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1.
Anticancer Res ; 39(11): 6403-6412, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704874

RESUMO

BACKGROUND: Cytokines, metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) take part in many processes involved in tumor progression and invasion such as degradation of the extracellular matrix, influence on immune cells associated with tumor tissue, and angiogenesis. Thus, the aim of this study was to compare the concentration of plasma levels and tissue expression of macrophage colony-stimulating factor (M-CSF), vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP)-2 and MMP9, and their tissue inhibitors TIMP1 and TIMP2 in patients with cervical cancer, patients with high-grade cervical intraepithelial dysplasia (CIN3) and patients with ectropion. PATIENTS AND METHODS: Concentration and expression of all tested parameters was measured in serum with enzyme-linked immunosorbent assay (ELISA) and in tissue with immunohistochemistry method. RESULTS: The epithelial expression of M-CSF and TIMP1 in cancer tissue was much stronger as compared to that in ectropion and CIN3. In the case of MMP2, lack of or weak expression in epithelial cells was observed in all tested groups. Our studies showed statistical differences of tested parameters in tissue expression and in plasma concentrations in patients with cervical cancer, patients with CIN3 and patients with ectropion. Moreover, data revealed positive correlation between plasma level and cervical cancer cell expression of VEGF. CONCLUSION: Our findings indicate a potential role of all the proteins tested here in cervical cancer diagnosis, especially VEGF. However, further studies will show whether they play a role in the progression of cancerous changes in epithelial tissue of the cervix.


Assuntos
Fator Estimulador de Colônias de Macrófagos/análise , Metaloproteases/análise , Inibidores Teciduais de Metaloproteinases/análise , Displasia do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/química , Fator A de Crescimento do Endotélio Vascular/análise , Adenocarcinoma/sangue , Adenocarcinoma/química , Adulto , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/química , Citocinas/análise , Citocinas/sangue , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/sangue , Metaloproteinase 2 da Matriz/análise , Metaloproteinase 2 da Matriz/sangue , Metaloproteinase 9 da Matriz/análise , Metaloproteinase 9 da Matriz/sangue , Metaloproteases/sangue , Pessoa de Meia-Idade , Inibidor Tecidual de Metaloproteinase-1/análise , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/análise , Inibidor Tecidual de Metaloproteinase-2/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Displasia do Colo do Útero/sangue , Neoplasias do Colo do Útero/sangue , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto Jovem
2.
Virchows Arch ; 474(3): 375-381, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30580386

RESUMO

Macrophage colony stimulating factor and IL-34 are associated with clinical vestibular schwannoma progression. Investigating the biology behind vestibular schwannoma progression helps understanding tumor growth. Inflammation is important in the microenvironment of neoplasms. Macrophages are major players in the intratumoral infiltrate. These tumor-associated macrophages are known to stimulate angiogenesis and cell growth. M-CSF and IL-34 are cytokines that can regulate tumor-infiltrating macrophages. They are expressed by tumors and form potential targets for therapy. The goal of this study was to investigate these cytokines in vestibular schwannomas and to see if their expression is related to angiogenesis, macrophage numbers, cystic degeneration, and volumetric tumor progression. Immunohistochemical expression of M-CSF and IL-34 was analyzed in ten fast-growing vestibular schwannomas and in ten slow-growing vestibular schwannomas. Expression M-CSF and IL-34 were compared between fast- versus slow-growing and cystic versus non-cystic tumors. Data on macrophage numbers and microvessel density, known from earlier research, was also included. All tumors expressed M-CSF and its expression was higher in fast-growing tumors (p = 0.003) and in cystic tumors (p = 0.035). CD163 expression was higher in tumors with strong M-CSF expression (p = 0.003). All tumors expressed IL-34 as well, but no significant differences were found in relation to clinicopathological characteristics. This study demonstrated the expression of M-CSF and IL-34 in vestibular schwannomas. The results suggest that M-CSF is related to macrophage activity and tumor progression, making it a potential target for therapy. If a similar assumption can be made for IL-34 remains unclear.


Assuntos
Biomarcadores Tumorais/análise , Proliferação de Células , Interleucinas/análise , Fator Estimulador de Colônias de Macrófagos/análise , Neuroma Acústico/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/química , Macrófagos/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica , Neuroma Acústico/diagnóstico por imagem , Neuroma Acústico/patologia , Estudos Retrospectivos , Fatores de Tempo , Carga Tumoral
3.
Int J Mol Sci ; 19(3)2018 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-29562615

RESUMO

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.


Assuntos
Neoplasias Pulmonares/imunologia , Macrófagos Alveolares/imunologia , Sarcoidose Pulmonar/imunologia , Escleroderma Sistêmico/imunologia , Idoso , Antígenos CD/análise , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Humanos , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos Alveolares/química , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células
4.
J Periodontol ; 88(12): 1339-1347, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28753101

RESUMO

BACKGROUND: Host inflammatory and immune responses play an important role in aggressive periodontitis (AgP). Thus, this study aims to evaluate levels of the innate immunity-related markers calprotectin, colony-stimulating factor (CSF)-1, macrophage migration inhibitory factor (MIF), monokine induced by interferon-γ (MIG), and matrix metalloproteinase (MMP)-8 in serum and saliva from patients with generalized AgP and those with gingivitis or a healthy periodontium. METHODS: This study enrolled 40 individuals (17 males and 23 females; mean age 33.30 ± 9.31 years), 15 with generalized AgP, 15 with gingivitis, and 10 who were periodontally healthy. Full-mouth periodontal examinations were performed, and serum and saliva were collected. Levels of calprotectin, CSF-1, MIF, MIG, and MMP-8 were measured using enzyme-linked immunosorbent assays. RESULTS: In serum, mean levels of calprotectin were 2.06-fold higher in patients with AgP than in healthy patients (P = 0.01). Serum levels of MMP-8 were significantly elevated in patients with AgP compared with both healthy patients and those with gingivitis, by 2.60-fold and 2.77-fold, respectively (P = 0.03 and P = 0.009, respectively). In saliva, levels of MMP-8 were 5.66-fold higher in patients with AgP than in healthy patients (P = 0.02). CSF-1, MIF, and MIG levels in both serum and saliva did not differ significantly among the groups. CONCLUSIONS: Serum levels of calprotectin and MMP-8 are elevated in patients with AgP. MMP-8 levels are also increased in saliva from patients with AgP. These results support involvement of innate immune response in the pathogenesis of AgP.


Assuntos
Periodontite Agressiva/imunologia , Imunidade Inata , Saliva/química , Adulto , Periodontite Agressiva/sangue , Periodontite Agressiva/metabolismo , Biomarcadores/análise , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CXCL9/análise , Quimiocina CXCL9/sangue , Feminino , Humanos , Complexo Antígeno L1 Leucocitário/análise , Complexo Antígeno L1 Leucocitário/sangue , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/sangue , Fatores Inibidores da Migração de Macrófagos/análise , Fatores Inibidores da Migração de Macrófagos/sangue , Masculino , Metaloproteinase 8 da Matriz/análise , Metaloproteinase 8 da Matriz/sangue , Pessoa de Meia-Idade , Adulto Jovem
5.
Zhonghua Zhong Liu Za Zhi ; 39(6): 412-418, 2017 Jun 23.
Artigo em Chinês | MEDLINE | ID: mdl-28635229

RESUMO

Objective: To investigate the key cytokine which polarizes M2 macrophages and promotes invasion and metastasis in non-small cell lung cancer (NSCLC). Methods: After co-culture with A549 cells in vitro, the proportion of CD14(+) CD163(+) M2 macrophages in monocytes and macrophage colony stimulating factor (M-CSF) levels in culture supernatant were detected by flow cytometry, ELISA assay and real-time qPCR, respectively. The effects of CD14(+) CD163(+) M2 macrophages on invasion of A549 cells and angiogenesis of HUVEC cells were measured by transwell assay and tubule formation assay, respectively. The clinical and prognostic significance of M-CSF expression in NSCLC was further analyzed. Results: The percentage of CD14(+) CD163(+) M2 macrophages in monocytes and the concentration of M-CSF in the supernatant followed by co-culture was (12.03±0.46)% and (299.80±73.76)pg/ml, respectively, which were significantly higher than those in control group [(2.80±1.04)% and (43.07±11.22)pg/ml, respectively, P< 0.05]. Human recombinant M-CSF promoted M2 polarization of macrophages in vitro. M2 macrophages enhanced the invasion of A549 cells (66 cells/field vs. 26 cells/field) and the angiogenesis of HUVEC cells (22 tubes/field vs. 8 tubes/field). The mRNA expression of M-CSF in stage Ⅰ-Ⅱ patients (16.23±4.83) was significantly lower than that in stage Ⅲ-Ⅳ (53.84±16.08; P<0.05). M-CSF levels were associated with poorer overall survival and disease-free survival in NSCLC patients (P<0.05). Conclusions: Tumor-derived M-CSF can induce CD14(+) CD163(+) M2 polarization of macrophages, which can further promote the metastasis and angiogenesis of NSCLC. M-CSF could be used as a potential therapeutic target of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Polaridade Celular , Neoplasias Pulmonares/patologia , Fator Estimulador de Colônias de Macrófagos/fisiologia , Macrófagos/fisiologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Células Cultivadas , Técnicas de Cocultura , Meios de Cultura/análise , Intervalo Livre de Doença , Citometria de Fluxo , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/patologia , Monócitos/patologia , Invasividade Neoplásica , Neovascularização Patológica
6.
Braz. j. pharm. sci ; 52(3): 375-382, July-Sept. 2016. tab, graf
Artigo em Inglês | LILACS | ID: biblio-828262

RESUMO

ABSTRACT It is well established that protein malnutrition (PM) impairs immune defenses and increases susceptibility to infection. Macrophages are cells that play a central role in innate immunity, constituting one of the first barriers against infections. Macrophages produce several soluble factors, including cytokines and growth factors, important to the immune response. Among those growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). GM-CSF and M-CSF are important to monocyte and macrophage development and stimulation of the immune response process. Knowing the importance of GM-CSF and M-CSF, we sought to investigate the influence of PM on macrophage production of these growth factors. Two-month-old male BALB/c mice were subjected to PM with a low-protein diet (2%) and compared to a control diet (12%) mouse group. Nutritional status, hemogram and the number of peritoneal cells were evaluated. Additionally, peritoneal macrophages were cultured and the production of GM-CSF and M-CSF and mRNA expression were evaluated. To determine if PM altered macrophage production of GM-CSF and M-CSF, they were stimulated with TNF-α. The PM animals had anemia, leukopenia and a reduced number of peritoneal cells. The production of M-CSF was not different between groups; however, cells from PM animals, stimulated with or without TNF-α, presented reduced capability to produce GM-CSF. These data imply that PM interferes with the production of GM-CSF, and consequently would affect the production and maturation of hematopoietic cells and the immune response.


Assuntos
Ratos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/análise
7.
Cardiovasc Pathol ; 25(4): 284-292, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27135205

RESUMO

Evidence suggests that macrophage colony-stimulating factor (M-CSF) participates critically in atherosclerosis; little is known about the role of M-CSF in the development of neointimal hyperplasia following mechanical vascular injury. We examined the expression of M-CSF and its receptor, c-fms, in rodent and rabbit models of arterial injury. Injured rat carotid arteries expressed 3- to 10-fold higher levels of M-CSF and c-fms mRNA and protein following balloon injury as compared to uninjured arteries. In the rabbit, M-CSF protein expression was greatest in neointimal smooth muscle cells (SMCs) postinjury, with some expression in medial SMCs. M-CSF-positive SMCs exhibited markers of proliferation. At 30days postinjury, neointimal SMCs in the adjacent healed area near the border between injured and uninjured zone lost both proliferative activity and overexpression of M-CSF. The presence of induced M-CSF and c-fms expression correlated with the initiation of SMCs proliferation. M-CSF stimulated incorporation of [(3)H] thymidine in human aortic smooth muscle cells in a concentration-dependent manner. Serum-free conditioned medium from aortic SMCs also promoted DNA synthesis, and this effect was blocked by M-CSF specific antibody. To test further the role of M-CSF in vivo, we induced arterial injury by placing a periadventitial collar around the carotid arteries in compound mutant mice lacking apolipoprotein apoE (apoE(-/-)) and M-CSF. Loss of M-CSF abolished the neointimal hyperplastic response to arterial injury in apoE(-/-) mice. Local delivery of M-CSF to the injured artery restored neointimal proliferation, suggesting a critical role of M-CSF for the development of neointimal thickening following arterial injury.


Assuntos
Lesões das Artérias Carótidas/patologia , Fator Estimulador de Colônias de Macrófagos/biossíntese , Neointima/patologia , Animais , Lesões das Artérias Carótidas/metabolismo , Modelos Animais de Doenças , Immunoblotting , Fator Estimulador de Colônias de Macrófagos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Neointima/metabolismo , Coelhos , Ratos , Ratos Sprague-Dawley
8.
Int J Mol Sci ; 17(4)2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27110777

RESUMO

Heparin has been proven to enhance bone resorption and induce bone loss. Since osteoclasts play a pivotal role in bone resorption, the effect of heparin on osteoclastogenesis needs to be clarified. Since osteocytes are the key modulator during osteoclastogenesis, we evaluated heparin's effect on osteoclastogenesis in vitro by co-culturing an osteocyte cell line (MLO-Y4) and pre-osteoclasts (RAW264.7). In this co-culture system, heparin enhanced osteoclastogenesis and osteoclastic bone resorption while having no influence on the production of RANKL (receptor activator of NFκB ligand), M-CSF (macrophage colony-stimulating factor), and OPG (osteoprotegerin), which are three main regulatory factors derived from osteocytes. According to previous studies, heparin could bind specifically to OPG and inhibit its activity, so we hypothesized that this might be a possible mechanism of heparin activity. To test this hypothesis, osteoclastogenesis was induced using recombinant RANKL or MLO-Y4 supernatant. We found that heparin has no effect on RANKL-induced osteoclastogenesis (contains no OPG). However, after incubation with OPG, the capacity of MLO-Y4 supernatant for supporting osteoclast formation was increased. This effect disappeared after OPG was neutralized and reappeared after OPG was replenished. These results strongly suggest that heparin promotes osteocyte-modulated osteoclastogenesis in vitro, at least partially, through inhibiting OPG activity.


Assuntos
Heparina/farmacologia , Osteogênese/efeitos dos fármacos , Osteoprotegerina/metabolismo , Animais , Linhagem Celular , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Fibrinolíticos/farmacologia , Heparina/química , Heparina/metabolismo , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Osteoprotegerina/análise , Ligação Proteica/efeitos dos fármacos , Ligante RANK/análise , Ligante RANK/genética , Ligante RANK/metabolismo , Células RAW 264.7 , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia
9.
J Dent Res ; 95(3): 319-26, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26553885

RESUMO

The importance of osteoclast-mediated bone resorption in the process of osseointegration has not been widely considered. In this study, cell culture was used to investigate the hypothesis that the function of implant-adherent bone marrow stromal cells (BMSCs) in osteoclastogenesis is influenced by surface topography. BMSCs isolated from femur and tibia of Sprague-Dawley rats were seeded onto 3 types of titanium surfaces (smooth, micro, and nano) and a control surface (tissue culture plastic) with or without osteogenic supplements. After 3 to 14 d, conditioned medium (CM) was collected. Subsequently, rat bone marrow-derived macrophages (BMMs) were cultured in media supplemented with soluble receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) as well as BMSC CM from each of the 4 surfaces. Gene expression levels of soluble RANKL, osteoprotegerin, tumor necrosis factor α, and M-CSF in cultured BMSCs at different time points were measured by real-time polymerase chain reaction. The number of differentiated osteoclastic cells was determined after tartrate-resistant acid phosphatase staining. Analysis of variance and t test were used for statistical analysis. The expression of prominent osteoclast-promoting factors tumor necrosis factor α and M-CSF was increased by BMSCs cultured on both micro- and nanoscale titanium topographies (P < 0.01). BMSC CM contained a heat-labile factor that increased BMMs osteoclastogenesis. CM from both micro- and nanoscale surface-adherent BMSCs increased the osteoclast number (P < 0.01). Difference in surface topography altered BMSC phenotype and influenced BMM osteoclastogenesis. Local signaling by implant-adherent cells at the implant-bone interface may indirectly control osteoclastogenesis and bone accrual around endosseous implants.


Assuntos
Materiais Dentários/química , Células-Tronco Mesenquimais/fisiologia , Osteoclastos/fisiologia , Titânio/química , Fosfatase Ácida/análise , Animais , Interface Osso-Implante/patologia , Adesão Celular/fisiologia , Contagem de Células , Técnicas de Cultura de Células , Diferenciação Celular/fisiologia , Células Cultivadas , Meios de Cultivo Condicionados , Implantes Dentários , Isoenzimas/análise , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Masculino , Teste de Materiais , Nanoestruturas/química , Osteogênese/fisiologia , Osteoprotegerina/análise , Plásticos/química , Ligante RANK/análise , Ligante RANK/farmacologia , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Fosfatase Ácida Resistente a Tartarato , Fator de Necrose Tumoral alfa/análise
10.
J Dent Res ; 94(6): 821-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25762594

RESUMO

Dentin in permanent teeth rarely undergoes resorption in development, homeostasis, or aging, in contrast to bone that undergoes periodic resorption/remodeling. The authors hypothesized that cells in the mesenchymal compartment of dental pulp attenuate osteoclastogenesis. Mononucleated and adherent cells from donor-matched rat dental pulp (dental pulp cells [DPCs]) and alveolar bone (alveolar bone cells [ABCs]) were isolated and separately cocultured with primary rat splenocytes. Primary splenocytes readily aggregated and formed osteoclast-like cells in chemically defined osteoclastogenesis medium with 20 ng/mL of macrophage colony-stimulating factor (M-CSF) and 50 ng/mL of receptor activator of nuclear factor κB ligand (RANKL). Strikingly, DPCs attenuated osteoclastogenesis when cocultured with primary splenocytes, whereas ABCs slightly but significantly promoted osteoclastogenesis. DPCs yielded ~20-fold lower RANKL expression but >2-fold higher osteoprotegerin (OPG) expression than donor-matched ABCs, yielding a RANKL/OPG ratio of 41:1 (ABCs:DPCs). Vitamin D3 significantly promoted RANKL expression in ABCs and OPG in DPCs. In vivo, rat maxillary incisors were atraumatically extracted (without any tooth fractures), followed by retrograde pulpectomy to remove DPCs and immediate replantation into the extraction sockets to allow repopulation of the surgically treated root canal with periodontal and alveolar bone-derived cells. After 8 wk, multiple dentin/root resorption lacunae were present in root dentin with robust RANKL and OPG expression. There were areas of dentin resoprtion alternating with areas of osteodentin formation in root dentin surface in the observed 8 wk. These findings suggest that DPCs of the mesenchymal compartment have an innate ability to attenuate osteoclastogenesis and that this innate ability may be responsible for the absence of dentin resorption in homeostasis. Mesenchymal attenuation of dentin resorption may have implications in internal resorption in the root canal, pulp/dentin regeneration, and root resorption in orthodontic tooth movement.


Assuntos
Polpa Dentária/citologia , Dentina/fisiologia , Homeostase/fisiologia , Células-Tronco Mesenquimais/fisiologia , Reabsorção de Dente/fisiopatologia , Adulto , Processo Alveolar/citologia , Animais , Conservadores da Densidade Óssea/farmacologia , Agregação Celular/fisiologia , Técnicas de Cultura de Células , Diferenciação Celular/fisiologia , Colecalciferol/farmacologia , Técnicas de Cocultura , Cavidade Pulpar/citologia , Dentina/patologia , Dentina Secundária/anatomia & histologia , Humanos , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/farmacologia , Masculino , Osteoclastos/fisiologia , Osteoprotegerina/análise , Pulpectomia , Ligante RANK/análise , Ligante RANK/farmacologia , Ratos , Ratos Endogâmicos F344 , Ratos Sprague-Dawley , Ratos Transgênicos , Baço/citologia , Reimplante Dentário , Reabsorção de Dente/patologia
11.
J Oral Implantol ; 41(1): 10-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25699642

RESUMO

Osteoimmunology is the crosstalk between cells from the immune and skeletal systems, suggesting a role of pro-inflammatory cytokines in the stimulation of osteoclast activity. Endotoxin or bacterial challenges to inflammatory cells are directly relevant to dental implant pathologies involving bone resorption, such as osseointegration failure and peri-implantitis. While the endotoxin amount on implant devices is regulated by standards, it is unknown whether commercially available dental implants elicit different levels of adherent-endotoxin stimulated cytokines. The objective of this work is to develop a model system and evaluate endotoxin-induced expression of pro-inflammatory cytokine genes relevant to osteoclast activation on commercially available dental implants. Murine J774-A1 macrophages were cultured on Ti disks with different level of lipopolysaccharide (LPS) contamination to define the time-course of the inflammatory response to endotoxin, as evaluated by reverse transcription polymerase chain reaction analysis. The developed protocol was then used to measure adherent endotoxin on commercially available packaged and sterile dental implants in the "as-implanted" condition. Results show that tested dental implants induce variable expression of endotoxin-stimulated genes, sometimes above the level expected to promote bone resorption in vivo. Results are unaffected by the specific surface treatment; rather, they likely reflect care in cleaning and packaging protocols. In conclusion, expression of genes that enhance osteoclast activity through endotoxin stimulation of inflammatory cells is widely different on commercially available dental implants. A reappraisal of the clinical impact of adherent endotoxins on dental (and bone) implant devices is required in light of increasing knowledge on crosstalk between cells from the immune and skeletal systems.


Assuntos
Implantes Dentários , Endotoxinas/imunologia , Ataque Ácido Dentário/métodos , Animais , Reabsorção Óssea/imunologia , Linhagem Celular , Quimiocina CCL2/análise , Ciclo-Oxigenase 2/análise , Citocinas/imunologia , Corrosão Dentária/métodos , Materiais Dentários/química , Mediadores da Inflamação/imunologia , Interleucina-1/análise , Interleucina-6/análise , Lipopolissacarídeos/imunologia , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/imunologia , Camundongos , Osteoclastos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Propriedades de Superfície , Fatores de Tempo , Titânio/química , Fator de Necrose Tumoral alfa/análise
12.
J Dent Res ; 94(2): 362-70, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25503900

RESUMO

Clinical studies have shown that metabolic syndrome (MetS) is associated with increased risk of developing periodontitis. However, the underlying mechanisms remain largely unknown. Since it is known that lipopolysaccharide (LPS)-activated toll-like receptor 4 signaling pathways play a crucial role in periodontitis, we hypothesized that MetS enhances LPS-induced periodontal inflammation and alveolar bone loss. In this study, we induced MetS in C57BL/6 mice by feeding them high-fat diet (HFD), and we induced periodontitis by periodontal injection of Aggregatibacter actinomycetemcomitans LPS. We found that mice fed a HFD had significantly increased body weight, plasma lipids, insulin, and insulin resistance when compared with mice fed regular chow, indicating that the mice developed MetS. We also found that a HFD markedly increased LPS-induced alveolar bone loss, osteoclastogenesis, and inflammatory infiltration. Analysis of gene expression in periodontal tissue revealed that HFD and LPS injection cooperatively stimulated expression of cytokines that are known to be involved in periodontal tissue inflammation and osteoclastogenesis-such as interleukin 6, monocyte-chemotactic protein 1, receptor activator of nuclear factor kappa-B ligand, and macrophage colony-stimulating factor. To further understand the potential mechanisms involved in MetS-boosted tissue inflammation, our in vitro studies showed that palmitic acid-the most abundant saturated fatty acid (SFA) and the major SFA in the HFD used in our animal study-potently enhanced LPS-induced proinflammatory gene expression in macrophages. In sum, this study demonstrated that MetS was associated with increased periodontal inflammation and alveolar bone loss in an LPS-induced periodontitis animal model. This study also suggests that SFA palmitic acid may play an important role in MetS-associated periodontitis by enhancing LPS-induced expression of inflammatory cytokines in macrophages.


Assuntos
Perda do Osso Alveolar/fisiopatologia , Síndrome Metabólica/fisiopatologia , Periodontite/fisiopatologia , Aggregatibacter actinomycetemcomitans/fisiologia , Perda do Osso Alveolar/microbiologia , Animais , Quimiocina CCL2/análise , Citocinas/análise , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/etiologia , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Inflamação , Resistência à Insulina/fisiologia , Interleucina-6/análise , Lipopolissacarídeos/efeitos adversos , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Obesidade/sangue , Obesidade/etiologia , Osteoclastos/fisiologia , Ácido Palmítico/farmacologia , Periodontite/microbiologia , Ligante RANK/análise
13.
Med Mol Morphol ; 48(3): 169-76, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25547245

RESUMO

Tumor necrosis factor-α (TNF-α) directly and indirectly plays a crucial role in osteoclastogenesis. However, the indirect effects of TNF-α on colony-stimulating factor-1 receptor (CSF-1R)-mediated osteoclastogenesis achieved via periodontal ligament (PDL) cells are not fully understood. We herein examined the potency of osteoclast differentiation and maturation induced by fivefold supernatants in the stimulated human PDL cells with a physiologically high concentration (10 ng/mL) of recombinant TNF-α to human peripheral blood monocytes/macrophages in the simultaneous presence of the receptor activator of nuclear factor kappa-B ligand. The number of tartrate-resistant acid phosphatase-positive cells with multiple nuclei, but not those with a single nucleus, was decreased by approximately 50% by neutralization with rabbit IgG against either interleukin-34 (IL-34) or CSF-1. Small and large amounts of IL34 and CSF1 transcripts were measured in the stimulated PDL cells using real-time polymerase chain reaction. The corresponding amounts of proteins to IL34 and CSF1 transcripts were observed in the stimulated PDL cells on immunohistochemical staining or Western blotting. Moreover, 0.13 ng/mL of IL-34 and 5.0 ng/mL of CSF-1 were measured in the supernatants of the stimulated PDL cells using an enzyme-linked immunosorbent assay. IL-34 derived from the stimulated PDL cells with TNF-α appeared to synergistically function with CSF-1 in the CSF-1R-mediated maturation of osteoclastogenesis.


Assuntos
Diferenciação Celular , Interleucinas/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Ligamento Periodontal/citologia , Fator de Necrose Tumoral alfa/fisiologia , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucinas/análise , Interleucinas/genética , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/genética , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estimulação Química
14.
PLoS One ; 9(10): e108920, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25302610

RESUMO

Increased marrow medullary adipogenesis and an associated decrease in bone mineral density, usually observed in elderly individuals, is a common characteristic in senile osteoporosis. In this study we investigated whether cells of the medullary adipocyte lineage have the potential to directly support the formation of osteoclasts, whose activity in bone leads to bone degradation. An in vitro mesenchymal stem cell (MSC)-derived medullary adipocyte lineage culture model was used to study the expression of the important osteoclast mediators RANKL, M-CSF, SDF-1, and OPG. We further assessed whether adipocytes at a specific developmental stage were capable of supporting osteoclast-like cell formation in culture. In vitro MSC-derived medullary adipocytes showed an mRNA and protein expression profile of M-CSF, RANKL, and OPG that was dependent on its developmental/metabolic stage. Furthermore, RANKL expression was observed in MSC-derived adipocytes that were at a distinct lineage stage and these cells were also capable of supporting osteoclast-like cell formation in co-cultures with peripheral blood mononuclear cells. These results suggest a connection between medullary adipocytes and osteoclast formation in vivo and may have major significance in regards to the mechanisms of decreased bone density in senile osteoporosis.


Assuntos
Adipócitos/citologia , Células da Medula Óssea/citologia , Células-Tronco Mesenquimais/citologia , Osteoclastos/citologia , Adipócitos/metabolismo , Adipogenia , Células da Medula Óssea/metabolismo , Células Cultivadas , Quimiocina CXCL12/análise , Quimiocina CXCL12/genética , Técnicas de Cocultura , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/genética , Células-Tronco Mesenquimais/metabolismo , Osteoclastos/metabolismo , Osteoprotegerina/análise , Osteoprotegerina/genética , Ligante RANK/análise , Ligante RANK/genética , RNA Mensageiro/análise , RNA Mensageiro/genética
15.
Cancer Prev Res (Phila) ; 7(9): 896-905, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24950779

RESUMO

We hypothesized that (i) preclinical biologic evidence exists for the role of androgens in ovarian cancer development and (ii) flutamide treatment of women at high risk for ovarian cancer may identify meaningful tissue biomarkers of androgen action and of ovarian cancer initiation. We showed that androgen ablation of male mice led to a 24-fold decrease in tumor burden from serous ovarian cells. In a phase II study, we studied the effect of preoperative flutamide treatment (125 mg/day × 6 weeks) in 12 women versus 47 controls, 47% with BRCA mutation. We analyzed immunohistochemical scores of candidate proteins CSF-1, CSF-1R, and ErbB4 in the epithelium and stroma of fallopian tube, ovary, and ovarian endosalpingiosis. Flutamide decreased the levels, notably, of CSF-1 and ErbB4 in ovarian stroma (P ≤ 0.0006) and ovarian endosalpingiosis (P ≤ 0.01), ErbB4 in ovarian epithelium (P = 0.006), and CSF-1R in ovarian endosalpingiosis (P = 0.009). Our logistic regression model clearly distinguished the flutamide patients from controls (P ≤ 0.0001). Our analysis of the precision of this model of CSF-1 and ErbB4 expression in ovarian stroma achieved 100% sensitivity and 97% specificity (AUC = 0.99). Thus, our data suggest that a short 6-week exposure of flutamide reversed elevated levels of CSF-1 and ErbB4 (both of which we had previously found correlated with high risk status). CSF-1 and ErbB4 in ovarian stroma led to a model with high predictive value for flutamide sensitivity. The effect of flutamide on marker expression in ovarian endosalpingiosis, previously associated with BRCA carrier status, suggests that ovarian endosalpingiosis may be a latent precursor to pelvic serous cancers.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Biomarcadores Tumorais/análise , Flutamida/uso terapêutico , Neoplasias Ovarianas/prevenção & controle , Adulto , Animais , Antineoplásicos Hormonais/uso terapêutico , Área Sob a Curva , Ensaio de Imunoadsorção Enzimática , Neoplasias das Tubas Uterinas/metabolismo , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/prevenção & controle , Tubas Uterinas/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/biossíntese , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovariectomia , Ovário/metabolismo , Curva ROC , Receptor ErbB-4/análise , Receptor ErbB-4/biossíntese , Fatores de Risco , Salpingectomia
16.
J Oral Facial Pain Headache ; 28(1): 68-79, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24482790

RESUMO

AIMS: To investigate the changes in condylar cartilage and subchondral bone of the temporomandibular joint (TMJ) in a mouse model of incisor malocclusion. METHODS: By bonding a single (single group) or a pair (pair group) of metal tube(s) to the left incisor(s), a crossbite-like relationship was created between left-side incisors in mice. The morphological changes in the TMJ condyles were examined by hematoxylin and eosin and toluidine blue staining. Indices of osteoclastic activity, including tartrate-resistant acid phosphatase (TRAP) staining and macrophage colony stimulating factor (M-CSF) were investigated by histochemistry or real-time polymerase chain reaction (PCR). The osteoblastic activity was indexed by osteocalcin expression. Expressions of semaphorin 4D and its receptor, Plexin-B1, were detected by real-time PCR. Two-way analysis of variance was used to assess the differences between groups. RESULTS: One week and 3 weeks after bonding the metal tube(s), cartilage degradation and subchondral bone loss were evident histologically. Both indices of osteoclastic activity (TRAP and M-CSF) were significantly increased in cartilage and subchondral bone after bonding the metal tube(s). Osteocalcin expression in cartilage was significantly increased at week 3, while its expression in subchondral bone was significantly increased at week 1 but decreased at week 3. The semaphorin 4D expression in cartilage and subchondral bone was significantly decreased at week 1 but significantly increased at week 3. For Plexin-B1 expression, a significant increase was detected in subchondral bone at week 3. CONCLUSION: Bonding a single or a pair of metal tube(s) to left incisor(s) is capable of inducing remodeling in the TMJ, which involved cartilage degradation and alteration of osteoclastic and osteoblastic activity.


Assuntos
Antígenos CD/análise , Antígenos de Diferenciação de Linfócitos T/análise , Cartilagem Articular/patologia , Incisivo/patologia , Má Oclusão/patologia , Côndilo Mandibular/patologia , Proteínas do Tecido Nervoso/análise , Receptores de Superfície Celular/análise , Semaforinas/análise , Articulação Temporomandibular/patologia , Fosfatase Ácida/análise , Animais , Remodelação Óssea/fisiologia , Reabsorção Óssea/patologia , Condrócitos/patologia , Corantes , Modelos Animais de Doenças , Corantes Fluorescentes , Isoenzimas/análise , Fator Estimulador de Colônias de Macrófagos/análise , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/patologia , Osteocalcina/análise , Osteoclastos/patologia , Fosfatase Ácida Resistente a Tartarato
17.
J Endod ; 40(3): 372-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24565655

RESUMO

INTRODUCTION: Previous studies have revealed that orthodontic force affects dental pulp via the rupture of blood vessels and vacuolization of pulp tissues. We hypothesized that pulp tissues express inflammatory cytokines and regulators of odontoclast differentiation after excess orthodontic force. The purpose of this study was to investigate the effects of tensile force in human pulp cells and to measure inflammatory root resorption during tooth movement in pulpless rat teeth. METHODS: After cyclic tensile force application in human pulp cells, gene expression and protein concentration of macrophage colony-stimulating factor, receptor activator of nuclear factor kappa-B ligand, interleukin-1 beta, and tumor necrosis factor alpha were determined by real-time polymerase chain reaction and enzyme-linked immunoassay. Moreover, the role of the stretch-activated channel was evaluated by gadolinium (Gd(3+)) treatment. The upper right first molars of 7-week Wistar rats were subjected to pulpectomy and root canal filling followed by mesial movement for 6 months. RESULTS: The expression of cytokine messenger RNAs and proteins in the experimental group peaked with loading at 10-kPa tensile force after 48 hours (P < .01). Gd(3+) reduced the expression of these cytokine messenger RNAs and protein concentrations (P < .01). The amount of inflammatory root resorption was significantly larger in the control teeth than the pulpectomized teeth (P < .05). CONCLUSIONS: This study shows that tensile forces in the pulp cells enhance the expression of various cytokines via the S-A channel, which may lead to inflammatory root resorption during tooth movement. It also suggests that root canal treatment is effective for progressive severe inflammatory root resorption during tooth movement.


Assuntos
Polpa Dentária/citologia , Pulpectomia/métodos , Reabsorção da Raiz/etiologia , Técnicas de Movimentação Dentária/métodos , Adolescente , Adulto , Animais , Fenômenos Biomecânicos , Técnicas de Cultura de Células , Células Cultivadas , Polpa Dentária/fisiologia , Gadolínio/farmacologia , Humanos , Interleucina-1beta/análise , Canais de Potássio Ativados por Cálcio de Condutância Alta/análise , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Fator Estimulador de Colônias de Macrófagos/análise , Mecanotransdução Celular/fisiologia , Dente Molar/fisiopatologia , Ligante RANK/análise , Ratos , Ratos Wistar , Estresse Mecânico , Fatores de Tempo , Dente não Vital/fisiopatologia , Fator de Necrose Tumoral alfa/análise , Adulto Jovem
18.
Mod Pathol ; 27(4): 631-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24263966

RESUMO

The pattern of myometrial invasion in endometrioid endometrial carcinomas varies considerably; ie, from widely scattered glands and cell nests, often associated with a fibromyxoid stromal reaction (desmoplasia) and/or a lymphocytic infiltrate, to invasive glands with little or no stromal response. Recently, two distinct stromal signatures derived from a macrophage response (colony-stimulating factor 1, CSF1) and a fibroblastic response (desmoid-type fibromatosis, DTF) were identified in breast carcinomas and correlated with clinicopathologic features including outcome. In this study, we explored whether these stromal signatures also apply to endometrioid carcinomas and how their expression patterns correlated with morphologic changes. We studied the stromal signatures both by immunohistochemistry and in situ hybridization in 98 primary endometrioid carcinomas with (87 cases) and without (11 cases) myometrial invasion as well as in the corresponding regional lymph nodes metatases of 9 myoinvasive tumors. Desmoplasia correlated positively with the DTF expression signature. Likewise, mononuclear infiltrates were found in the stroma of tumors expressing CSF1. Twenty-four out of eighty-seven (27%) myoinvasive endometrioid carcinomas were positive for the macrophage signature and thirteen out of eighty-seven (15%) expressed the fibroblast signature. Eleven additional cases were positive for both DTF and CSF1 signatures (11/87; 13%). However, over half of the cases (39/87; 45%) and the majority of the non-myoinvasive tumors (8/11; 73%) failed to express any of the two stromal signatures. The macrophage response (CSF1) was associated with higher tumor grade, lymphovascular invasion, and PIK3CA mutations (P<0.05). There was a concordance in the expression of the CSF1 signature in the primary tumors and their corresponding lymph node metastases. This study is the first characterization of stromal signatures in endometrioid carcinomas. Our findings shed new light on the relationship between genetically different endometrioid carcinomas and various stromal responses. Preservation of the CSF1 macrophage stromal response in the metastases leds support to targeting the CSF1 pathway in endometrioid endometrial carcinomas.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Endometrioide/química , Neoplasias do Endométrio/química , Fibroblastos/química , Macrófagos/química , Células Estromais/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/secundário , Classe I de Fosfatidilinositol 3-Quinases , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Fibroblastos/patologia , Humanos , Imuno-Histoquímica , Hibridização In Situ , Fator Estimulador de Colônias de Macrófagos/análise , Macrófagos/patologia , Pessoa de Meia-Idade , Mutação , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Valor Preditivo dos Testes , Células Estromais/patologia , Microambiente Tumoral
19.
BMC Complement Altern Med ; 13: 217, 2013 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-24007208

RESUMO

BACKGROUND: Labisia Pumila var. alata (LPva) has shown potential as an alternative to estrogen replacement therapy (ERT) in prevention of estrogen-deficient osteoporosis. In earlier studies using postmenopausal model, LPva was able to reverse the ovariectomy-induced changes in biochemical markers, bone calcium, bone histomorphometric parameters and biomechanical strength. The mechanism behind these protective effects is unclear but LPva may have regulated factors that regulate bone remodeling. The aim of this study is to determine the bone-protective mechanism of LPva by measuring the expressions of several factors involved in bone formative and resorptive activities namely Osteoprotegerin (OPG), Receptor Activator of Nuclear Factor kappa-B Ligand (RANKL), Macrophage-Colony Stimulating Factor (MCSF) and Bone Morphogenetic Protein-2 (BMP-2). METHODS: Thirty-two female Wistar rats were randomly divided into four groups: Sham-operated (Sham), ovariectomized control (OVXC), ovariectomized with Labisia pumila var. alata (LPva) and ovariectomized with ERT (Premarin) (ERT). The LPva and ERT were administered via daily oral gavages at doses of 17.5 mg/kg and 64.5 µg/kg, respectively. Following two months of treatment, the rats were euthanized and the gene expressions of BMP-2, OPG, RANKL and MCSF in the femoral bones were measured using a branch - DNA technique. RESULTS: The RANKL gene expression was increased while the OPG and BMP-2 gene expressions were reduced in the OVXC group compared to the SHAM group. There were no significant changes in the MCSF gene expressions among the groups. Treatment with either LPva or ERT was able to prevent these ovariectomy-induced changes in the gene expressions in ovariectomized rats with similar efficacy. CONCLUSION: LPva may protect bone against estrogen deficiency-induced changes by regulating the RANKL, OPG and BMP-2 gene expressions.


Assuntos
Expressão Gênica/efeitos dos fármacos , Osteoporose Pós-Menopausa/metabolismo , Extratos Vegetais/farmacologia , Primulaceae/química , Análise de Variância , Animais , Proteína Morfogenética Óssea 2/análise , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Osteoprotegerina/análise , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ovariectomia , Ligante RANK/análise , Ligante RANK/genética , Ligante RANK/metabolismo , Ratos , Ratos Wistar
20.
Int J Mol Med ; 31(4): 874-80, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23443487

RESUMO

Macrophage colony-stimulating factor (M-CSF) is essential for differentiation from hematopoietic precursor cells into osteoclasts. M-CSF transiently increased the intracellular level of reactive oxygen species (ROS) through an NADPH oxidase (Nox) and induced the expression of receptor for activation of nuclear factor-κB (RANK) in early-stage osteoclast precursor cells (c-fms+RANK-). Blocking of the activity of Nox with diphenylene iodonium inhibited ROS production, activation of extracellular signal-regulated kinase (ERK), and the expression of RANK, PU.1 and MITF. The suppression of Nox2, but not Nox1, expression by RNA interference inhibited ROS production and RANK expression. These results suggested that ROS produced in response to M-CSF via a process mediated by Nox2 acted as an intracellular signaling mediator for RANK expression through the activation of ERK and the expression of PU.1 and MITF in early-stage osteoclast precursor cells.


Assuntos
Diferenciação Celular/fisiologia , Fator Estimulador de Colônias de Macrófagos/metabolismo , Osteoclastos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Inibidores Enzimáticos/farmacologia , Feminino , Flavonoides/farmacologia , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/genética , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Oniocompostos/farmacologia , Ratos , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/análise , Receptor Ativador de Fator Nuclear kappa-B/genética , Transdução de Sinais/efeitos dos fármacos
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