Training Program - Technical Training
• Effective date (Start): April 01, 2006
• Effective date (End): March 31, 2007
• Field of knowledge: Health Sciences - Dentistry - Periodontology
• Principal Investigator: Carlos Rossa Junior
• Grantee: Morgana Rodrigues Guimarães Stabili
• Host Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated research grant: 05/04247-4 - Role of Nod and MyD88 proteins on the regulation of bacterial antigen-induced expression of RANKL and on the modulation of inflammation: a study on relevant cells of the periodontium, AP.R

Abstract

Bone resorption is one of the major characteristics of destructive periodontal disease. It is currently thought that ii is the result of the immune/inflammatory response initiated by bacterial antigens from microorganisms present in the dental biofilm. Despite the great number of different bacterial species in the dental biofilm, Gram-negative microorganisms were demonstrated to have a very important role on periodontal disease pathogenesis. Lipopolysaccharide (LPS) is a bacterial cell wall component which is acknowledged as one of the main virulence factors of these microorganisms. Importantly, LPS can exert its deleterious effects independently of bacterial cell viability. Thus, the mere presence of LPS in proximity with the periodontal tissues can initiate the expression and production of inflammatory mediators and other cytokines which can culminate in degradation of both soft and hard tissues. Recently, a molecule called receptor-activator of nuclear factor kappa-B ligand (RANKL) was identified as a member of a new cytokine system controlling osteoclast differentiation and activation. This is considered one of the main breakthroughs in bone biology, since it now constitutes the paradigm of osteoclastogenesis. Knowledge of this system have a profound impact on understanding and probably on therapy of dsiseases and conditions associated with imbalances on bone turnover, including estrogen deficiency-associated osteoporosis, Paget disease, reumathoid arthritis, bone fracture repair, tumor metastasis into bone and periodontal disease. Considering the relevance of LPS in the pathogenesis of periodontal disease, the decisive role of RANKL in osteoclastic bone resorption and the relevance of expression of some cytokines to the modulation of inflammation, the aim of this proposal is to study the influence of the utilization of different intracellular signaling pathways after stimulation with LPS on the regulation of expression of RANKL and of cytokines involved in the modulation of inflammation. The main hypotesis is that the signaling pathways activated after LPS stimulation will have a decisive influence on expression of both RANKL and inflammatory cytokines. Comprehension of these molecular mechanisms controlling expression of RANKL and of these cytokines can yield important information for the development of new therapeutic strategies aiming at minimizing/preventing bone resorption. This information could be used in subsequent studies using in vivo models. The specific objectives proposed are: 1) Determine the role of MyD88-dependent and independent signaling pathways on LPS-induced expression of RANKL, of its antagonist OPG and also on the levels of cytokines involved in modulation of inflammatory response (IL-2, IL-10, IFN-gamma, IFN-beta); 2) Assess the role of Nod proteins on the expression of RANKL, of its antagonist OPG and also on the levels of cytokines involved in modulation of inflammatory response (IL-2, IL-10, IFN-gamma, IFN-beta) after stimulation with bacterial antigens