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1.
Braz Dent J ; 31(1): 63-68, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159708

RESUMO

The present study evaluated polymorphisms in RANK, RANKL and OPG-encoding genes to assess whether they are associated with mucositis and peri-implantitis in a population from the Brazilian Amazon region. One hundred and fourteen patients with dental implants were included in the study. After clinical and radiographic examination, the sample was categorized into 4 groups, according to the peri-implant status: Healthy (n=71), Mucositis (n=30), Peri-implantitis (n=13) and Diseased (Mucositis + Peri-implantitis, n=43). Genomic DNA was extracted from buccal cells from saliva, and the genetic polymorphism in osteoprotegerin (OPG), Kappa nuclear factor activator receptor (RANKL) and nuclear kappa factor activator receptor (RANK) were genotyped by the real time PCR. Univariate and multivariate statistical analyses were performed to compare clinical variables among groups and to evaluate genotypes and alleles distributions and the established alpha was 5%. Age, peri-implant biotype, diabetes and presence of peri-implant biofilm were associated with mucositis (p<0.05) and peri-implantitis (p<0.05). Smoking, alcoholism, and periodontal biofilms were also associated with the presence of peri-implantitis (p<0.05). Univariate and multivariate analysis did not demonstrate an association of peri-implantitis or mucositis with any genetic polymorphism in RANK (rs3826620), RANKL (rs9594738) and OPG (rs2073618) (p>0.05). The studied genetic polymorphism in RANK, RANKL and OPG were not associated with mucositis and peri-implantitis in a Brazilian population from the Amazon region.


Assuntos
Implantes Dentários , Osteoprotegerina/genética , Peri-Implantite , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Brasil , Humanos , Mucosa Bucal , Polimorfismo Genético
2.
Orthod Craniofac Res ; 23(2): 210-222, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31837114

RESUMO

OBJECTIVE: To investigate the association of genetic polymorphisms (tagSNPs type) of RANK/RANKL/OPG genes with the loss of orthodontic mini-implants (MIs). SETTING AND SAMPLE POPULATION: One hundred and thirty-five patients of both sexes, with mean age of 48.7 ± 10 (20-76 years), were studied. The control group was composed of 104 patients, with no MI lost and functioning for at least 6 months and the case group, of 31 patients with at least one MI lost. MATERIALS AND METHODS: Cells were obtained by mouthwash with 3% glucose solution for 1 minute and scraping the buccal mucosa with sterilized spatula. DNA was extracted from buccal epithelial cells with 10 M ammonium acetate and 1 mM EDTA. Genotyping was performed by the real-time polymerase chain reaction (PCR) technique. Univariate and multivariate analyses were performed (P < .05). RESULTS: No markers were associated with MI loss after Benjamini and Hochberg false discovery rate correction of Univariate tests. In the multivariate analysis, the variables that associated with MI loss were the number of MIs installed (P < .000) and the polymorphism rs8086340 in the RANK gene (P = .018). CONCLUSION: A higher number of MIs installed (P < .000) and polymorphism rs8086340 in the RANK gene (P = .018) were associated with loss of orthodontic MIs after multivariate analysis.


Assuntos
Implantes Dentários , Falha de Restauração Dentária , Osteoprotegerina , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptor Ativador de Fator Nuclear kappa-B/genética
3.
Breast Cancer Res ; 21(1): 132, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796128

RESUMO

BACKGROUND: ERBB-2 is overexpressed in about 20% of breast cancers (BCs), indicating poor prognosis. The receptor activator of nuclear factor-κB (RANK) pathway is implicated in ERBB-2 (+) BC. The purpose of this study was to elucidate the underlying molecular mechanism of this interaction and the beneficial impact of dual targeting of RANK and ERBB-2 pathways. METHODS: We used SKBR3, MCF7, MDA-MB-453, and BT-474 human BC cell lines. We examined RANK and RANKL expression using RT-PCR, Western blot, and immunofluorescence. The evaluation of RANK expression in a cohort of BC patients was performed using immunohistochemistry. The interaction between RANK and ERBB family members was detected using proximity ligation assay (PLA), which enables the visualization of interacting proteins. We used inhibitors of both pathways [trastuzumab (T), pertuzumab (P), denosumab (D)]. NF-κB pathway activation was studied using Western blot. Cell growth and viability was evaluated using XTT, flow cytometry, and clonogenic assay. For cell migration evaluation, scratch assay was performed. Data were analyzed by one-way ANOVA. RESULTS: Cell lines express RANK and RANKL. RANK immunostaining was also detected in human BC tissue samples. RANK receptor dimerizes with ERBB family members. RANK/ERBB-2 dimer number seems to be associated with ERBB-2 expression (SKBR3, 5.4; BT-474, 8.2; MCF7, 0.7; MDA-MB-453, 0.3). RANK/ERBB-2 dimers were decreased in the presence of the inhibitors D, T, and P, while they were increased after RANKL (R) treatment in SKBR3 (m, 5.4; D, 1.2; T, 1.9; DT, 0.6; TP, 1; DTP, 0.4; R, 11.8) and BT-474 (m, 8.2; D, 3.1; T, 4.3; DT, 0.7; TP, 3.4; DTP, 3.2; R, 11.6). Combination targeting of SKBR3 further decreased NF-κB pathway activation compared to single targeting. In SKBR3, RANKL and ERBB-2 blockage resulted in reduced cell proliferation, increased apoptosis, and lower metastatic potential compared to mock cells (m) and reversed values in RANKL presence. The combination treatment of SKBR3 with D, T, and P had an advantage in functional traits compared to single targeting. Denosumab suppressed NF-κB signaling and diminished proliferation rate in MDA-MB-453 cells. MCF7 did not correspond to inhibitors. CONCLUSIONS: The results indicate a novel physical and molecular association between ERBB-2 and RANK pathways that affects ERBB-2 (+) BC growth. We also present data suggesting that the combination of anti-ERBB-2 agents and RANKL inhibitors have a potential direct anti-tumor effect and should be further tested in certain BC patients.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias da Mama/metabolismo , Receptores ErbB/antagonistas & inibidores , Terapia de Alvo Molecular , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células Cultivadas , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(10): 1291-1295, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31658533

RESUMO

Objective: To explore the relationship between the tumor necrosis factor receptor superfamily members 11A (TNFRSF11A) and 11B (TNFRSF11B) gene polymorphisms and the outcome of hepatitis C virus (HCV) infection. Methods: In this case-control study, 749 cases of persistent HCV infection, 494 cases of spontaneous clearance and 1 486 control subjects were included from 2008 to 2016. TaqMan-MGB probe method was used to detect the genotype of TNFRSF11A rs1805034 and TNFRSF11B rs2073617. The genotypes distribution of the two single nucleotide polymorphisms (SNP) were analyzed in different populations. Results: Co-dominant model showed that individuals carrying the rs2073617 CC genotype were prone to have chronic HCV infection, compared with individuals carrying the rs2073617 TT genotype (OR=1.517, 95%CI: 1.055-2.181, P=0.024). Recessive model results showed that individuals carrying rs2073617 CC genotype were more likely to develop chronic HCV infection compared with individuals carrying rs2073617 TT or TC genotype (OR=1.435, 95%CI: 1.033-1.996, P=0.032). Additive model showed that the risk for chronic HCV infection increased with the increase of the number of rs2073617 C alleles (OR=1.204, 95%CI: 1.013-1.431, P=0.035). Conclusion: The genetic polymorphism of TNFRSF11B rs2073617 might be related with the chronicity of HCV infection.


Assuntos
Hepatite C Crônica/genética , Osteoprotegerina/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Estudos de Casos e Controles , Genótipo , Hepacivirus , Humanos , Polimorfismo de Nucleotídeo Único
5.
Mol Biol Rep ; 46(5): 5425-5432, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364017

RESUMO

Obesity is a complex disorder that is influenced by genetic and environmental factors. DNA methylation is an epigenetic mechanism that is involved in development of obesity and its metabolic complications. The aim of this study was to investigate the association between the RANKL and c-Fos gene methylation on obesity with body mass index (BMI), lipid parameters, homeostasis model assessment of insulin resistance (HOMA-IR), plasma leptin, adiponectin and resistin levels. The study included 68 obese and 46 non-obese subjects. Anthropometric parameters, including body weight, body mass index, waist circumference, and waist-hip ratio, were assessed. Serum glucose, triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), plasma leptin, adiponectin and resistin levels were measured. Methylation status of RANKL and c-Fos gen were evaluated by MS-HRM. Statistically significant differences were observed between obese patients and the controls with respect to RANKL and c-Fos gene methylation status (p < 0.001). Also, statistically significant importance was observed RANKL gene methylation and increased level of leptin in obese subjects (p = 0.0081). At the same time, statistically significant association between methylation of c-Fos and increased level of adiponectin was observed in obese patients (p = 0.03) On the other hand, decreased level of resistin was observed where the c-Fos was unmetyladed in controls (p = 0.01). We conclude that methylation of RANKL and c-Fos genes have significant influences on obesity and adipokine levels. Based on literature this was the first study which shows the interactions between RANKL and c-Fos methylation and obesity.


Assuntos
Epigênese Genética/genética , Regulação da Expressão Gênica/genética , Obesidade/genética , Adiponectina/análise , Adiponectina/sangue , Adulto , Antropometria , Índice de Massa Corporal , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Metilação de DNA/genética , Feminino , Genes fos/genética , Humanos , Resistência à Insulina/genética , Leptina/análise , Leptina/sangue , Masculino , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/genética , Triglicerídeos/sangue
6.
Med Sci Monit ; 25: 5961-5968, 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400110

RESUMO

BACKGROUND The aim of this study was to determine the effects of myeloma cells exposed to fluid shear stress on osteocytes and osteoclasts, and clarify the potential underlying mechanisms. MATERIAL AND METHODS A flow and a non-flow model were established using a flow fluid chamber. The myeloma cell line U266 and murine osteocytic MLO-Y4 cells were cultured in vitro. The osteocytes and osteoclasts were examined under a microscope. Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP) activity. RANKL and osteoprotegerin (OPG) gene expression were detected using reverse transcription-quantitative polymerase chain reaction. RESULTS Compared with the controls, Y4 cells cultured with U266 culture supernatant showed altered morphology, fewer osteocytes, increased RANKL gene expression, a higher RANKL/OPG gene ratio, and a greater number of TRAP-positive osteoclasts (P<0.05 for all). Compared to the no-flow model, the flow model showed a higher number of Y4 cells, increased OPG gene expression, decreased RANKL gene expression, a lower RANKL/OPG gene ratio, and fewer TRAP-positive osteoclasts (P<0.05 for all). CONCLUSIONS Our study revealed that fluid shear stress ameliorated the inhibitory effects of myeloma cells on osteocyte growth and inhibited osteoclast proliferation by means of decreasing RANKL/OPG gene expression. This may have clinical implications in patients with multiple myeloma in that mechanical loading with low-intensity vibration or mild exercise may prevent the progression of myeloma bone disease.


Assuntos
Mieloma Múltiplo/metabolismo , Osteoclastos/metabolismo , Osteócitos/metabolismo , Animais , Fenômenos Biomecânicos/fisiologia , Linhagem Celular Tumoral , Regulação da Expressão Gênica/genética , Humanos , Hidrodinâmica , Camundongos , Osteoprotegerina/metabolismo , Osteoprotegerina/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Estresse Mecânico , Microambiente Tumoral/fisiologia
7.
Int J Low Extrem Wounds ; 18(3): 287-293, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31304802

RESUMO

Studies addressing the link between gene polymorphism and Charcot neuropathic osteoarthopathy (CN) have been limited to analyse osteoprotegerin gene. Aim is to understand the association of RANKL gene variants on the susceptibility of diabetic neuropathy and CN and to measure the serum levels of sRANKL among Indian population with type 2 diabetes. 77 subjects (48 males: 29 females) were recruited and divided into 3 groups. Group 1 Control: normal glucose tolerance (NGT). Group 2: Type 2 diabetes mellitus and neuropathy (DPN). Group 3: Established type 2 diabetes mellitus, DPN, and CN. Subjects were genotyped for RANKL SNP 693 C/G and 643 C/T using polymerase chain reaction-restriction fragment length polymorphism. sRANKL levels were measured using ELISA (enzyme-linked immunosorbent assay). The serum levels of sRANKL were significantly different between the 3 groups. In RANKL -643 C/T the frequency of "CT" genotype and the minor allele "T" was greater among the DPN and CN group compared with the NGT. Further statistical analysis found a significant difference in genotypic frequencies between DPN and NGT subjects with CT genotype. In RANK L -693 C/G the frequency of homozygote mutant "GG" and the minor allele "G" was greater among the DPN and CN group compared with the NGT. Significant differences in genomic frequencies were observed among "GG" genotype. RANKL -643 C/T was significantly associated with DPN alone while -693 C/G was significantly associated with both DPN and CN. Thus, the study suggests RANKL polymorphism might be considered as an independent risk factor for the development of CN.


Assuntos
Artropatia Neurogênica , Diabetes Mellitus Tipo 2 , Neuropatias Diabéticas , Receptor Ativador de Fator Nuclear kappa-B , Artropatia Neurogênica/etnologia , Artropatia Neurogênica/etiologia , Artropatia Neurogênica/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Neuropatias Diabéticas/etnologia , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Feminino , Frequência do Gene , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Osteoprotegerina/metabolismo , Polimorfismo de Nucleotídeo Único , Receptor Ativador de Fator Nuclear kappa-B/sangue , Receptor Ativador de Fator Nuclear kappa-B/genética
8.
DNA Cell Biol ; 38(7): 734-746, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31149839

RESUMO

Multiple gene polymorphisms have been demonstrated to correlate with the susceptibility to osteonecrosis of the femoral head (ONFH). However, as a complex disease induced by multiple genes, the development of ONFH has rarely been reported to involve in gene interaction. In this study, we first explored the association of 10 variants interactions in receptor activator of nuclear factor-kappa B (RANK), RANK ligand (RANKL), osteoprotegerin (OPG), tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear factor of activated T cells cytoplasmic 1 (NFATC1) genes with the development and clinical phenotypes of ONFH in a 377 ONFH case-control study with using Mass ARRAY® platform. Our results showed that not only a total of 6 interactional variants in the paired 10 variants interactions were significantly associated with the development of ONFH (OPG rs2073617 and NFATC1 rs754093, p < 0.019; OPG rs2073618 and NFATC1 rs754093, p < 0.008; OPG rs2073617 and RANKL rs1054016, p < 0.039, respectively) but also a total of 4 paired interactional variants were found to involve significantly in the increased risk of bilateral hip lesions in ONFH (OPG rs2073617 and TRAF6 rs5030411, p = 0.044; RANK rs884205 and TRAF6 rs5030411, p = 0.045, respectively). Moreover, the results from generalized multifactor dimensionality reduction also showed that the five best models were identified and associated significantly with ONFH risk, p = 0.001, 0.01, 0.01, 0.01, and 0.01, respectively. Our results first suggest that the variants in RANK/RANKL/OPG pathway genes affected the development of ONFH in gene interaction manner through the interaction of the paired variants and multiple variants.


Assuntos
Necrose da Cabeça do Fêmur/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição NFATC/genética , Osteoprotegerina/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Fator 6 Associado a Receptor de TNF/genética
9.
Tohoku J Exp Med ; 248(2): 87-97, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31189751

RESUMO

Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.


Assuntos
Ligante RANK/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
10.
Int Immunopharmacol ; 73: 461-470, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170675

RESUMO

Cilostazol exerts potent anti-inflammatory effects and celecoxib, a COX-2 specific inhibitor, improves the unsatisfactory profile of NSAIDs. It was aimed to assess the anti-arthritic potential of celecoxib add-on for cilostazol therapy in collagen induced arthritis (CIA), and to elucidate the implication of interleukin (IL)-10 in the action of cilostazol and celecoxib cotreatment. Cotreatment of RAW 264.7 cells with 10 µM cilostazol and 0.3 µM celecoxib synergistically suppressed RANKL-induced increases in RANK mRNA and protein levels. When cultured in the presence of RANKL for 5 days, RANKL-stimulated expressions of osteoclastogenic genes (OSCAR, DC-STAMP, and cathepsin K mRNA) and the expression of RANK mRNA were markedly elevated. Furthermore, these gene expressions, including that of RANK, were significantly suppressed by cotreatment with cilostazol (10 µM) and celecoxib (0.3 µM). In addition, this co-treatment strongly down-regulated RANKL-induced NFATc1 protein and TRAP activity (key osteoclastogenic factors), and these down-regulations were significantly prevented by pretreating cells with IL-10 neutralizing antibody. Furthermore, increased osteoclast formation and extensive resorption pit formation by bone marrow-derived monocytes obtained from C57BL/6 mice cultured in the presence of M-CSF/RANKL were markedly suppressed by cilostazol and celecoxib cotreatment. Consequently, hindlimb paw thicknesses in DBA/1J CIA mice were significantly reduced by cilostazol (10 mg/kg/d) and celecoxib (5 mg/kg/d) cotreatment. These results were accompanied by synergistic suppression of cartilage depletion and bone erosion and reductions in arthritis scores in the CIA mice. In conclusion, serum IL-10 levels in these mice were markedly increased by cilostazol and celecoxib cotreatment, whereas elevated serum IL-1ß levels were markedly reduced. Cotreatment with low-dose cilostazol and celecoxib may ensure the synergistic anti-arthritic potential.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artrite Experimental/tratamento farmacológico , Celecoxib/uso terapêutico , Cilostazol/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Catepsina K/genética , Celecoxib/farmacologia , Cilostazol/farmacologia , Citocinas/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas do Tecido Nervoso/genética , Osteoclastos/efeitos dos fármacos , Osteoclastos/metabolismo , Ligante RANK/farmacologia , Células RAW 264.7 , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Superfície Celular/genética
11.
J Anim Physiol Anim Nutr (Berl) ; 103(4): 1224-1232, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062421

RESUMO

Hydroxyapatite, a mineral form of calcium (Ca) and phosphorus (P) that gives bones their rigidity, is the major and essential component of bones and teeth in the human and animal body. A suitable ratio of Ca and P is vital for bone growth. The aim of this study was to explore the effects of dietary calcium to available phosphorus ratios (Ca/AP) on bone metabolism and osteoclast activity of the osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B ligand (RANKL) signalling pathway in piglets. At days 15 and 29, the piglets were assessed for growth performance, blood indicators, cytokines and the OPG/RANK/RANKL signalling pathway. Our results showed that piglets fed a dietary Ca/AP ratio of 2:1 increases growth performance and regulates blood indicators and cytokines (parathyroid hormone (PTH), calcitonin (CT), vitamin D3 (VD3 ), insulin-like growth factor-1 (IGF-1), transforming growth factor-ß (TGF-ß), interleukin-1 (IL-1), interleukin-6 (IL-6), carboxyterminal propeptide of type I procollagen (PICP), tartrate-resistant acid phosphatase (TRACP), alkaline phosphatase (ALP) and osteocalcin (OCN) content). We also demonstrated that this ratio affects hormone secretion and further bone metabolism through the OPG/RANK/RANKL signalling pathway of osteoclasts. These results indicate that a suitable dietary Ca/AP ratio is vital for bone growth and reduce the incidence of bone diseases such as osteoporosis, providing a practical basis for the raising of piglets.


Assuntos
Osso e Ossos/efeitos dos fármacos , Cálcio na Dieta/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoprotegerina/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Suínos , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Cálcio na Dieta/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Osteoclastos/fisiologia , Osteoprotegerina/genética , Fósforo na Dieta/administração & dosagem , Fósforo na Dieta/farmacologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética
12.
Gynecol Endocrinol ; 35(11): 981-984, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31126201

RESUMO

Osteoporosis is characterized by reduced bone mineral density (BMD) and quality, increasing the risk of fractures. A large number of genes involved in bone metabolism have been implicated in the genesis of osteoporosis; these include RANK and RANKL. Polymorphisms of these genes have been implicated in osteoporosis. The aim of this study was to determine the association of the RANK rs3018362 and RANKL rs12585014 polymorphisms with risk of osteoporosis. Four hundred Mexican women aged 40 years old or above were genotyped by real-time PCR and several demographic and risk factors were explored. The GA and AA genotypes of the rs3018362 polymorphism were associated with a high risk of osteoporosis in the dominant model (p=.0062; OR = 2.16, 95% CI: 1.24-3.78). In summary, the rs3018362 polymorphism in the RANK gene seems to be associated with osteoporosis of the lumbar spine while the RANKL rs12585014 is not, although more studies are needed to confirm these results.


Assuntos
Vértebras Lombares , Osteoporose/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Doenças da Coluna Vertebral/genética , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
13.
Mediators Inflamm ; 2019: 8029863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015798

RESUMO

Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.


Assuntos
Osteoprotegerina/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Espondilite Anquilosante/genética , Adolescente , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Predisposição Genética para Doença/genética , Genótipo , Antígeno HLA-B27/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
14.
Am J Orthod Dentofacial Orthop ; 155(4): 529-542, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30935608

RESUMO

OBJECTIVES: The aim of this study was to investigate the association of clinical variables and polymorphisms in the RANKL, RANK, and OPG genes with external apical root resorption (EARR). METHODS: The sample was composed of 338 unrelated patients of both sexes, average age 14.9 years (range 8-21) with Class II Division 1 malocclusion, orthodontically treated. Periapical radiographs of the maxillary central incisor with the longer root (reference tooth) were taken before treatment and 6 months after starting treatment. DNA was extracted from buccal epithelial cells with the use of 10 mol/L ammonium acetate and 1 mmol/L EDTA. The analysis of 42 polymorphisms in the RANKL, RANK, and OPG genes was performed by means of real-time polymerase chain reaction. Univariate and multivariate analyzes were performed to verify the association of clinical and genetic variables with EARR (P <0.05). RESULTS: The initial root length and patient age were associated with EARR. Considering the study of polymorphisms of RANKL, no significant association was found of genetic polymorphisms with EARR. For RANK polymorphisms, only rs12455775 was associated with EARR. Regarding OPG polymorphisms, an association of rs3102724, rs2875845, rs1032128, and rs3102728 with EARR was found. After multivariate analysis, the initial root length, rapid maxillary expansion, and rs3102724 of the OPG gene were associated with EARR. CONCLUSIONS: Longer roots of upper central incisors and rapid maxillary expansion, as well as allele A of the rs3102724 polymorphism of the OPG gene, were associated with EARR in the study population.


Assuntos
Osteoprotegerina/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Reabsorção da Raiz/genética , Ápice Dentário , Adolescente , Criança , Feminino , Estudos de Associação Genética , Humanos , Masculino , Má Oclusão de Angle Classe II/terapia , Ortodontia Corretiva , Polimorfismo de Nucleotídeo Único/genética , Ápice Dentário/metabolismo , Adulto Jovem
15.
J Endod ; 45(5): 526-531, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30871729

RESUMO

INTRODUCTION: The outcome of root canal treatment has been reported as intimately related to the host response. Genetic polymorphisms might be associated with apical periodontitis repair. The aim of this study was to evaluate the association between receptor activator of nuclear factor kappa B (RANK), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) genetic polymorphisms with persistent apical periodontitis (PAP) in Brazilian subjects. METHODS: Subjects with at least 1 year of follow-up after nonsurgical root canal therapy were recalled. Sixty-four subjects with signs/symptoms of PAP and 86 subjects with root canal-treated teeth exhibiting healthy periradicular tissues (healed) were included. Genomic DNA was extracted from saliva and used for RANK (rs3826620), RANKL (rs9594738), and OPG (rs2073618) genotyping by real-time exact tests, and odds ratio were implemented using Epi Info 3.5.2 (Centers for Disease Control and Prevention, Atlanta, GA). A logistic regression analysis was also performed using the time of follow-up as the covariate. All tests were performed with an established alpha of 0.05 (P = .05). RESULTS: An association between allele distribution and the polymorphism in RANK was observed. Subjects who carry the T allele had a lower risk of having PAP (P < .05). In RANKL polymorphism, the genotype distribution was statistically significant different between the PAP and healed groups (P = .05). The time of follow-up was associated with PAP (P < .05). In the logistic regression analysis using time as a covariant, RANK (P < .05) and RANKL (P < .05) were associated with PAP. The polymorphism rs2073618 in OPG was not associated with PAP (P > .05). CONCLUSIONS: These findings suggest that polymorphisms in RANK and RANKL genes are associated with PAP.


Assuntos
Periodontite Periapical , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Brasil , Humanos , Osteoprotegerina , Periodontite Periapical/genética , Polimorfismo Genético , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética
16.
Cell Mol Life Sci ; 76(11): 2077-2091, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30887097

RESUMO

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.


Assuntos
Hiperfosfatemia/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Calcificação Vascular/metabolismo , Animais , Fosfatos de Cálcio/química , Fosfatos de Cálcio/metabolismo , Transdiferenciação Celular , Condrócitos/metabolismo , Condrócitos/patologia , Regulação da Expressão Gênica , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Hiperfosfatemia/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Ligante RANK/genética , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Calcificação Vascular/complicações , Calcificação Vascular/genética , Calcificação Vascular/patologia
17.
Medicine (Baltimore) ; 98(13): e14933, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30921190

RESUMO

The present study aimed to explore genetic association of receptor activator nuclear factor κB (RANK) polymorphisms with individual susceptibility to knee osteoarthritis (OA) in different Kellgren-Lawrence (KL) grades.This case-control study included 138 knee OA patients and 145 healthy individuals. RANK rs1805034 and rs8086340 polymorphisms were genotyped through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The effects of RANK polymorphisms on knee OA risk were analyzed via χ test or Fisher exact test, and the results were expressed using odds ratios (ORs) with corresponding 95% confidence intervals (CIs).The C allele of rs1805034 polymorphism had significantly higher frequency in knee OA patients than in controls (P = .044), indicating that this allele could increase the risk of knee OA (OR = 1.424, 95% CI = 1.010-2.008). Besides, the CC genotype and C allele of the rs1805034 polymorphism were significantly associated with elevated risk of knee OA in moderate grade (CC vs TT: P = .018, OR = 3.071, 95% CI = 1.187-7.941; C vs T: P = .012, OR = 1.787, 95% CI = 1.131-2.823). However, rs8086340 polymorphism had no significant association with knee OA riskThe C allele of RANK rs1805034 polymorphism is closely correlated with increased risk of knee OA, especially for moderate grade.


Assuntos
NF-kappa B/genética , Osteoartrite do Joelho/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/classificação , Osteoartrite do Joelho/diagnóstico por imagem , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição/genética , Fatores de Risco
18.
J Craniomaxillofac Surg ; 47(5): 766-770, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30795980

RESUMO

PURPOSE: To evaluate the association between polymorphisms in genes that regulate bone metabolism, such as OPG, RANK, RANKL, and HIF1A, in patients with temporomandibular joint (TMJ) ankylosis. METHODS: The sample consisted of 181 individuals, the study included 17 individuals with TMJ ankylosis and 164 controls. DNA was extracted from buccal epithelial cells. The genotyping of genetic polymorphisms in OPG (rs2073618), RANK (rs3826620), RANKL (rs9594738), and HIF1A (rs2301113 and rs2057482) was performed by real-time PCR using TaqMan™ technology (Applied Biosystems). The data were subjected to statistical analysis with a level of significance of 0.05. RESULTS: The OPG (rs2073618) polymorphism was associated with TMJ ankylosis, both in the additive model and in the dominant model (p < 0.05). In the additive model, when the individuals carried the CC genotype, they presented as 10.80 times more likely to develop the condition (p = 0.03). In the dominant model, individuals that carried at least one C allele were 5.76 times more likely to have TMJ ankylosis, than those with the G allele (p = 0.01). CONCLUSION: The polymorphism rs2073618 of OPG is a possible marker that is associated with the risk of manifestation of TMJ ankylosis.


Assuntos
Anquilose/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Osteoprotegerina/genética , Ligante RANK/genética , Receptor Ativador de Fator Nuclear kappa-B/genética , Transtornos da Articulação Temporomandibular/genética , Humanos , Pacientes , Polimorfismo de Nucleotídeo Único , Articulação Temporomandibular
19.
Int J Biol Macromol ; 129: 579-587, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30735778

RESUMO

A homogenous polysaccharide (DAP), with a molecular weight of 2.61 × 104 Da, was isolated from the roots of Dipsacus asper Wall. Gas chromatography (GC) indicated that DAP was composed of galactose and mannose with a molar ratio of 1:1. The purpose of this study was to evaluate the effect of DAP on the progress of bone loss in the ovariectomized (OVX) rat model of osteoporosis. Administration of DAP (50 and 200 mg/kg/body wt. day) for 12 weeks significantly prevented OVX-induced bone loss, biomechanical reduction, the body weight gain, the loss of the uterus weight, as well as increased U-Ca/Cr, U-P/Cr, ALP, TRAP, OC and DPD/Cr levels in rats, which was further supported by the histopathological examinations. Furthermore, we found that the mechanism by which DAP elicited anti-osteoporotic effects was mediated by up-regulation of VEGF and OPG, but down-regulation of RANK and RANKL in both protein and mRNA expression in OVX rats, as well as the activation of PI3K/Akt/eNOS signaling pathway, indicating that DAP can be clinically used as a potential alternative medicine for the prevention and treatment of postmenopausal osteoporosis.


Assuntos
Dipsacaceae/química , Osteoporose/tratamento farmacológico , Polissacarídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Osteoporose/genética , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ovariectomia , Fosfatidilinositol 3-Quinases/metabolismo , Raízes de Plantas/química , Polissacarídeos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Útero/efeitos dos fármacos , Útero/patologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Pharmacology ; 103(3-4): 163-172, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695776

RESUMO

OBJECTIVES: Present investigation determines the protective effect of cimiracemate A against glucocorticoid-induced osteoporosis rat. METHODS: Osteoporosis was induced by injecting methylprednisolone acetate (21 mg/kg) for the period of 6 weeks, and the rats were treated with cimiracemate A 5 and 10 mg/kg, p.o. 60 min after the administration of methylprednisolone acetate (21 mg/kg) for the duration of 6 weeks. Effect of cimiracemate A was observed by estimating the microarchitecture of bone and histopathological changes by micro-CT scan and light microscope. Moreover, lipid profile, mediators of inflammation, and parameters that affect bone formation were determined in the serum and western blot assay, and reverse transcription polymerase chain reaction was done for the estimation of protein expression in the bone tissues. Moreover, cytotoxic effect of cimiracemate A on bone marrow macrophages and bone marrow stromal cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. RESULTS: Result of the investigation suggests that treatment with cimiracemate A ameliorates the microarchitecture of bone and histopathological changes in the glucocorticoid-induced osteoporosis rat. Level of lipid and mediators of inflammation was significantly reduced in the serum of cimiracemate A-treated rats than the negative control group. However, the activity of tartrate-resistant acid phosphatase and the level of collagen type I fragments in the serum were found to be reduced, and osteocalcin level was enhanced in cimiracemate A-treated rats than the negative control group. Moreover, treatment with cimiracemate A attenuates the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), receptor activator of nuclear factor κ B (RANK), and osteoprotegerin (OPG) protein in glucocorticoid-induced osteoporosis rats. CONCLUSION: In conclusion, our study suggests that cimiracemate A protects the glucocorticoid-induced osteoporosis by regulating the RANKL/RANK/OPG signaling pathway.


Assuntos
Conservadores da Densidade Óssea/farmacologia , Remodelação Óssea/efeitos dos fármacos , Cinamatos/farmacologia , Fêmur/efeitos dos fármacos , Acetato de Metilprednilosona , Osteoporose/prevenção & controle , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Fêmur/fisiopatologia , Camundongos , Osteoporose/induzido quimicamente , Osteoporose/metabolismo , Osteoporose/fisiopatologia , Osteoprotegerina/genética , Ligante RANK/genética , Ratos Wistar , Receptor Ativador de Fator Nuclear kappa-B/genética , Transdução de Sinais/efeitos dos fármacos , Microtomografia por Raio-X
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