Abstract The assay for the carboxyterminal telopeptide of type I collagen, ICTP, has been shown to be a reliable marker in many pathological conditions but insensitive to changes in physiological bone turnover. This has induced uncertainty and confusion regarding the role of ICTP assay in the study of collagen metabolism in bones. Especially, since another assay for the carboxyterminal telopeptide of type I collagen, serum CrossLaps ELISA, sensitively follows the changes in physiological bone turnover. To find out the reasons for the discrepancy we characterized the antigenic determinant of the ICTP assay by comparing human and bovine antigens after trypsin and chymotrypsin treatments. An assay for bovine ICTP was developed contemporarily with the present study. The epitope lies on the phenylalanine rich region of two telopeptide chains. We were able to show that the region is destroyed by cathepsin K, an osteoclastic enzyme responsible for physiological bone turnover, but not by several matrix metalloproteinases (MMPs), which are important collagen degrading enzymes in pathological conditions. Cathepsin K treatment had no effect on the CrossLaps assay. The CrossLaps assay is also able to measure the MMP-derived fragments, but usually their amount is so low in serum that it is masked by the cathepsin K-derived collagen degradation. The results explain the apparent discrepancy regarding the different behaviour of ICTP and CrossLaps assays in various conditions as also verified in our study with rheumatoid arthritis patients. The ICTP assay was also found to measure only trivalently cross-linked forms of the carboxyterminal telopeptide which contains two telopeptide chains, and is therefore unable to react with divalently or histidinohydroxylysinonorleucine (HHL)-cross-linked forms of the carboxyterminal telopeptide. These forms can be measured with the SP4 (synthetic peptide 4) assay. We utilized this property in analyzing the skin samples of 18 breast cancer patients on both the irradiated and unirradiated side. The content of HHL was increased on the irradiated side, as were type I collagen synthesis and degradation. In conclusion, there are two assays for two different degradation products of the trivalently cross-linked carboxyterminal telopeptide of type I collagen, ICTP and CrossLaps, the former measuring the MMP-derived and the latter the cathepsin K-derived collagen degradation.

Indiana University-Purdue University Indianapolis (IUPUI) / Many factors are present in the development of skeletal tissue. Some factors lead to an increase in bone mass while some lead to a decrease. One factor that is known to have an influence on skeletal development is Signal Transducer and Activator of Transcription 3 (Stat3). This knowledge arose because of a mutation in the Stat3 gene in humans causing a disease called Hyper-IgE Syndrome. This mutation leads to a variety of issues, including decreased bone mass. Because of this, our lab has sought to study Stat3 in its relation to bone. Many studies have already been conducted that discern how Stat3 influences skeletal biology by observing its role in osteoclasts, osteoblasts, and other bone cells. Its role is still unclear, and many studies have provided seemingly contradictory results in how it works on bone tissue. Our lab set up several different studies in order to further elucidate what role Stat3 plays in skeletal development by looking at its effects on osteoblasts and osteoclasts, the bone-forming and bone-destroying cells of the body, respectively. We conditionally knocked out Stat3 in the osteoblasts of mice and compared several different bone parameters to their wild type counterparts at 8 weeks of age. Differences were noted in bone phenotype, including decreased femur length, weight, bone mineral density, and bone mineral content in the cKO compared to their WT counterparts. While no significant difference in trabecular integrity was noted, several differences were observed in cortical bone. These differences indicate that Stat3 has a positive role in osteoblast differentiation, leading to an overall positive effect on bone mass. To observe the role of Stat3 in osteoclasts, in vitro experiments were set up in which pre-osteoclast RAW 264.7 cells were manipulated with Stat3 siRNA or a Stat3 overexpression construct and RANKL to induce differentiation. Using qPCR and western blot assays, it was determined that when Stat3 is knocked down, several important genes in osteoclastogenesis and osteoclast function are more highly expressed than in the control groups. When Stat3 is overexpressed, a similar pattern is observed where these same genes are downregulated in the presence of higher Stat3 levels. These results indicate that Stat3 has an overall inhibitory effect on osteoclastogenesis and osteoclast function, indicating it has a positive effect on bone mass. Future studies could be performed to further elucidate the effects of Stat3 on skeletal development. Isolating the osteoblasts from cKO and WT mice and performing qPCR and western blot assays could be useful in finding out how Stat3 is influencing these cells. Further studies could also be done on the RAW 264.7 cells to find where Stat3 is interacting with the RANKL pathway. A resorption assay could be done with these cells to better understand how function might be influenced by Stat3.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that may affect many tissues and organs but principally attacks synovial joints. All the symptoms of RA are mainly caused by cell inflammation, which results in cellular infiltration and synovial hyperplasia, finally leading to severe bone erosion. Existing drugs (steroids, non-steroid antiinflammatory drugs, disease-modifying anti-rheumatic drugs, etc.) can attenuate the symptoms of RA; however, these drugs also have many side effects. Therefore, it is necessary to discover new drugs for RA. Excavatolide B (Exc-B) is derived from the gorgonian coral. In our preliminary observations, Exc-B strongly inhibited lipopolysaccharide (LPS)-induced proinflammatory inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW264.7 macrophages. The present study also showed that Exc-B significantly attenuates the expressions of osteoclast-like gene, cathepsin K, and matrix metalloproteinase (MMP)-9 in LPS-treated RAW 264.7 cells. Moreover, in the adjuvant-induced RA animal model, Exc-B effectively reduced the swelling and arthritic index from the morphological viewpoint as well as reduced bone erosion and synovial hyperplasia from the pathological viewpoint. Our data indicates that Exc-B can inhibit disease progression in RA. Hence, Exc-B may serve as a useful therapeutic agent for the treatment of RA.

O remodelamento ósseo é um processo metabólico, dentro do qual os osteoblastos e os osteoclastos, participam ativamente. Portanto, qualquer alteração neste equilíbrio, pode provocar uma modificação na densidade mineral do osso, situação observada em certas doenças osteolíticas como osteoporose, artrite reumatóide e periodontite. Nos últimos anos, há um crescente interesse em avaliar o papel da glicólise na proliferação, sobrevivência e diferenciação dos diferentes tipos celulares. Em particular, tem sido evidenciado o efeito regulador da frutose 1,6-bisfosfato (FBP), um intermediário da via glicolítica de alta energia. Considerando que ainda não existem dados na literatura que correlacionem a FBP com o funcionamento dos osteoclastos, este trabalho tem por finalidade avaliar seu papel na osteoclastogênese e reabsorção óssea in vitro. Para isso, pré-osteoclastos murinos derivados da medula óssea foram diferenciados em osteoclastos na presença de M-CSF, RANKL e duas concentrações da FBP (100 e 300 ?M). Os resultados obtidos amostram que a FBP inibe a diferenciação osteoclástica em uma relação dose-dependente, sem afetar a viabilidade celular. Observa-se também, que o tratamento com FBP diminui a expressão de genes marcadores como, Nfatc1, Trap e Catepsina K (p < 0.01) e das proteínas NFATc1 e catepsina K. Como também, promove uma redução na atividade reabsortiva dos osteoclastos depois de 96 h de cultura. O efeito inibidor da FBP não depende da atividade da piruvato quinase M2 (PKM2). Em conjunto, estes dados sugerem que a FBP é um metabolito regulador importante da osteoclastogênese, demonstrando ser um agente potencial para o tratamento de doenças osteolíticas. / Bone remodeling is a coordinated metabolic process, where the osteoblasts and osteoclasts participate actively. Therefore, any alteration in this balance may cause a change in the bone mineral density, a condition observed in certain bone loss-associated diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Recently, there has been a growing interest in assessing the role of the glycolysis on the proliferation, survival, and differentiation of the different cell types. In particular, it has been demonstrated the protective effect of the Fructose 1,6-bisphosphate (FBP), a high-energy glycolytic intermediate. Considering that there is no evidence in the literature that associate FBP with the function of osteoclasts, this work aims to evaluate its role in osteoclastogenesis and bone resorption in vitro. To this end, murine bone marrow derived pre-osteoclasts were differentiated into osteoclasts in the presence of M-CSF, RANKL and two concentrations of FBP (100 and 300 ?M). The results showed that FBP inhibits the differentiation of osteoclasts in a dose dependent manner, without affecting the cell viability. It was also observed that the treatment with the FBP decreases the expression of marker genes such as Nfatc1, Trap and Cathepsin K (p < 0.01) and the NFATc1 and cathepsin K protein levels. As well, the treatment with FBP resulted in markedly fewer osteoclast activity after 96 h of culture. FBP osteoclast inhibitory effect does not involve Pyruvate Kinase M2 (PKM2) activity. Together, these data denote the important regulatory role of the FBP on osteoclastogenesis, proving to be a potential agent for the treatment of bone loss-associated diseases.

O remodelamento ósseo é um processo metabólico, dentro do qual os osteoblastos e os osteoclastos, participam ativamente. Portanto, qualquer alteração neste equilíbrio, pode provocar uma modificação na densidade mineral do osso, situação observada em certas doenças osteolíticas como osteoporose, artrite reumatóide e periodontite. Nos últimos anos, há um crescente interesse em avaliar o papel da glicólise na proliferação, sobrevivência e diferenciação dos diferentes tipos celulares. Em particular, tem sido evidenciado o efeito regulador da frutose 1,6-bisfosfato (FBP), um intermediário da via glicolítica de alta energia. Considerando que ainda não existem dados na literatura que correlacionem a FBP com o funcionamento dos osteoclastos, este trabalho tem por finalidade avaliar seu papel na osteoclastogênese e reabsorção óssea in vitro. Para isso, pré-osteoclastos murinos derivados da medula óssea foram diferenciados em osteoclastos na presença de M-CSF, RANKL e duas concentrações da FBP (100 e 300 ?M). Os resultados obtidos amostram que a FBP inibe a diferenciação osteoclástica em uma relação dose-dependente, sem afetar a viabilidade celular. Observa-se também, que o tratamento com FBP diminui a expressão de genes marcadores como, Nfatc1, Trap e Catepsina K (p < 0.01) e das proteínas NFATc1 e catepsina K. Como também, promove uma redução na atividade reabsortiva dos osteoclastos depois de 96 h de cultura. O efeito inibidor da FBP não depende da atividade da piruvato quinase M2 (PKM2). Em conjunto, estes dados sugerem que a FBP é um metabolito regulador importante da osteoclastogênese, demonstrando ser um agente potencial para o tratamento de doenças osteolíticas. / Bone remodeling is a coordinated metabolic process, where the osteoblasts and osteoclasts participate actively. Therefore, any alteration in this balance may cause a change in the bone mineral density, a condition observed in certain bone loss-associated diseases such as osteoporosis, rheumatoid arthritis and periodontitis. Recently, there has been a growing interest in assessing the role of the glycolysis on the proliferation, survival, and differentiation of the different cell types. In particular, it has been demonstrated the protective effect of the Fructose 1,6-bisphosphate (FBP), a high-energy glycolytic intermediate. Considering that there is no evidence in the literature that associate FBP with the function of osteoclasts, this work aims to evaluate its role in osteoclastogenesis and bone resorption in vitro. To this end, murine bone marrow derived pre-osteoclasts were differentiated into osteoclasts in the presence of M-CSF, RANKL and two concentrations of FBP (100 and 300 ?M). The results showed that FBP inhibits the differentiation of osteoclasts in a dose dependent manner, without affecting the cell viability. It was also observed that the treatment with the FBP decreases the expression of marker genes such as Nfatc1, Trap and Cathepsin K (p < 0.01) and the NFATc1 and cathepsin K protein levels. As well, the treatment with FBP resulted in markedly fewer osteoclast activity after 96 h of culture. FBP osteoclast inhibitory effect does not involve Pyruvate Kinase M2 (PKM2) activity. Together, these data denote the important regulatory role of the FBP on osteoclastogenesis, proving to be a potential agent for the treatment of bone loss-associated diseases.

No description available.

No description available.

O biofilme bacteriano é o agente etiológico primário no desenvolvimento da resposta inflamatória observada na doença periodontal. Os receptores do tipo NOD (NLRs) são proteínas citosólicas que reconhecem componentes microbianos presentes no citoplasma liberados por bactérias invasoras. Sabendo que bactérias periodontopatogênicas têm a capacidade de invadir e colonizar diversas células do tecido periodontal, o presente projeto tem o objetivo de estudar a participação dos receptores do tipo NOD (NOD1 e NOD2) no reconhecimento das bactérias Porphyromonas gingivalis, na modulação da resposta imune e no processo de reabsorção óssea. Camundongos isogênicos machos da linhagem C57BL/6 (WT) e camundongos deficientes para o receptor NOD1 (NOD1-/-) e receptor NOD2 (NOD2-/-) foram infectados com Phorphyromonas gingivalis utilizando um modelo experimental de doença periodontal. O grau de reabsorção óssea foi avaliado por análise morfométrica macroscópica e histológica da maxila, além da quantificação do número de osteoclastos na crista óssea alveolar. O grau de inflamação local foi realizado por contagem do número total de bactérias orais, quantificação de neutrófilos no tecido gengival (MPO) e avaliação dos mediadores inflamatórios por ELISA. Foi também avaliada a expressão de marcadores osteogênicos e osteoclastogênicos no tecido gengival pela técnica de qPCR. Animais NOD1-/- e NOD2-/- apresentaram menor delta de reabsorção óssea quando comparados aos animais WT. Animais NOD2-/- infectados apresentaram debilitado controle bacteriano quando comparados aos animais WT infectados. Animais NOD1-/- e NOD2-/- infectados apresentaram baixa expressão de Cxcl1 e MPO quando comparados aos animais WT infectados. Além disso, foi observado que animais NOD2-/- infectados apresentaram reduzida produção de TNF-&alpha; e elevada produção de IL-10 quando comparados aos animais WT infectados. Não foi detectado diferença estatística na expressão de fatores osteogênicos, Runx2 e osteocalcina, entre animais WT, NOD1-/- e NOD2-/- infectados. Embora não houve diferença no número de células TRAP positivas presentes na crista óssea alveolar entre os grupos no tempo avaliado, animais WT infectados apresentaram elevada expressão gênica de RANKL/OPG quando comparados aos animais NOD2-/- infectados. Além disso, a expressão de marcadores de atividades dos osteoclastos, catepsina k e matrix metaloproteinase-9, foi significantemente baixa nos animais NOD1-/- e NOD2-/- infectados quando comparados aos animais WT infectados. Esses resultados permitem sugerir que independente das variáveis observadas, verificamos que a ausência dos dois receptores impede a rápida progressão da reabsorção óssea alveolar observada na periodontite, portanto os receptores NOD1 e NOD2 contribuem para progressão da reabsorção óssea no modelo experimental de periodontite. / The bacterial biofilm has been identified as an etiological agent in the pathogenesis of periodontal disease. The NOD-like receptors (NLRs) are cytoplasmic proteins that sense microbial by products released by invasive bacteria. Since periodontopathogenic bacteria are able to invade and colonize some periodontal tissue cells, the purpose of this study is to determine the role of NOD1 and NOD2 receptors in the recognition of invasive periodontopathogenic bacteria such as Porphyromonas gingivalis, modulating the immune response and bone resorption. Isogenic strain C57BL/6 males (WT), NOD1 (NOD1-/-) and NOD2 (NOD2-/-) knockout mice were infected with Porphyromonas gingivalis in an experimental model of periodontal disease. Alveolar bone resorption was evaluated by macroscopic and histological morphometric analysis, quantification of osteoclasts numbers in bone crest alveolar. Imune inflammatory response was evaluated by, bacterial load, neutrophils quantification and inflammatory mediators levels by ELISA. We also evaluated the osteogenic and osteoclastogenic markers expression in gingival tissue by Real time PCR techniques. NOD1-/- and NOD2-/- animals showed lower bone resorption when compared to WT animals. NOD2-/- infected animals expressed higher bacterial load compared to WT infected ones. NOD1-/- and NOD2-/- infected animals presented lower Cxcl1 and MPO levels compared to WT infected animals. In addition, NOD2-/- infected animals presented lower level of TNF-&alpha; and higher level of IL-10 when compared to WT infected animals. There was no significant difference in the osteogenic factors expression, Runx2 and osteocalcin, when compared NOD1-/- and NOD2-/- infected animals to WT infected ones. Although there was no difference in TRAP-positive cells number evaluated in the alveolar bone crest among the studied groups, WT infected animals showed elevated ratio RANKL/OPG when compared to NOD2-/- infected animals. Moreover, the expression of osteoclasts activity markers, cathepsin k and matrix metalloproteinase-9, was significantly lower in NOD1-/- and NOD2-/- infected animals compared to WT infected ones. These results suggest that NOD1 and NOD2 receptors contribute to progression of bone resorption in experimental model of periodontitis, since the lack of NOD like receptors impair the bone resorption.

A citocina IL-33 apresenta papel dual e está envolvida com a resolução ou progressão de inúmeras doenças, além disso, acredita-se que a via IL-33/ST2 esteja envolvida no equilíbrio entre a atividade de osteoclastos e osteoblastos. O objetivo deste estudo foi avaliar o papel do receptor ST2 no desenvolvimento e progressão de lesões periapicais experimentalmente induzidas em camundongos. Lesões periapicais foram induzidas em primeiros molares inferiores de camundongos WT e ST2 knockout (KO). Decorridos 7 e 14 dias, as amostras de mandíbula foram submetidas às análises: determinação da área de lesão periapical em cortes histológicos e do volume por microtomografia computadorizada (&mu;CT); contagem de osteoclastos submetidos ao ensaio de histoenzimologia (TRAP); expressão gênica de marcadores osteogênicos e osteoclastogênicos por q-PCR; quantificação de neutrófilos por ensaio de mieloperoxidases. Os linfonodos foram submetidos à análise da expressão dos fatores transcricionais T-bet, GATA-3, RORc e Foxp-3 por q-PCR. Análise estatística utilizada foi One-way ANOVA, seguido de pós-teste de Bonferroni. Aos 14 dias, observou-se maior extensão da lesão periapical em animais WT que em ST2KO (p<0,05). O tamanho da lesão nos animais ST2KO permaneceu igual em função do tempo. Foi observada maior quantidade de neutrófilos na lesão do grupo WT aos 7 dias, em comparação aos animais ST2KO (p<0,05). Na expressão de T-bet, GATA-3, RORc e Foxp-3 não foram observadas diferenças estatisticamente significantes. O número de osteoclastos contados nos animais ST2KO foi maior que o observado em WT aos 7dias e aos 14 dias (p<0,05). A expressão de Runx2 foi maior no grupo lesão dos animais ST2KO quando comparado a seu respectivo controle. Os outros marcadores relacionados com a formação óssea não apresentaram diferenças estatisticamente significantes. Dentre os marcadores relacionados com a reabsorção óssea, a catepsina K e o MMP-9 apresentaram maior expressão aos 14 dias, na lesão dos animais WT quando comparada à expressão na lesão dos animais ST2KO (p<0,05). Com base nos resultados obtidos no presente estudo, pode-se concluir que na ausência do receptor ST2 as lesões periapicais são menos extensas e embora em maior quantidade, os osteoclastos são menos ativos. Nossos resultados sugerem um importante papel da via IL-33/ST2 na ativação dos osteoclastos e desenvolvimento da lesão periapical. / The IL -33 cytokine presents a dual role and is involved either in the resolution and progression of many diseases. Furthermore, it is believed that this pathway is involved between osteoclast and osteoblast activity balance. The aim of this study was to evaluate the role of ST2 receptor in the development and progression of experimentally induced periapical lesions in mice. Periapical lesions were induced in first molars of WT and ST2 knockout (KO) mice. After 7 and 14 days, jaw samples were subjected to various analysis: determination of periapical lesions area by histology and volume by computed microtomography (&mu;CT); osteoclasts number by TRAP histoenzymology; osteogenic and osteoclastogenic markers expression by q-PCR; neutrophil quantification by myeloperoxidase activity. The expression of transcription factors T-bet, GATA-3, RORC and Foxp-3 in lymph nodes were analysed by q-PCR. Statistical analysis was done by One-way ANOVA and Bonferroni post-test. It was observed a greater extent in periapical lesions of WT compared to ST2KO animals at 14 days (p<0.05). There is no progression in the lesion of ST2KO mice with the time. A larger number of neutrophils in WT group was observed, compared to ST2KO mice evaluated at 7 days (p<0.05). The expression of T-bet, GATA-3, RORc and Foxp-3 were not statistically significant different among the groups. The number of osteoclasts in lesions of ST2KO animals were greater than the observed in WT, at 7 and 14 days (p<0.05). Although, other osteogenic markers showed no statistically significant difference, Runx2 expression in ST2KO was higher in lesion side compared to control side at 14 days. The markers related to bone resorption, cathepsin K and MMP-9, were significantly abrogated in the lesion side of ST2KO mice, at 14 days (p<0.05). Based on the results, it can be concluded that although larger amounts of osteoclast were counted in ST2KO, the lesion was less extensive and osteoclasts less active. It all suggests that the IL-33/ST2 pathway play an important role in osteoclasts activation and periapical lesion development.

O biofilme bacteriano é o agente etiológico primário no desenvolvimento da resposta inflamatória observada na doença periodontal. Os receptores do tipo NOD (NLRs) são proteínas citosólicas que reconhecem componentes microbianos presentes no citoplasma liberados por bactérias invasoras. Sabendo que bactérias periodontopatogênicas têm a capacidade de invadir e colonizar diversas células do tecido periodontal, o presente projeto tem o objetivo de estudar a participação dos receptores do tipo NOD (NOD1 e NOD2) no reconhecimento das bactérias Porphyromonas gingivalis, na modulação da resposta imune e no processo de reabsorção óssea. Camundongos isogênicos machos da linhagem C57BL/6 (WT) e camundongos deficientes para o receptor NOD1 (NOD1-/-) e receptor NOD2 (NOD2-/-) foram infectados com Phorphyromonas gingivalis utilizando um modelo experimental de doença periodontal. O grau de reabsorção óssea foi avaliado por análise morfométrica macroscópica e histológica da maxila, além da quantificação do número de osteoclastos na crista óssea alveolar. O grau de inflamação local foi realizado por contagem do número total de bactérias orais, quantificação de neutrófilos no tecido gengival (MPO) e avaliação dos mediadores inflamatórios por ELISA. Foi também avaliada a expressão de marcadores osteogênicos e osteoclastogênicos no tecido gengival pela técnica de qPCR. Animais NOD1-/- e NOD2-/- apresentaram menor delta de reabsorção óssea quando comparados aos animais WT. Animais NOD2-/- infectados apresentaram debilitado controle bacteriano quando comparados aos animais WT infectados. Animais NOD1-/- e NOD2-/- infectados apresentaram baixa expressão de Cxcl1 e MPO quando comparados aos animais WT infectados. Além disso, foi observado que animais NOD2-/- infectados apresentaram reduzida produção de TNF-&alpha; e elevada produção de IL-10 quando comparados aos animais WT infectados. Não foi detectado diferença estatística na expressão de fatores osteogênicos, Runx2 e osteocalcina, entre animais WT, NOD1-/- e NOD2-/- infectados. Embora não houve diferença no número de células TRAP positivas presentes na crista óssea alveolar entre os grupos no tempo avaliado, animais WT infectados apresentaram elevada expressão gênica de RANKL/OPG quando comparados aos animais NOD2-/- infectados. Além disso, a expressão de marcadores de atividades dos osteoclastos, catepsina k e matrix metaloproteinase-9, foi significantemente baixa nos animais NOD1-/- e NOD2-/- infectados quando comparados aos animais WT infectados. Esses resultados permitem sugerir que independente das variáveis observadas, verificamos que a ausência dos dois receptores impede a rápida progressão da reabsorção óssea alveolar observada na periodontite, portanto os receptores NOD1 e NOD2 contribuem para progressão da reabsorção óssea no modelo experimental de periodontite. / The bacterial biofilm has been identified as an etiological agent in the pathogenesis of periodontal disease. The NOD-like receptors (NLRs) are cytoplasmic proteins that sense microbial by products released by invasive bacteria. Since periodontopathogenic bacteria are able to invade and colonize some periodontal tissue cells, the purpose of this study is to determine the role of NOD1 and NOD2 receptors in the recognition of invasive periodontopathogenic bacteria such as Porphyromonas gingivalis, modulating the immune response and bone resorption. Isogenic strain C57BL/6 males (WT), NOD1 (NOD1-/-) and NOD2 (NOD2-/-) knockout mice were infected with Porphyromonas gingivalis in an experimental model of periodontal disease. Alveolar bone resorption was evaluated by macroscopic and histological morphometric analysis, quantification of osteoclasts numbers in bone crest alveolar. Imune inflammatory response was evaluated by, bacterial load, neutrophils quantification and inflammatory mediators levels by ELISA. We also evaluated the osteogenic and osteoclastogenic markers expression in gingival tissue by Real time PCR techniques. NOD1-/- and NOD2-/- animals showed lower bone resorption when compared to WT animals. NOD2-/- infected animals expressed higher bacterial load compared to WT infected ones. NOD1-/- and NOD2-/- infected animals presented lower Cxcl1 and MPO levels compared to WT infected animals. In addition, NOD2-/- infected animals presented lower level of TNF-&alpha; and higher level of IL-10 when compared to WT infected animals. There was no significant difference in the osteogenic factors expression, Runx2 and osteocalcin, when compared NOD1-/- and NOD2-/- infected animals to WT infected ones. Although there was no difference in TRAP-positive cells number evaluated in the alveolar bone crest among the studied groups, WT infected animals showed elevated ratio RANKL/OPG when compared to NOD2-/- infected animals. Moreover, the expression of osteoclasts activity markers, cathepsin k and matrix metalloproteinase-9, was significantly lower in NOD1-/- and NOD2-/- infected animals compared to WT infected ones. These results suggest that NOD1 and NOD2 receptors contribute to progression of bone resorption in experimental model of periodontitis, since the lack of NOD like receptors impair the bone resorption.