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1.
Chem Biol Interact ; 325: 109088, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360554

RESUMO

Osteoarthritis (OA) is one of the most common degenerative joint diseases in aging people. The activation of chondrocytes and their dysregulation are closely related to the pathogenesis of OA. GPR55 is an unique orphan G-receptor which binds to cannabinoids. In this study, we explored the role of GPR55 in advanced glycation end productions (AGEs)- induced chondrocytes activation in cultured cells. We showed that AGEs dose dependently induced GPR55 expression in ATDC5 chondrocytes. The blockage of GPR55 by its newly discovered antagonist-CID16020046 mitigated AGEs- induced increase in cellular ROS and decrease in antioxidant NRF2. Moreover, CID16020046 showed a dose-response suppressive effect on AGEs- induced expression of the major inflammatory mediators, including COX-2 and iNOS, and the production of NO and PGE2. CID16020046 also dose responsively inhibited AGEs- induced key effectors of cartilage degradation such as MMP-3 and MMP-13. In consequence, CID16020046 showed robust inhibition on AGEs- induced type II collagen degradation. Mechanistically, our data demonstrated that CID16020046 mediated GPR55 blockage ameliorated AGEs- induced NF-κB activation as revealed by its inhibition on IκBα, nuclear p65 translocation and NF-κB promoter activity. Collectively, our study demonstrates that GPR55 signaling mediates AGEs- induced chondrocyte activation, and the targeted blockage of GPR55 pathway could be therapeutic choice in the treatment of osteoarthritis.


Assuntos
Compostos Azabicíclicos/farmacologia , Benzoatos/farmacologia , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Produtos Finais de Glicação Avançada/farmacologia , Receptores de Canabinoides/metabolismo , Linhagem Celular , Condrócitos/metabolismo , Colágeno Tipo II/metabolismo , Ciclo-Oxigenase 2/genética , Dinoprostona/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/biossíntese , Estresse Oxidativo/efeitos dos fármacos , Proteólise/efeitos dos fármacos
2.
Nat Genet ; 52(4): 371-377, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32203465

RESUMO

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Encefálicas/genética , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Adenocarcinoma de Pulmão/patologia , Animais , Neoplasias Encefálicas/patologia , Estudos de Casos e Controles , Linhagem Celular , Variações do Número de Cópias de DNA/genética , Feminino , Genes myc/genética , Genômica/métodos , Células HEK293 , Humanos , Neoplasias Pulmonares/patologia , Masculino , Metaloproteinase 13 da Matriz/genética , Camundongos , Camundongos Nus , Mutação/genética , Metástase Neoplásica/patologia , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
3.
Chem Biol Interact ; 322: 108968, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32004530

RESUMO

Osteoarthritis (OA) is one of the most prevalent degenerative joint diseases, and the risk of developing OA significantly increases with age as well as with concomitant diseases, such as diabetes. Advanced glycation end products (AGEs) accumulate in the body over time and are associated with increased expression of various molecules involved in the pathophysiology of OA. Prostaglandin E2 (PGE2), along with its precursor cyclooxygenase (COX)-2, plays an integral role in the pathogenesis of OA and is highly upregulated in response to AGEs. The most significant event in OA is excessive degradation of the cartilage extracellular matrix, which is composed primarily of type II collagen and aggrecan. In the present study, we investigated the involvement of the receptor for glucagon-like peptide (GLP)-1 in the response of chondrocytes to insult from AGEs using the selective GLP-1 agonist dulaglutide. Firstly, our results indicate that AGEs reduced the expression of the receptor for GLP-1 (GLP-1R) in human SW1353 chondrocytes. Interestingly, we found that treatment with dulaglutide could ameliorate deterioration of the components of the articular extracellular matrix (ECM), such as type II collagen and aggrecan, induced by AGEs through downregulation of matrix metalloproteinase (MMP)-3 and MMP-13 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5. We also found that dulaglutide exerted a potent inhibitory effect against the expression of several proinflammatory cytokines and chemokines closely associated with OA, as well as the production of reactive oxygen species (ROS). Finally, we showed that the effects of dulaglutide were mediated through the nuclear factor kappa-B (NF-κB) pathway. Our findings indicate that dulaglutide displayed a robust protective effect against AGEs-induced damage in chondrocytes, suggesting that it might be a possible therapeutic agent for the treatment of OA.


Assuntos
Agrecanas/metabolismo , Colágeno Tipo II/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Produtos Finais de Glicação Avançada/metabolismo , Fragmentos Fc das Imunoglobulinas/farmacologia , Proteólise/efeitos dos fármacos , Proteínas Recombinantes de Fusão/farmacologia , Linhagem Celular , Quimiocinas/análise , Quimiocinas/metabolismo , Condrócitos/citologia , Condrócitos/metabolismo , Citocinas/análise , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Peptídeos Semelhantes ao Glucagon/farmacologia , Humanos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
4.
Am J Med Sci ; 359(1): 17-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31785770

RESUMO

BACKGROUND: The purpose of this study was to demonstrate the role of renin-angiotensin system (RAS)-related components, vascular endothelial growth factor (VEGF) and atrial metalloproteinase-13 (MMP-13) in synovial tissue and synovial fluid from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). MATERIALS AND METHODS: Thirty-four patients with RA and 41 patients with OA were included in the study. Renin, angiotensin-converting enzyme (ACE), VEGF and MMP-13 protein levels in the synovial fluid were measured by enzyme-linked immunosorbent assay. Quantitative real-time polymerase chain reaction analysis, western blot analysis and immunohistochemistry were used to quantify renin, ACE, angiotensin type 1 and type 2 receptors, VEGF and MMP-13 in OA and RA. Additionally, the correlation was determined by Pearson's coefficient. RESULTS: In synovial fluid, expression levels of renin, ACE, VEGF and MMP-13 in patients with RA were significantly higher than those in patients with OA. In synovial tissue, the RAS components VEGF and MMP-13 were also elevated in patients with RA. The results of immunohistochemistry in synovial tissue also showed that the RAS components VEGF and MMP-13 were significantly increased in patients with RA. Notably, the Pearson coefficient demonstrated that the levels of the RAS components were positively correlated with the expression of VEGF and MMP-13 in OA and RA. CONCLUSIONS: The present results suggest that RAS-related components in RA and OA, including renin, ACE, angiotensin type 1 and type 2 receptors, are associated with increased expression of VEGF and play an important role in angiogenesis. Furthermore, there was a significant positive correlation between the expression of VEGF and MMP-13.


Assuntos
Artrite Reumatoide/metabolismo , Regulação da Expressão Gênica , Osteoartrite/metabolismo , Sistema Renina-Angiotensina/fisiologia , Idoso , Artrite Reumatoide/complicações , Feminino , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite/complicações , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Renina/genética , Renina/metabolismo , Líquido Sinovial/química , Líquido Sinovial/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
BMC Vet Res ; 15(1): 419, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752879

RESUMO

BACKGROUND: Osteoarthritis (OA), the most common form of arthritic disease, results from destruction of joint cartilage and underlying bone. It affects animals, including Asian elephants (Elephas maximus) in captivity, leading to joint pain and lameness. However, publications regarding OA pathogenesis in this animal are still limited. Therefore, this study aimed to investigate the effect of proinflammatory cytokines, including interleukin-1 beta (IL-1ß), IL-17A, tumor necrosis factor-alpha (TNF-α), and oncostatin M (OSM), known mediators of OA pathogenesis, and lipopolysaccharides on the expression of cartilaginous degrading enzymes, matrix metalloproteinase (MMP)-3 and MMP-13, in elephant articular chondrocytes (ELACs) cultures. Anti-arthritic drugs and the active compounds of herbal plants were tested for their potential attenuation against overproduction of these enzymes. RESULTS: Among the used cytokines, OSM showed the highest activation of MMP3 and MMP13 expression, especially when combined with IL-1ß. The combination of IL-1ß and OSM was found to activate phosphorylation of the mitogen-activated protein kinase (MAPK) pathway in ELACs. Lipopolysaccharides or cytokine-induced expressions were suppressed by pharmacologic agents used to treat OA, including dexamethasone, indomethacin, etoricoxib, and diacerein, and by three natural compounds, sesamin, andrographolide, and vanillylacetone. CONCLUSIONS: Our results revealed the cellular mechanisms underlying OA in elephant chondrocytes, which is triggered by proinflammatory cytokines or lipopolysaccharides and suppressed by common pharmacological or natural medications used to treat human OA. These results provide a more basic understanding of the pathogenesis of elephant OA, which could be useful for adequate medical treatment of OA in this animal.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/toxicidade , Elefantes/metabolismo , Lipopolissacarídeos/toxicidade , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Animais , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Regulação para Cima/efeitos dos fármacos
6.
Biomed Res Int ; 2019: 2365416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781601

RESUMO

Cartilage dysplasia is one of the important reasons for the weakness of pig limbs and hooves. Porcine rickets with weak limbs and hooves bring huge economic losses to the pig industry. However, research on the development of pig cartilage is lacking. This study investigated the key genes and molecular mechanisms involved in cartilage development via an RNA-seq technique. Samples of proximal tibia cartilage were collected from three normal piglets with 1 day, 14 days, and 28 days of age, respectively, and then these samples were divided into two comparison groups (1-day vs. 14-day group, 14-day vs. 28-day group). Through the transcriptome analysis, 108 differentially expressed genes (DEGs), such as FORL2, were obtained from 1-day vs. 14-day comparison group, and 3602 DEGs were obtained from 14-day vs. 28-day comparison group, including SOX9, BMP6, and MMP13. The gene ontology (GO) functional and KEGG pathway enrichment revealed that many functions of DEGs were related to bone development. The pathways of DEGs from Day 1 vs. Day 14 were mainly enriched in mineral absorption, but the DEGs of Day 14 vs. Day 28 were enriched in osteoclast differentiation. Then, the expression patterns of six candidate genes were verified via qPCR. In conclusion, candidate genes affecting cartilage development in Yorkshire pigs were obtained by transcriptome analysis, and the clues showed that Day 14 to Day 28 is a more active and extensive period in cartilage developments, which played a key role in revealing the molecular mechanism of pig cartilage development basis, also compensating for vacancies in cartilage research.


Assuntos
Cartilagem/crescimento & desenvolvimento , Condrogênese/genética , Tíbia/crescimento & desenvolvimento , Transcriptoma/genética , Animais , Cartilagem/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Metaloproteinase 13 da Matriz/genética , RNA Mensageiro/genética , Fatores de Transcrição SOX9/genética , Suínos/genética , Suínos/crescimento & desenvolvimento , Tíbia/metabolismo
7.
Int J Mol Sci ; 20(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652545

RESUMO

Inflammatory processes in the skin augment collagen degradation due to the up-regulation of matrix metalloproteinases (MMPs). The aim of the present project was to study the specific impact of MMP-3 on collagen loss in skin and its interplay with the collagenase MMP-13 under inflammatory conditions mimicked by the addition of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Skin explants from MMP-3 knock-out (KO) mice or from transgenic (TG) mice overexpressing MMP-3 in the skin and their respective wild-type counterparts (WT and WTT) were incubated ex vivo for eight days. The rate of collagen degradation, measured by released hydroxyproline, was reduced (p < 0.001) in KO skin explants compared to WT control skin but did not differ (p = 0.47) between TG and WTT skin. Treatment with the MMP inhibitor GM6001 reduced hydroxyproline media levels from WT, WTT and TG but not from KO skin explants. TNF-α increased collagen degradation in the WT group (p = 0.0001) only. More of the active form of MMP-13 was observed in the three MMP-3 expressing groups (co-incubation with receptor-associated protein stabilized MMP-13 subforms and enhanced detection in the media). In summary, the innate level of MMP-3 seems responsible for the accelerated loss of cutaneous collagen under inflammatory conditions, possibly via MMP-13 in mice.


Assuntos
Colágeno/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Pele/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Animais , Dipeptídeos/farmacologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Proteólise , Pele/efeitos dos fármacos
8.
Molecules ; 24(20)2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31614911

RESUMO

Combinations of IL-1ß and other proinflammatory cytokines reportedly promote the severity of arthritis. We aimed to investigate the effects of IL-1ß combined with IL-17A on cartilage degradation and synthesis in in vitro models. Cartilage explant degradation was determined using sulfated glycosaminoglycans (S-GAGs) levels, matrix metalloproteinase (MMP13) gene expression, uronic acid, and collagen contents. Cell morphology and accumulation of proteoglycans were evaluated using hematoxylin-eosin and safranin O staining, respectively. In the pellet culture model, expressions of cartilage-specific anabolic and catabolic genes were evaluated using real-time qRT-PCR. Early induction of MMP13 gene expression was found concomitantly with significant S-GAGs release. During the prolonged period, S-GAGs release was significantly elevated, while MMP-13 enzyme levels were persistently increased together with the reduction of the cartilaginous matrix molecules. The pellet culture showed anabolic gene downregulation, while expression of the proinflammatory cytokines, mediators, and MMP13 genes were elevated. After cytokine removal, these effects were restored to nearly basal levels. This study provides evidence that IL-1ß combined with IL-17A promoted chronic inflammatory arthritis by activating the catabolic processes accompanied with the suppression of cartilage anabolism. These suggest that further applications, which suppress inflammatory enhancers, especially IL-17A, should be considered as a target for arthritis research and therapy.


Assuntos
Artrite Reumatoide/genética , Interleucina-17/genética , Interleucina-1beta/genética , Metaloproteinase 13 da Matriz/genética , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Cartilagem Articular/crescimento & desenvolvimento , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese/genética , Regulação da Expressão Gênica , Glicosaminoglicanos/genética , Glicosaminoglicanos/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Metabolismo , Proteoglicanas/genética , Suínos , Fator de Necrose Tumoral alfa/genética
9.
Arch Oral Biol ; 108: 104547, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31525531

RESUMO

OBJECTIVE: This study investigated the risk and prognostic value of single nucleotide polymorphisms (SNP) inIL-8, MMP-1 and MMP-13 in oral and oropharyngeal squamous cell carcinomas (SCCs). DESIGN: SNPs rs2227532 and rs4073 inIL-8, rs2071230 and rs470558 in MMP-1, and rs2252070 in MMP-13 were genotyped in 125 oral and oropharyngeal SCC patients and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as SNP-SNP interaction and gene-environmental factor (GxE) interaction. Univariate and multivariate methods were applied for survival analyses. RESULTS: With exception of rs2227532, all the SNPs were in Hardy-Weinberg equilibrium in the control. No associations between rs4073 in IL-8 and rs2071230 and rs470558 in MMP-1 were observed, but rs2252070 in MMP-13, in the dominant model, was associated in a protective manner to oral and oropharyngeal SCC (OR: 0.20, 95% CI: 0.06-0.71, p = 0.007). All SNPs interact significantly with cigarette smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC, but they showed no influence on survival of the patients. CONCLUSIONS: Our results show that rs2252070 inMMP-13 may confer protection effect against oral and oropharyngeal SCC. In addition, the combined effects of IL-8 (rs4073), MMP-1 (rs2071230 and rs470558) and MMP-13 (rs2252070) with environmental carcinogens, such as tobacco and alcohol, are related to increased risk for oral and oropharyngeal SCC development.


Assuntos
Carcinoma de Células Escamosas , Interleucina-8 , Metaloproteinase 13 da Matriz , Metaloproteinase 1 da Matriz , Neoplasias Bucais , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Humanos , Interleucina-8/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 13 da Matriz/genética , Neoplasias Bucais/genética , Polimorfismo de Nucleotídeo Único , Prognóstico
10.
PLoS One ; 14(9): e0221940, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513610

RESUMO

Although doxorubicin (DOX)-induced cardiomyopathy causes lethal heart failure (HF), no early detection or effective treatment methods are available. The principal mechanisms of cardiotoxicity are considered to involve oxidative stress and apoptosis of cardiomyocytes. However, the effect of DOX on cardiac fibroblasts at non-lethal concentrations remains unknown. The aim of this study was to investigate the direct effect of doxorubicin on the activation of cardiac fibroblasts independent of cell death pathways. We first found that DOX induced α-SMA expression (marker of trans-differentiation) at a low concentration range, which did not inhibit cell viability. DOX also increased MMP1, IL-6, TGF-ß and collagen expression in human cardiac fibroblasts (HCFs). In addition, DOX promoted Akt and Smad phosphorylation. A Smad inhibitor prevented DOX-induced α-SMA and IL-6 protein expression. An PI3K inhibitor also prevented MMP1 mRNA expression in HCFs. These findings suggest that DOX directly induces fibrotic changes in HCFs via cell death-independent pathways. Furthermore, we confirmed that these responses are organ- and species-specific for HCFs based on experiments using different types of human and murine fibroblast cell lines. These results suggest potentially new mechanisms of DOX-induced cardiotoxicity from the viewpoint of fibrotic changes in cardiac fibroblasts.


Assuntos
Doxorrubicina/farmacologia , Fibroblastos/citologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , Miócitos Cardíacos/citologia , Actinas/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colágeno/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Especificidade de Órgãos , Transdução de Sinais/efeitos dos fármacos , Especificidade da Espécie
11.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502578

RESUMO

Chondrosenescence (chondrocyte senescence) and subchondral bone deterioration in osteoarthritic rats were analyzed after treatment with the estrogenic herb Labisia pumila (LP) or diclofenac. Osteoarthritis (OA) was induced in bilaterally ovariectomized (OVX) rats by injecting mono-iodoacetate into the right knee joints. Rats were grouped (n = 8) into nontreated OVX+OA control, OVX+OA + diclofenac (5 mg/kg) (positive control), OVX+OA + LP leaf extract (150 and 300 mg/kg) and healthy sham control. After 8 weeks' treatment, their conditions were evaluated via serum biomarkers, knee joint histology, bone histomorphometry, protein and mRNA expressions. The LP significantly reduced cartilage erosion, femur bone surface alteration, bone loss and porosity and increased trabecular bone thickness better than diclofenac and the non-treated OA. The cartilage catabolic markers' (matrix metalloproteinase (MMP)-13, RUNX2, COL10a, ERa, CASP3 and HIF-2 alpha) mRNA expressions were down-regulated and serum bone formation marker, PINP, was increased by LP in a dose-dependent manner. The LP (containing myricetin and gallic acid) showed protection against chondrosenescence, chondrocyte death, hypoxia-induced cartilage catabolism and subchondral bone deterioration. The bone and cartilage protective effects were by suppressing proteases (collagen break-down), bone resorption and upregulating subchondral bone restoration. The cartilage ER alpha over-expression showed a strong positive correlation with MMP-13, COL10 alpha1, histological, micro-computed tomography evidence for cartilage degradation and chondrosenescence.


Assuntos
Envelhecimento/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Osteoartrite/tratamento farmacológico , Extratos Vegetais/farmacologia , Primulaceae/química , Envelhecimento/genética , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Diclofenaco/farmacologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Ácido Gálico/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Iodoacetatos/farmacologia , Metaloproteinase 13 da Matriz/genética , Metabolismo/efeitos dos fármacos , Osteoartrite/genética , Osteoartrite/patologia , Ovariectomia , Extratos Vegetais/química , Ratos
12.
BMJ Case Rep ; 12(8)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31413057

RESUMO

Metaphyseal dysplasias are a heterogeneous group of skeletal dysplasias characterised by metaphyseal irregularities. Due to the presence of metaphyseal changes accompanied with bowing deformity of lower limb, they are likely to be mistaken for rickets. We present a case of a 7-year-old boy, finally diagnosed with metaphyseal dysplasia, Spahr type (MDST) (OMIM # 250400) after his exome sequencing revealed novel variations in the MMP13 gene (OMIM * 600108). This is a rare skeletal dysplasia with only a few cases reported in literature. A compilation of the presentation of the reported cases is given to help the reader understand this rare disorder. To the best of our knowledge, this case of MDST is the first to be reported from India.


Assuntos
Osteocondrodisplasias/diagnóstico , Criança , Diagnóstico Diferencial , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Raquitismo/diagnóstico
13.
Artif Cells Nanomed Biotechnol ; 47(1): 3259-3264, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31368822

RESUMO

Impairment of type II collagen caused by MMPs in response to overproduction of IL-1ß is an important step in the pathological progression of osteoarthritis (OA). Lunasin, a well-known peptide present in the soybean, has displayed a positive impact on numerous physiological functions. Little information in the effects of lunasin on cartilage degradation has been sought in clinical research before. Here, we report that lunasin suppressed the increase in MMP-3 and MMP-13 caused by IL-1ß. In addition, we found that lunasin could prevent the decrease in TIMP-1 and TIMP-2 expressions caused by IL-1ß. Notably, lunasin suppressed reduction of type II collagen, the basis for articular cartilage. Lunasin also attenuated activation of the JAK2/STAT1/IRF-1 pathway. These effects of lunasin suggest that it might become a promising therapeutic agent for chondro-protective therapy.


Assuntos
Colágeno Tipo II/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Proteínas de Plantas/farmacologia , Cartilagem Articular/citologia , Proliferação de Células/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Interleucina-1beta/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
14.
BMC Complement Altern Med ; 19(1): 191, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362725

RESUMO

BACKGROUND: Wnt/ß-catenin signaling pathway is closely related to osteoarthritis. In our preliminary study, ß-catenin conditional activation (cAct) mice that specifically over-express ß-catenin gene in cartilage chondrocyte exhibits osteoarthritis-like phenotype in the lumbar disc and knee joint. Therefore, we used the mice to model FJ-OA and test the potential curative effect of Velvet Antler Polypeptide (VAP) on this mice model. METHODS: We tested the effect of VAP on ß-catenin conditional activation mice, and used Cre negative littermates as controls. Micro-CT, histology and histomorphometry analysis were performed to evaluate the curative effect of VAP on mice facet joint-like phenotype. Expression of ß-catenin and collagen II was detected by immunohistochemistry (IHC) and western-blot., MMP13, ADAMTS4 and ADAMTS5 was detected by immunofluorescence (IF). RT-PCR analysis was preformed to detect mRNA expression of cartilage degrading enzymes, such as MMP13, ADAMTS4 and ADAMTS5. RESULTS: Results of micro-CT (µCT) analysis showed that VAP could partially reverse lumbar disc osteophyte formation observed in ß-catenin(ex3)Col2ER mice. Histology data revealed VAP partially improved facet joint cartilage tissue invades. Histomorphometry analysis showed an increase in total cartilage area after VAP treatment. IHC show that VAP reduced ß-catenin protein levels and moderately up-regulated collagen II protein levels. RT-PCR and IF data showed that VAP down-regulated the expression of extracellular matrix synthesis (ECM) degradation enzymes MMP13, ADAMTS4 and ADAMTS5. CONCLUSION: Taken together, VAP may modulate ECM by inhibits MMP13, ADAMTS4 and ADAMTS5 via Wnt /ß-catenin signaling pathway. Velvet Antler Polypeptide may be a potential medicine for FJ-OA.


Assuntos
Chifres de Veado/química , Osteoartrite/tratamento farmacológico , Peptídeos/administração & dosagem , beta Catenina/metabolismo , Proteína ADAMTS4/genética , Proteína ADAMTS4/metabolismo , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Animais , Apoptose/efeitos dos fármacos , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Cervos , Humanos , Articulações/efeitos dos fármacos , Articulação do Joelho/efeitos dos fármacos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Osteoartrite/genética , Osteoartrite/metabolismo , beta Catenina/genética
15.
Eur Arch Otorhinolaryngol ; 276(11): 3203-3211, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31440816

RESUMO

PURPOSE: To investigate the contribution of MMP-13 in tumor aggressiveness, by acting on the reorganization of the extracellular matrix, regulating the biological activity of cytokines in odontogenic epithelial lesions, as well as to evaluate the role of EMMPRIN as an inducer of MMP-13. METHODS: Twenty solid ameloblastomas (SAs), 10 unicystic ameloblastomas (UAs), 20 odontogenic keratocysts (OKCs), and 20 adenomatoid odontogenic tumors (OATs) were selected. The expression of MMP-13 and EMMPRIN was evaluated in epithelial/connective tissue by determining the score of immunoreactive cells. RESULTS: Higher concentration of MMP-13 was observed in epithelium of SAs and OKCs (p = 0.316), while in connective, MMP-13 was more expressed in OKCs and UAs (p = 0.213). OKCs exhibited the highest immunoreactivity score for EMMPRIN in the epithelium (p = 0.091). In connective tissue, a larger number of immunoreactive cells were observed in OKCs and UACs (p = 0.357). There was a moderate correlation (r = 0.343/p = 0.004) between MMP-13/EMMPRIN in epithelium and strong correlation (r = 0.474/p < 0.001) in connective tissue. CONCLUSION: We suggest that the OKCs, SAs and UAs presented greater immunoexpression for MMP-13 and EMMPRIN, since they were lesions of more aggressive behavior, with smaller expressions in the AOTs that are admittedly indolent. However, we did not find a statistically significant difference between the expression of MMP-13 and EMMPRIN in lesions studied. The positive correlation found between MMP-13 and EMMPRIN in the epithelial and connective tissue of odontogenic lesions analyzed, seems to be related to the role of EMMPRIN as an inducer of MMP-13 expression.


Assuntos
Ameloblastoma , Basigina/metabolismo , Matriz Extracelular , Metaloproteinase 13 da Matriz/metabolismo , Cistos Odontogênicos , Tumores Odontogênicos , Ameloblastoma/genética , Ameloblastoma/metabolismo , Ameloblastoma/patologia , Biomarcadores Tumorais/metabolismo , Correlação de Dados , Epitélio/metabolismo , Epitélio/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Metaloproteinase 13 da Matriz/genética , Cistos Odontogênicos/genética , Cistos Odontogênicos/metabolismo , Cistos Odontogênicos/patologia , Tumores Odontogênicos/genética , Tumores Odontogênicos/metabolismo , Tumores Odontogênicos/patologia
16.
Food Funct ; 10(8): 5008-5017, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31355395

RESUMO

Supplementation with cartilage constituents, such as glucosamine, chondroitin sulfate and collagen peptide, are believed to reduce pain associated with joint disorders, such as rheumatoid arthritis (RA). Here, we administered daily, 10 mg glucosamine or 100 mg chicken cartilage hydrolysate (CH) to SKG/Jcl mice, a model for spontaneous RA, for 5 weeks and evaluated their effects on RA development. In SKG mice, the administration of glucosamine had no reducing effect on RA score but suppressed the expression of Mmp13 and Col3a1 genes in articular cartilage. In contrast, administration of CH suppressed the RA score and levels of plasma interleukin-6 and interleukin-17 to half, although the differences were not significant. Mice administered with glucosamine also showed decreased bone strength of femur and these adverse effects could be eliminated when glucosamine was used in conjunction with CH. These results suggest that CH and glucosamine exert effects on different aspects in SKG mice.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Cartilagem/química , Glucosamina/administração & dosagem , Hidrolisados de Proteína/administração & dosagem , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Galinhas , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-17/sangue , Interleucina-6/sangue , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C
17.
Mediators Inflamm ; 2019: 6768504, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275058

RESUMO

Dysregulation of multiple microRNAs widely takes place during rheumatoid arthritis (RA) and experimental arthritides. This study is performed to explore the possible mechanism underlying DICER1 deficiency-mediated inflammation in human synoviocytes SW982. Firstly, RNAi of DICER1 led to increased COX2, MMP3, and MMP13 protein production, while DICER1 overexpression could reduce MMP13 expression. Secondly, the increase of IL-8 and decrease of TGF-ß1 and TIMP1 were determined in the supernatant derived from DICER1 siRNA-treated cells, while DICER1 overexpression was found capable to reverse this effect. Ingenuity pathway analysis (IPA) software predicted that the Dicer1 deficiency-induced dysregulated cytokines in synoviocytes could possibly lead to the inflammatory disorders in the synovial tissue. Moreover, DICER1 deficiency could also reduce apoptosis, while DICER1 overexpression was found to decrease the proliferation and enhance apoptosis. In addition, DICER1 deficiency could lower the expression of multiple RA-related miRNAs such as miR-155. Meanwhile, DICER1 overexpression could rescue their low expression levels. And then, gain or loss of miR-155 function could regulate the protein levels of MMP3 and MMP13. These results indicated that DICER1 might play its role through regulating its downstream RA-related miRNAs. Our data demonstrated that DICER1 deficiency could cause multiple proinflammatory events in human synoviocytes SW982. This mechanism study might provide the possible target molecule to modify the inflammatory destruction and overproliferation in synoviocytes.


Assuntos
RNA Helicases DEAD-box/metabolismo , Inflamação/metabolismo , Ribonuclease III/metabolismo , Sinoviócitos/metabolismo , Apoptose/genética , Apoptose/fisiologia , Western Blotting , Linhagem Celular , Proliferação de Células/genética , Proliferação de Células/fisiologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , RNA Helicases DEAD-box/genética , Humanos , Inflamação/genética , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Interferência de RNA , Ribonuclease III/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
Nutrients ; 11(7)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262076

RESUMO

Rice porridge containing Allium fistulosum (Welsh onion) root water extract (RAFR) has anti-inflammatory bioactive compounds. We examined whether the long-term administration of rice porridge with RAFR would prevent or delay the progression of osteoarthritis and menopausal symptoms in estrogen-deficient animals by ovariectomy. The rats consumed 40% fat energy diets containing 250 mg RAFR (rice: Allium fistulosum root = 13:1)/kg body weight (bw) (OVX-OA-RAFR-Low), 750 mg RAFR/kg bw (OVX-OA-RAFR-High) and 750 mg starch and protein/kg bw(OVX), respectively. After consuming the assigned diets for eight weeks, monoiodoacetate (OVX-OA) or saline (OVX) were injected into the knee joints of the rats for an additional three weeks. Sham rats were administered saline injections (normal-control). OVX-OA-RAFR improved oral glucose tolerance and also protected against decreases in bone mineral density and lean body mass in the legs and increases in fat mass in the abdomen, compared to the OVX and OVX-OA. OVX-OA-RAFR improved swelling and limping scores, normalized weight distribution between the osteoarthritic and normal limbs, and increased maximum running speeds compared to the OVX-OA. The OVX-OA deteriorated the articular cartilage by reducing the articular matrix and bone loss in the knee joint and it prevented knee joint deterioration when compared to the OVX. The improvement in osteoarthritis symptoms in OVX-OA-RAFR decreased the mRNA expression of matrix metallo-proteinase-1 and matrix metalloproteinase-13, tumor necrosis factor-α, and interleukin-1ß and interleukin-6 in the articular cartilage compared to OVX-OA rats. In conclusions, RAFR is effective in treating osteoarthritis symptoms and it may be used for a therapeutic agent in osteoarthritis-induced menopausal women.


Assuntos
Artrite Experimental/dietoterapia , Comportamento Animal , Glicemia/metabolismo , Densidade Óssea , Fêmur/fisiopatologia , Articulações/fisiopatologia , Cebolas , Oryza , Extratos Vegetais/farmacologia , Raízes de Plantas , Ração Animal , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Biomarcadores/sangue , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Ingestão de Energia , Feminino , Fêmur/metabolismo , Fêmur/patologia , Articulações/metabolismo , Articulações/patologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Atividade Motora , Valor Nutritivo , Ratos Sprague-Dawley , Fatores de Tempo
19.
Cell Physiol Biochem ; 53(1): 172-185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31264811

RESUMO

BACKGROUND/AIMS: MicroRNAs (miRs) are transcribed as stem-loop precursors harboring two different miRs on either side of the structure. Both miRs can modulate levels of cellular transcripts based on sequence complementarity between the miR and the mRNA target. The miR of the current study, miR-675, is encoded in the H19 gene with high expression in fetal/placental tissues but low levels in most adult tissues except for skeletal muscle and articular cartilage. miR-675 has a supportive role in expression of the major collagen component of articular cartilage (COL2A1) but it is unknown which arm contributes to this effect. Objectives: To determine the active arm of miR-675 in human articular chondrocytes. To evaluate effects of overexpression of both arms of miR-675 on MMP1 and MMP13, two enzymes involved in breakdown of COL2A1. To investigate whether abundance of both arms of miR-675 is dynamic. METHODS: miR-arm activity was determined by association with the AGO2 complex using immunoprecipitation with an AGO2 specific antibody. miR overexpression and inhibition was used to identify indirect downstream effects on two targets of the Matrix-Metalloprotease family, MMP1 and MMP13. Data was evaluated by qPCR and enzymatic activity assays. Early passage human articular chondrocytes (up to passage 2) obtained from cartilage from both healthy and osteoarthritis affected tissue were used. To evaluate miR-675 levels in a different model, myotube differentiation was employed. RESULTS: We show that both arms of miR-675 have opposing effects on MMP1 and MMP13; however only one arm, miR-675-3' is active in human articular chondrocytes. We demonstrate that during myotube differentiation, high expression of both arms of miR-675 is observed as well as an increase in expression of MMP1. CONCLUSION: We show that both arms of miR-675 result in opposing effects on two downstream molecules MMP1 and MMP13. We propose that miR abundance may arise as response to direct target transcript levels and are thus dynamic to meet the requirements of the cellular environment.


Assuntos
Condrócitos/metabolismo , Regulação da Expressão Gênica , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 1 da Matriz/genética , MicroRNAs/genética , Osteoartrite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/citologia , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Criança , Condrócitos/citologia , Condrócitos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/patologia , Regulação para Cima , Adulto Jovem
20.
Int Immunopharmacol ; 75: 105752, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310910

RESUMO

BACKGROUND: Downregulation of histone deacetylase-4 (HDAC4) contributes to cartilage degeneration in osteoarthritis (OA) because it promotes upregulation of runt-related transcription factor-2 (Runx-2) and osteoarthritis-related genes. The effect of HDAC4 upregulation on cartilage damage in OA remains unknown. METHODS: Rat chondrocytes were infected with Ad-GFP or Ad-HDAC4-GFP for 48 h, stimulated with interleukin-1ß (IL-1ß, 10 ng/mL) for 24 h, and then harvested for RT-qPCR. Male Sprague-Dawley rats in 3 groups were given anterior cruciate ligament transection (ACLT) or sham operation, and knee injections with different adenovirus (Ad) vectors at 48 h after surgery and every 3 weeks thereafter: ACLT+Ad-GFP (n = 17); ACLT+Ad-HDAC4-GFP (n = 20); and sham+Ad-GFP (n = 15). Three ACLT-Ad-HDAC4-GFP rats were sacrificed at different times to examine the expression of HDAC4. Two ACLT-Ad-GFP rats and two ACLT-Ad-HDAC4-GFP rats were euthanized at week-2; articular cartilage was harvested and expression of HDAC4 was determined by RT-qPCR. All other rats were euthanized at week-8. Cartilage damage and OA progression was assessed using radiography, fluorescence molecular tomography (FMT), histology, immunohistochemistry (IHC), ELISA, and RT-qPCR. RESULTS: Overexpression of HDAC4 in chondrocytes stimulated by IL-1ß reduced the levels of Runx-2, MMP-13, and Collagen X, but increased the levels of Collagen II and Aggrecan. Upregulation of HDAC4 reduced osteophyte formation and cartilage damage, and increased articular cartilage anabolism. CONCLUSION: HDAC4 attenuated articular cartilage damage by repression of Runx-2, MMP-13, and collagen X and induction of collagen II and ACAN in this rat model of OA. Upregulation of HDAC4 may provide chondroprotection in OA patients.


Assuntos
Adenoviridae/genética , Histona Desacetilases/genética , Osteoartrite , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Células Cultivadas , Condrócitos/metabolismo , Colágeno/genética , Colágeno/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Progressão da Doença , Interleucina-1beta/farmacologia , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Ratos Sprague-Dawley , Transdução Genética
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