A Controversial Role for IL-12 in Immune Response and Bone Resorption at Apical Periodontal Sites

Periapical lesions are inflammatory conditions of tooth periapical tissues, triggered by dental pulp infection and characterized by exudation of immune cells to the affected tissues and production of inflammatory mediators such as cytokines. The inflammatory periapical reaction is mainly driven by Th1, Th2, and Th17 responses, and such polarization may modulate progression of the disease and expression of bone proresorptive cytokines. IL-12 is a potent inducer of IFN-γ production, which stimulates Th1 effector cells. Many evidences have shown a positive correlation between the bone resorptive cytokine IL-1β and the production of IL-12 and IFN-γ. Furthermore, IL-12 may have a potential role in the release of bone resorptive mediators and blockade of Th2 cytokines, affecting the progression of periapical bone loss. Nevertheless, IL-12 and IFN-γ have also been described as suppressors of osteoclast differentiation and activation, favoring bone maintenance. This paper focuses on the controversial roles of IL-12 in periapical lesions

Estudo comparativo entre homeopatia e nimesulida na prevenção da reabsorção óssea em periodontite experimental em ratos

Periodontitis is a chronic disease characterized by bone loss and inflammatory changes. We studied the effect of a homeopathic agent (Mercúrios Corrosivos 6 CH) and a non-steroidal anti-inflammatory drug (nimesulide) on the alveolar bone loss progression in experimentally induced periodontitis in rats. Sixty (60) Wistar rats were separated into group 1 (homeopathy), group 2 (nimesulide) and group 3 (saline solution). Silk ligatures were placed at the gingival margin level of the lower right first molar of all rats. Alveolar bone loss was evaluated by light microscopic analysis and analyzed using software Image J. The results were submitted to the analysis of variance (ANOVA) and Tukey’s posttest (

Increased levels of Porphyromonas gingivalis are associated with ischemic and hemorrhagic cerebrovascular disease in humans: an in vivo study

Objective: This study investigated the role of periodontal disease in the development of stroke or cerebral infarction in patients by evaluating the clinical periodontal conditions and the subgingival levels of periodontopathogens. Material and Methods: Twenty patients with ischemic (I-CVA) or hemorrhagic (H-CVA) cerebrovascular episodes (test group) and 60 systemically healthy patients (control group) were evaluated for: probing depth, clinical attachment level, bleeding on probing and plaque index. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans were both identified and quantified in subgingival plaque samples by conventional and real-time PCR, respectively. Results: The test group showed a significant increase in each of the following parameters: pocket depth, clinical attachment loss, bleeding on probing, plaque index and number of missing teeth when compared to control values (p<0.05, unpaired t-test). Likewise, the test group had increased numbers of sites that were contaminated with P. gingivalis (60%x10%; p<0.001; chi-squared test) and displayed greater prevalence of periodontal disease, with an odds ratio of 48.06 (95% CI: 5.96-387.72; p<0.001). Notably, a positive correlation between probing depth and the levels of P. gingivalis in ischemic stroke was found (r=0.60; p=0.03; Spearman's rank correlation coefficient test). A. actinomycetemcomitans DNA was not detected in any of the groups by conventional or real-time PCR. Conclusions: Stroke patients had deeper pockets, more severe attachment loss, increased bleeding on probing, increased plaque indexes, and in their pockets harbored increased levels of P. gingivalis. These findings suggest that periodontal disease is a risk factor for the development of cerebral hemorrhage or infarction. Early treatment of periodontitis may counteract the development of cerebrovascular episodes.FAPESP (The State of Sao Paulo Research Foundation)FAPESP (The State of Sao Paulo Research Foundation) [2006/02376-4]CAPES (Coordination of Support for Higher Education)CAPES (Coordination of Support for Higher Education

Differential expression of cytokines in the pressure and tension sides during the orthodontic movement

The aim of this work was evaluate the pro and antinflamatory cytokines expression, collagen type-I, remodeling tecidual mediator (MMP-1) and its inhibitor (TIMP-1), osteoclastogenic factors (RANKL) and osteoblastogenics (CBFA-1), in the different sides under tension forces and pressure, in the orthodontic movement. Quantitative examinations of reaction in chain of polymerase was realized (RealTime-PCR), using mRNA proceeding from samples of periodontal tooth ligament submitted to orthodontic forces. Tooth that has orthodontic extraction indication was utilized, after application of forces in maxillary and no-movement tooth in the control group. The results showed that the side of pressure had more expression of TGF-beta, TNF-a, RANKL e MMP1, and less expression of COL-1 when compared with control group, while tension side showed more expression of TGF-beta, IL-10, COL-1 and CBFA-1. Comparing the both sides was observed more expression of IL-10, COL-1 and CBFA-1 in the tension side, and more expression of TNF-a, RANKL and MMP-1 in the pressure side. The results indicate that cytokines standard determines the nature of the tecidual reply to the orthodontic force, modifying and guiding the equilibry between reabsortion and neoformation of the bone.Este trabalho se propõe a investigar o padrão expressão de citocinas pró e antiinflamatórias, colágeno tipo I, mediador de remodelação tecidual (MMP-1) e seu inibidor (TIMP-1), fatores osteoclastogênico (RANKL) e osteoblastogênico (CBFA-1), nos diferentes lados sob forças de tensão e pressão, na movimentação ortodôntica. Foram realizados exames quantitativos de reação em cadeia de polimerase (RealTime-PCR), utilizando RNAm proveniente de amostras de ligamento peridontal de dentes submetidos a forças ortodônticas. Foram utilizados dentes que apresentavam indicação ortodôntica de extração, pós-expansão rápida da maxila, e dentes não movimentados como grupo controle, com consentimento informado e declaração de doação dos dentes para pesquisa. Os resultados demonstraram que o lado de pressão apresentou maior expressão de TGF-beta, TNF-a, RANKL e MMP-1, e menor expressão de COL-1 em comparação com o controle, enquanto o lado de tensão apresentou maior expressão de TGF-beta, IL-10, COL-1 e CBFA-1. Comparando os lados de pressão e tensão, observamos maior expressão de IL-10, COL-1 e CBFA-1 no lado de tensão, e maior expressão de TNF-a, RANKL e MMP-1 no lado de pressão. Os resultados obtidos sugerem que o padrão de citocinas determina a natureza da resposta tecidual à força ortodôntica, alterando e guiando o equilíbrio entre reabsorção e neoformação óssea

Differential expression of osteoblast and osteoclast chemmoatractants in compression and tension sides during orthodontic movement

Orthodontic tooth movement is achieved by the remodeling of alveolar bone in response to mechanical loading, and is supposed to be mediated by several host mediators, such as chemokines. In this study we investigated the pattern of mRNAs expression encoding for osteoblast and osteoclast related chemokines, and further correlated them with the profile of bone remodeling markers in palatal and buccal sides of tooth under orthodontic force, where tensile (T) and compressive (C) forces, respectively, predominate. Real-time PCR was performed with periodontal ligament mRNA from samples of T and C sides of human teeth submitted to rapid maxillary expansion, while periodontal ligament of normal teeth were used as controls. Results showed that both T and C sides exhibited significant higher expression of all targets when compared to controls. Comparing C and T sides, C side exhibited higher expression of MCP-1/CCL2, MIP-1 alpha/CCL3 and RANKL, while T side presented higher expression of OCN. The expression of RANTES/CCL5 and SDF-1/CXCL12 was similar in C and T sides. Our data demonstrate a differential expression of chemokines in compressed and stretched PDL during orthodontic tooth movement, suggesting that chemokines pattern may contribute to the differential bone remodeling in response to orthodontic force through the establishment of distinct microenvironments in compression and tension sides. (C) 2008 Elsevier Ltd. All rights reserved

Absence of functional TLR4 impairs response of macrophages after Candida albicans infection

Candida albicans is recognized by phagocytic cells through a set of recognition receptors patterns. Recently, we showed the importance of TLR2 in the regulation of neutrophil survival after C. albicans infection. In the present work, we analyzed the involvement of TLR4 in the recognition of C. albicans by neutrophils and macrophages. Our results show that the absence of functional TLR4 resulted in lower chemotaxis of neutrophils to the site of infection, lower levels of TNF-alpha, CXCL1 and nitric oxide, and dissemination and persistence of the pathogen in lymph nodes and spleen. In vitro, the phagocytic activity, nitric oxide production and myeloperoxidase activity, CXCL1, IL-1 beta production by neutrophils from TLR4-defective mice were not changed. In contrast, macrophages from TLR4-defective mice demonstrated lower phagocytosis and lower levels of CXCL1, IL-1 beta and TNF-alpha. Together, these data demonstrate that TLR4 signals are important for the recognition of C. albicans by macrophages and their absence allows persistence of the infection.</

The Potential Role of Suppressors of Cytokine Signaling in the Attenuation of Inflammatory Reaction and Alveolar Bone Loss Associated with Apical Periodontitis

Inflammatory cytokines contribute to periapical tissue destruction. Their activity is potentially regulated by suppressors of cytokine signaling (SOCS), which down-regulate signal transduction as part of an inhibitory feedback loop. We investigated the expression of the cytokines tumor necrosis factor alpha (TNF-alpha); interleukin (IL)-10 and RANKL; and SOCS-1, -2, and -3 by real-time polymerase chain reaction in 57 periapical granulomas and 38 healthy periapical tissues. Periapical granulomas exhibited significantly higher SOCS-1, -2, and -3, TNF-alpha, IL-10, and RANKL messenger RNA levels when compared with healthy controls. Significant positive correlations were found between SOCS1 and IL-10 and between SOCS3 and IL-10. Significant inverse correlations were observed between SOCS1 and TNF-alpha, SOCS1 and RANKL, and SOCS3 and TNF-alpha. Increased SOCS-1, -2, and -3 messenger RNA levels in periapical granulomas may be related to the downregulation of inflammatory cytokines in these lesions; therefore, SOCS molecules may play a role in the dynamics of periapical granulomas development. (J Endod 2008;34:1480-1484)FAPESP Fundacao de Amparo A Pesquisa do Estado de Sao Paul

Experimental model of tooth movement in mice: A standardized protocol for studying bone remodeling under compression and tensile strains

During orthodontic tooth movement (OTM), alveolar bone is resorbed by osteoclasts in compression sites (CS) and is deposited by osteoblasts in tension sites (TS). The aim of this study was to develop a standardized OTM protocol in mice and to investigate the expression of bone resorption and deposition markers in CS and TS. An orthodontic appliance was placed in C57BL6/J mice. To define the ideal orthodontic force, the molars of the mice were subjected to forces of 0.1 N, 0.25 N, 0.35 N and 0.5 N. The expression of mediators that are involved in bone remodeling at CS and TS was analyzed using a Real-Time PCR. The data revealed that a force of 0.35 N promoted optimal OTM and osteoclast recruitment without root resorption. The levels of TNF-alpha, RANKL, MMP13 and OPG were all altered in CS and TS. Whereas TNF-a and Cathepsin K exhibited elevated levels in CS. RUNX2 and OCN levels were higher in TS. Our results suggest that 0.35 N is the ideal force for OTM in mice and has no side effects. Moreover, the expression of bone remodeling markers differed between the compression and the tension areas, potentially explaining the distinct cellular migration and differentiation patterns in each of these sites. (C) 2012 Elsevier Ltd. All rights reserved.Fundacao de Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG, Brazil)Fundacao de Amparo a Pesquisas do Estado de Minas Gerais (FAPEMIG, Brazil)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), BrazilConselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil

CCR2 Deficiency Results in Increased Osteolysis in Experimental Periapical Lesions in Mice

Introduction: Periapical lesions are chronic inflammatory disorders of periradicular tissues caused by etiologic agents of endodontic origin. The inflammatory chemokines are thought to be involved in the latter observed osteolysis. With a murine model of experimental periapical lesion, the objective of this study was to evaluate the role of the chemokine receptor CCR2 in the lesion progression, osteoclast differentiation and activation, and expression of inflammatory osteolysis-related mediators. Methods: For lesion induction, right mandibular first molars were opened surgically with a (1)/(4) carbine bur, and 4 bacterial strains were inoculated in the exposed dental pulp; left mandibular first molars were used as controls. Animals were killed at 3, 7, 14, and 21 days after surgeries to evaluate the kinetics of lesion development. Results: CCR2 KO mice showed wider lesions than WT mice. CCR2 KO mice also expressed higher levels of the osteoclastogenic and osteolytic factors, receptor activator of nuclear factor kappa B ligand (RANKL) and cathepsin K, of the proinflammatory cytokine tumor necrosis factor alpha, and of the neutrophil migration related chemokine, KC. Conclusions: These results suggest that CCR2 is important in host protection to periapical osteolysis. (J Endod 2010;36:244-250)CNPqConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPES