Base de dados : MEDLINE
Pesquisa : D08.811.277.656.675.374.102.500.875 [Categoria DeCS]
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[PMID]:29241192
[Au] Autor:Mao G; Wu P; Zhang Z; Zhang Z; Liao W; Li Y; Kang Y
[Ad] Endereço:Department of Joint Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
[Ti] Título:MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1ß-Induced Catabolism in Human Articular Chondrocytes.
[So] Source:Cell Physiol Biochem;44(1):38-52, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are secreted enzymes belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family that play significant roles in the progression of osteoarthritis (OA). Here, we aimed to determine whether the expression of ADAMTS-4/5 in chondrogenesis and inflammation is regulated by microRNA-92a-3p (miR-92a-3p). METHODS: MiR-92a-3p and ADAMTS-4/5 expressions were determined by quantitative polymerase chain reaction (qPCR). To investigate the repressive effect of miR-92a-3p on ADAMTS-4/5 expression, chondrogenic human mesenchymal stem cells (hMSCs) and human chondrocytes were transfected with mature miR-92a-3p or an antisense inhibitor (anti-miR-92a-3p), respectively. ADAMTS-4/5 protein production was quantified by enzyme-linked immunosorbent assay (ELISA), and miR-92a-3p involvement in IL-1ß-mediated catabolic effects was examined by immunoblotting. The roles of activated MAP kinases (MAPK) and nuclear factor (NF)-κB were evaluated by using specific inhibitors. Interaction between miR-92a-3p and its putative binding site in the 3'-untranslated region (3'-UTR) of ADAMTS-4/5 mRNA was confirmed by luciferase reporter assay. RESULTS: miR-92a-3p expression was elevated in chondrogenic hMSCs, with significantly lower expression in OA cartilage than in normal cartilage. Stimulation with IL-1ß significantly reduced miR-92a-3p expression in primary human chondrocytes (PHCs). Transfection of chondrocytes with miR-92a-3p downregulated IL-1ß-induced ADAMTS-4/5 expression, and the activity of a reporter construct containing the 3'-UTR of human ADAMTS-4/5 mRNA. MiR-92a-3p expression was suppressed upon IL-1ß-induced activation of MAPK and NF-κB in chondrocytes. CONCLUSION: MiR-92a-3p is an important regulator of ADAMTS-4/5 in human chondrocytes and may contribute to the development of OA.
[Mh] Termos MeSH primário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Condrogênese/efeitos dos fármacos
Condrogênese/genética
Interleucina-1beta/farmacologia
MicroRNAs/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS4/antagonistas & inibidores
Proteína ADAMTS4/genética
Proteína ADAMTS5/antagonistas & inibidores
Proteína ADAMTS5/genética
Adulto
Idoso
Antagomirs/metabolismo
Células da Medula Óssea/citologia
Cartilagem Articular/metabolismo
Cartilagem Articular/patologia
Células Cultivadas
Condrócitos/citologia
Condrócitos/efeitos dos fármacos
Condrócitos/metabolismo
Feminino
Expressão Gênica/efeitos dos fármacos
Seres Humanos
Masculino
Células Mesenquimais Estromais/citologia
Células Mesenquimais Estromais/efeitos dos fármacos
Células Mesenquimais Estromais/metabolismo
MicroRNAs/antagonistas & inibidores
MicroRNAs/genética
Meia-Idade
Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores
Proteínas Quinases Ativadas por Mitógeno/metabolismo
NF-kappa B/antagonistas & inibidores
NF-kappa B/metabolismo
Osteoartrite do Joelho/genética
Osteoartrite do Joelho/metabolismo
Osteoartrite do Joelho/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antagomirs); 0 (Interleukin-1beta); 0 (MIRN92 microRNA, human); 0 (MicroRNAs); 0 (NF-kappa B); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171215
[St] Status:MEDLINE
[do] DOI:10.1159/000484579


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[PMID]:29293679
[Au] Autor:Bauters D; Bedossa P; Lijnen HR; Hemmeryckx B
[Ad] Endereço:Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
[Ti] Título:Functional role of ADAMTS5 in adiposity and metabolic health.
[So] Source:PLoS One;13(1):e0190595, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies with gene-deficient mice (ADAMTS5-P) revealed that ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs, member 5) plays a functional role in adiposity and metabolic health. To confirm these observations, we have performed similar studies with an independently generated strain of ADAMTS5 deficient mice (ADAMTS5-J). Upon cold exposure as well as after high-fat diet feeding (diet-induced obesity or DIO model), these knockout (KO) mice developed less subcutaneous and gonadal white adipose tissue (WAT) as compared to their wild-type (WT) littermates (reduction was more pronounced in ADAMTS5-P mice). Enhanced browning of WAT, as monitored by expression of UCP-1 was seen in the ADAMTS5-J KO mice upon cold exposure but not in the DIO model (seen in both conditions with the ADAMTS5-P mice). Brown adipose tissue (BAT) mass was not different between KO and WT ADAMTS5-J mice, either upon cold exposure or in the DIO model (in contrast to the enhanced BAT mass with the ADAMTS5-P mice). Energy expenditure and thermogenesis were not significantly different between KO and WT ADAMTS5-J mice (in contrast to somewhat enhanced levels in ADAMTS5-P mice). Insulin sensitivity was improved in the ADAMTS5-J KO mice, and they were protected against non-alcoholic steatohepatitis in the DIO model (as the ADAMTS5-P mice). These data are thus similar for both strains of KO mice, confirming specificity of the phenotype, but some quantitative and qualitative differences are also observed.
[Mh] Termos MeSH primário: Proteína ADAMTS5/fisiologia
Adiposidade/fisiologia
[Mh] Termos MeSH secundário: Proteína ADAMTS5/genética
Tecido Adiposo Marrom/metabolismo
Animais
Western Blotting
Calorimetria
Temperatura Baixa
Dieta Hiperlipídica
Metabolismo Energético
Regulação da Expressão Gênica
Camundongos
Camundongos Knockout
Termogênese
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.4.24.- (ADAMTS5 Protein)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180103
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190595


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[PMID]:28464560
[Au] Autor:Wilkinson DJ; Habgood A; Lamb HK; Thompson P; Hawkins AR; Désilets A; Leduc R; Steinmetzer T; Hammami M; Lee MS; Craik CS; Watson S; Lin H; Milner JM; Rowan AD
[Ad] Endereço:Newcastle University, Newcastle upon Tyne, UK.
[Ti] Título:Matriptase Induction of Metalloproteinase-Dependent Aggrecanolysis In Vitro and In Vivo: Promotion of Osteoarthritic Cartilage Damage by Multiple Mechanisms.
[So] Source:Arthritis Rheumatol;69(8):1601-1611, 2017 08.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To assess the ability of matriptase, a type II transmembrane serine proteinase, to promote aggrecan loss from the cartilage of patients with osteoarthritis (OA) and to determine whether its inhibition can prevent aggrecan loss and cartilage damage in experimental OA. METHODS: Aggrecan release from human OA cartilage explants and human stem cell-derived cartilage discs was evaluated, and cartilage-conditioned media were used for Western blotting. Gene expression was analyzed by real-time polymerase chain reaction. Murine OA was induced by surgical destabilization of the medial meniscus, and matriptase inhibitors were administered via osmotic minipump or intraarticular injection. Cartilage damage was scored histologically and aggrecan cleavage was visualized immunohistochemically using specific neoepitope antibodies. RESULTS: The addition of soluble recombinant matriptase promoted a time-dependent release of aggrecan (and collagen) from OA cartilage, which was sensitive to metalloproteinase inhibition and protease-activated receptor 2 antagonism. Although engineered human (normal) cartilage discs failed to release aggrecan following matriptase addition, both matrix metalloproteinase- and aggrecanase-mediated cleavages of aggrecan were detected in human OA cartilage. Additionally, while matriptase did not directly degrade aggrecan, it promoted the accumulation of low-density lipoprotein receptor-related protein 1 (LRP-1) in conditioned media of the OA cartilage explants. Matriptase inhibition via neutralizing antibody or small molecule inhibitor significantly reduced cartilage damage scores in murine OA, which was associated with reduced generation of metalloproteinase-mediated aggrecan cleavage. CONCLUSION: Matriptase potently induces the release of metalloproteinase-generated aggrecan fragments as well as soluble LRP-1 from OA cartilage. Therapeutic targeting of matriptase proteolytic activity reduces metalloproteinase activity, further suggesting that this serine proteinase may have potential as a disease-modifying therapy in OA.
[Mh] Termos MeSH primário: Agrecanas/efeitos dos fármacos
Cartilagem Articular/efeitos dos fármacos
Osteoartrite do Joelho/metabolismo
Serina Endopeptidases/farmacologia
[Mh] Termos MeSH secundário: Proteína ADAMTS4/efeitos dos fármacos
Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/efeitos dos fármacos
Proteína ADAMTS5/metabolismo
Idoso
Idoso de 80 Anos ou mais
Agrecanas/metabolismo
Animais
Anticorpos Neutralizantes/farmacologia
Western Blotting
Cartilagem Articular/metabolismo
Cartilagem Articular/patologia
Endopeptidases/efeitos dos fármacos
Endopeptidases/metabolismo
Feminino
Perfilação da Expressão Gênica
Seres Humanos
Imuno-Histoquímica
Técnicas In Vitro
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Masculino
Metaloproteinases da Matriz/efeitos dos fármacos
Metaloproteinases da Matriz/metabolismo
Proteínas de Membrana/antagonistas & inibidores
Proteínas de Membrana/metabolismo
Meniscos Tibiais/cirurgia
Camundongos
Meia-Idade
Osteoartrite do Joelho/patologia
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Recombinantes/farmacologia
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aggrecans); 0 (Antibodies, Neutralizing); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 0 (Membrane Proteins); 0 (Recombinant Proteins); EC 3.4.- (Endopeptidases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.109 (ST14 protein, human); EC 3.4.21.109 (St14 protein, mouse); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Matrix Metalloproteinases); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.99.- (aggrecanase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180119
[Lr] Data última revisão:
180119
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/art.40133


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[PMID]:28728848
[Au] Autor:Liu Y; Zhu H; Yan X; Gu H; Gu Z; Liu F
[Ad] Endereço:Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.
[Ti] Título:Endoplasmic reticulum stress participates in the progress of senescence and apoptosis of osteoarthritis chondrocytes.
[So] Source:Biochem Biophys Res Commun;491(2):368-373, 2017 Sep 16.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endoplasmic reticulum stress (ERS) has been shown to participate in many disease pathologies. Recent reports have reported that ERS exists in human osteoarthritis (OA) chondrocytes. During OA, chondrocytes exhibit increased level of some senescence marker, such as senescence-associated ß-galactosidase (SA ß-gal) activity. However, the persistence and accumulation of senescent cells in various tissues can also impair function and have been involved in the pathogenesis of many age-related diseases, including OA. In this present study, we used IL-1ß (10 ng/ml) to mimic OA chondrocytes and we found that IL-1ß stimulated chondrocytes caused the increasing expression of ADAMTS5 and MMP13, decreasing COL2A1 expression, which were in accord with OA chondrocytes changes. Our data also showed that ERS is involved in the OA chondrocytes, SA ß-gal activity significantly increases and inhibition of ERS can decrease the SA ß-gal activity, apoptosis of OA chondrocytes and increase cell viability. These results help us to open new perspectives for the development of molecular-targeted treatment approaches and thus present an effective novel therapeutic approach for OA.
[Mh] Termos MeSH primário: Condrócitos/efeitos dos fármacos
Estresse do Retículo Endoplasmático/efeitos dos fármacos
Interleucina-1beta/farmacologia
Osteoartrite/genética
Fenilbutiratos/farmacologia
[Mh] Termos MeSH secundário: Proteína ADAMTS5/genética
Proteína ADAMTS5/metabolismo
Apoptose/efeitos dos fármacos
Cartilagem Articular/citologia
Cartilagem Articular/efeitos dos fármacos
Cartilagem Articular/metabolismo
Sobrevivência Celular/efeitos dos fármacos
Senescência Celular/efeitos dos fármacos
Condrócitos/citologia
Condrócitos/metabolismo
Colágeno Tipo II/genética
Colágeno Tipo II/metabolismo
Estresse do Retículo Endoplasmático/genética
Regulação da Expressão Gênica
Seres Humanos
Interleucina-1beta/antagonistas & inibidores
Metaloproteinase 13 da Matriz/genética
Metaloproteinase 13 da Matriz/metabolismo
Modelos Biológicos
Osteoartrite/metabolismo
Osteoartrite/patologia
Cultura Primária de Células
Transdução de Sinais
beta-Galactosidase/antagonistas & inibidores
beta-Galactosidase/genética
beta-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (COL2A1 protein, human); 0 (Collagen Type II); 0 (IL1B protein, human); 0 (Interleukin-1beta); 0 (Phenylbutyrates); 7WY7YBI87E (4-phenylbutyric acid); EC 3.2.1.23 (beta-Galactosidase); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (ADAMTS5 protein, human); EC 3.4.24.- (MMP13 protein, human); EC 3.4.24.- (Matrix Metalloproteinase 13)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE


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[PMID]:28613895
[Au] Autor:Durham TB; Marimuthu J; Toth JL; Liu C; Adams L; Mudra DR; Swearingen C; Lin C; Chambers MG; Thirunavukkarasu K; Wiley MR
[Ad] Endereço:Eli Lilly and Company , Lilly Corporate Center, Indianapolis, Indiana 46285, United States.
[Ti] Título:A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose.
[So] Source:J Med Chem;60(13):5933-5939, 2017 Jul 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC is 5 mg q.d.
[Mh] Termos MeSH primário: Proteína ADAMTS4/antagonistas & inibidores
Proteína ADAMTS5/antagonistas & inibidores
Inibidores Enzimáticos/química
Inibidores Enzimáticos/uso terapêutico
Hidantoínas/química
Hidantoínas/uso terapêutico
Osteoartrite/tratamento farmacológico
[Mh] Termos MeSH secundário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Agrecanas/metabolismo
Animais
Inibidores Enzimáticos/sangue
Inibidores Enzimáticos/farmacologia
Seres Humanos
Hidantoínas/sangue
Hidantoínas/farmacologia
Masculino
Simulação de Acoplamento Molecular
Osteoartrite/enzimologia
Osteoartrite/metabolismo
Ratos
Ratos Endogâmicos Lew
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Enzyme Inhibitors); 0 (Hydantoins); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.82 (ADAMTS4 Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00650


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[PMID]:28546218
[Au] Autor:Li F; Song R; Ao L; Reece TB; Cleveland JC; Dong N; Fullerton DA; Meng X
[Ad] Endereço:From the Department of Surgery, University of Colorado Denver, Aurora (F.L., R.S., L.A., T.B.R., J.C.C., D.A.F., X.M.); and Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (F.L., N.D.).
[Ti] Título:ADAMTS5 Deficiency in Calcified Aortic Valves Is Associated With Elevated Pro-Osteogenic Activity in Valvular Interstitial Cells.
[So] Source:Arterioscler Thromb Vasc Biol;37(7):1339-1351, 2017 Jul.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Extracellular matrix proteinases are implicated in the pathogenesis of calcific aortic valve disease. The ADAMTS5 (a disintegrin and metalloproteinase with thrombospondin motifs 5) enzyme is secreted, matrix-associated metalloendopeptidase, capable of degrading extracellular matrix proteins, particularly matrilin 2. We sought to determine the role of the ADAMTS5/matrilin 2 axis in mediating the phenotype transition of valvular interstitial cells (VICs) associated with calcific aortic valve disease. APPROACH AND RESULTS: Levels of ADAMTS5, matrilin 2, and α-SMA (α-smooth muscle actin) were evaluated in calcified and normal human aortic valve tissues and VICs. Calcified aortic valves have reduced levels of ADAMTS5 and higher levels of matrilin 2 and α-SMA. Treatment of normal VICs with soluble matrilin 2 caused an increase in α-SMA level through Toll-like receptors 2 and 4, which was accompanied by upregulation of runt-related transcription factor 2 and alkaline phosphatase. In addition, ADAMTS5 knockdown in normal VICs enhanced the effect of matrilin 2. Matrilin 2 activated nuclear factor (NF) κB and NF of activated T cells complex 1 and induced the interaction of these 2 NFs. Inhibition of either NF-κB or NF of activated T cells complex 1 suppressed matrilin 2's effect on VIC phenotype change. Knockdown of α-SMA reduced and overexpression of α-SMA enhanced the expression of pro-osteogenic factors and calcium deposit formation in human VICs. CONCLUSIONS: Matrilin 2 induces myofibroblastic transition and elevates pro-osteogenic activity in human VICs via activation of NF-κB and NF of activated T cells complex 1. Myofibroblastic transition in human VICs is an important mechanism of elevating the pro-osteogenic activity. Matrilin 2 accumulation associated with relative ADAMTS5 deficiency may contribute to the mechanism underlying calcific aortic valve disease progression.
[Mh] Termos MeSH primário: Proteína ADAMTS5/deficiência
Estenose da Valva Aórtica/enzimologia
Valva Aórtica/enzimologia
Valva Aórtica/patologia
Calcinose/enzimologia
Transdiferenciação Celular
Miofibroblastos/enzimologia
Osteogênese
[Mh] Termos MeSH secundário: Proteína ADAMTS5/genética
Actinas/genética
Actinas/metabolismo
Adulto
Idoso
Fosfatase Alcalina/metabolismo
Estenose da Valva Aórtica/genética
Estenose da Valva Aórtica/patologia
Calcinose/genética
Calcinose/patologia
Estudos de Casos e Controles
Células Cultivadas
Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo
Seres Humanos
Masculino
Proteínas Matrilinas/metabolismo
Meia-Idade
Miofibroblastos/patologia
NF-kappa B/metabolismo
Fatores de Transcrição NFATC/genética
Fatores de Transcrição NFATC/metabolismo
Fenótipo
Interferência de RNA
Transdução de Sinais
Receptor 2 Toll-Like/genética
Receptor 2 Toll-Like/metabolismo
Receptor 4 Toll-Like/genética
Receptor 4 Toll-Like/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ACTA2 protein, human); 0 (Actins); 0 (Core Binding Factor Alpha 1 Subunit); 0 (MATN2 protein, human); 0 (Matrilin Proteins); 0 (NF-kappa B); 0 (NFATC Transcription Factors); 0 (NFATC1 protein, human); 0 (RUNX2 protein, human); 0 (TLR2 protein, human); 0 (TLR4 protein, human); 0 (Toll-Like Receptor 2); 0 (Toll-Like Receptor 4); EC 3.1.3.1 (Alkaline Phosphatase); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (ADAMTS5 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170721
[Lr] Data última revisão:
170721
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.309021


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[PMID]:28544596
[Au] Autor:Ouhaddi Y; Nebbaki SS; Habouri L; Afif H; Lussier B; Kapoor M; Narumiya S; Pelletier JP; Martel-Pelletier J; Benderdour M; Fahmi H
[Ad] Endereço:University of Montreal Hospital Research Center and University of Montreal, Montreal, Quebec, Canada.
[Ti] Título:Exacerbation of Aging-Associated and Instability-Induced Murine Osteoarthritis With Deletion of D Prostanoid Receptor 1, a Prostaglandin D Receptor.
[So] Source:Arthritis Rheumatol;69(9):1784-1795, 2017 Sep.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: D prostanoid receptor 1 (DP1), a receptor for prostaglandin D , plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown. This study was undertaken to explore the roles of DP1 in the development of OA in murine models and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA. METHODS: The development of aging-associated OA and destabilization of the medial meniscus (DMM)-induced OA was compared between DP1-deficient (DP1 ) and wild-type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and micro-computed tomography. Cartilage explants from DP1 and WT mice were treated with interleukin-1α (IL-1α) ex vivo, to evaluate proteoglycan degradation. The effect of intraperitoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice. RESULTS: Compared to WT mice, DP1 mice had exacerbated cartilage degradation in both models of OA, and this was associated with increased expression of matrix metalloproteinase 13 and ADAMTS-5. In addition, DP1 mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1 mice showed enhanced proteoglycan degradation following treatment with IL-1α. Intraperitoneal injection of BW245C attenuated the severity of DMM-induced cartilage degradation and bony changes in WT mice. CONCLUSION: These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of the functions of DP1 may constitute a potential therapeutic target for the development of novel OA treatments.
[Mh] Termos MeSH primário: Artrite Experimental/genética
Artrite Experimental/patologia
Osteoartrite do Joelho/genética
Osteoartrite do Joelho/patologia
Receptores de Prostaglandina/deficiência
[Mh] Termos MeSH secundário: Proteína ADAMTS5/metabolismo
Animais
Cartilagem/efeitos dos fármacos
Cartilagem/patologia
Progressão da Doença
Hidantoínas/farmacologia
Interleucina-1alfa/farmacologia
Metaloproteinase 13 da Matriz/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Proteoglicanas/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hydantoins); 0 (Interleukin-1alpha); 0 (Proteoglycans); 0 (Receptors, Prostaglandin); 0 (prostanoid D receptor 1, mouse); 75693-75-3 (BW 245C); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Matrix Metalloproteinase 13); EC 3.4.24.- (Mmp13 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/art.40160


  8 / 302 MEDLINE  
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[PMID]:28341660
[Au] Autor:Wang K; Song Y; Liu W; Wu X; Zhang Y; Li S; Kang L; Tu J; Zhao K; Hua W; Yang C
[Ad] Endereço:Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
[Ti] Título:The noncoding RNA linc-ADAMTS5 cooperates with RREB1 to protect from intervertebral disc degeneration through inhibiting ADAMTS5 expression.
[So] Source:Clin Sci (Lond);131(10):965-979, 2017 May 01.
[Is] ISSN:1470-8736
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Previous studies have indicated the important roles of ADAMTS5 in intervertebral disc degeneration (IDD). However, the mechanisms that regulate ADAMTS5 expression in nuclear pulposus (NP) cells remain largely unknown. Evidence suggests that intergenic transcription may be associated with genes that encode transcriptional regulators. Here, we identified a long intergenic noncoding RNA, linc-ADAMTS5, which was transcribed in the opposite direction to ADAMTS5. In the present study, through mining computational algorithm programs, and publicly available data sets, we identified Ras-responsive element-binding protein 1 (RREB1) as a crucial transcription factor regulating the expression of ADAMTS5 in NP cells. RNA pull-down, RNA immunoprecipitation (RIP), binding assays, and gain- and loss-of-function studies indicated that a physical interaction between linc-ADAMTS5 and splicing factor proline/glutamine-rich (SFPQ) facilitated the recruitment of RREB1 to binding sites within the ADAMTS5 promoter to induce chromatin remodeling. This resulted in subdued ADAMTS5 levels in cultured NP cells involving histone deacetylases (HDACs). In clinical NP tissues, linc-ADAMTS5 and RREB1 were correlated negatively with ADAMTS5 expression. Taken together, these results demonstrate that RREB1 cooperates with noncoding RNA linc-ADAMTS5 to inhibit ADAMTS5 expression, thereby affecting degeneration of the extracellular matrix (ECM) of the intervertebral disc (IVD).
[Mh] Termos MeSH primário: Proteína ADAMTS5/genética
Proteínas de Ligação a DNA/metabolismo
Regulação para Baixo
Degeneração do Disco Intervertebral/metabolismo
RNA Longo não Codificante/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Proteína ADAMTS5/metabolismo
Adolescente
Adulto
Proteínas de Ligação a DNA/genética
Feminino
Seres Humanos
Degeneração do Disco Intervertebral/genética
Masculino
Meia-Idade
RNA Longo não Codificante/genética
Fatores de Transcrição/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (LOC101926975 long non-coding RNA, human); 0 (LOC105372760 lncRNA, human); 0 (RNA, Long Noncoding); 0 (RREB1 protein, human); 0 (Transcription Factors); EC 3.4.24.- (ADAMTS5 Protein)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170727
[Lr] Data última revisão:
170727
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE
[do] DOI:10.1042/CS20160918


  9 / 302 MEDLINE  
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[PMID]:28235248
[Au] Autor:Yamamoto K; Santamaria S; Botkjaer KA; Dudhia J; Troeberg L; Itoh Y; Murphy G; Nagase H
[Ad] Endereço:University of Oxford, Oxford, UK.
[Ti] Título:Inhibition of Shedding of Low-Density Lipoprotein Receptor-Related Protein 1 Reverses Cartilage Matrix Degradation in Osteoarthritis.
[So] Source:Arthritis Rheumatol;69(6):1246-1256, 2017 Jun.
[Is] ISSN:2326-5205
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The aggrecanase ADAMTS-5 and the collagenase matrix metalloproteinase 13 (MMP-13) are constitutively secreted by chondrocytes in normal cartilage, but rapidly endocytosed via the cell surface endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP-1) and subsequently degraded. This endocytic system is impaired in osteoarthritic (OA) cartilage due to increased ectodomain shedding of LRP-1. The aim of this study was to identify the LRP-1 sheddase(s) in human cartilage and to test whether inhibition of LRP-1 shedding prevents cartilage degradation in OA. METHODS: Cell-associated LRP-1 and soluble LRP-1 (sLRP-1) released from human cartilage explants and chondrocytes were measured by Western blot analysis. LRP-1 sheddases were identified by proteinase inhibitor profiling and gene silencing with small interfering RNAs. Specific monoclonal antibodies were used to selectively inhibit the sheddases. Degradation of aggrecan and collagen in human OA cartilage was measured by Western blot analysis using an antibody against an aggrecan neoepitope and a hydroxyproline assay, respectively. RESULTS: Shedding of LRP-1 was increased in OA cartilage compared with normal tissue. Shed sLRP-1 bound to ADAMTS-5 and MMP-13 and prevented their endocytosis without interfering with their proteolytic activities. Two membrane-bound metalloproteinases, ADAM-17 and MMP-14, were identified as the LRP-1 sheddases in cartilage. Inhibition of their activities restored the endocytic capacity of chondrocytes and reduced degradation of aggrecan and collagen in OA cartilage. CONCLUSION: Shedding of LRP-1 is a key link to OA progression. Local inhibition of LRP-1 sheddase activities of ADAM-17 and MMP-14 is a unique way to reverse matrix degradation in OA cartilage and could be effective as a therapeutic approach.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacologia
Colagenases/efeitos dos fármacos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/efeitos dos fármacos
Osteoartrite/tratamento farmacológico
Proteólise/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteína ADAM17/análise
Proteína ADAM17/metabolismo
Proteína ADAMTS5/metabolismo
Adolescente
Adulto
Agrecanas/efeitos dos fármacos
Cartilagem Articular/metabolismo
Criança
Condrócitos/fisiologia
Colágeno/efeitos dos fármacos
Endocitose/efeitos dos fármacos
Feminino
Seres Humanos
Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia
Masculino
Metaloproteinase 13 da Matriz/metabolismo
Metaloproteinase 14 da Matriz/análise
Metaloproteinase 14 da Matriz/metabolismo
Meia-Idade
Osteoartrite/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aggrecans); 0 (Antibodies, Monoclonal); 0 (Low Density Lipoprotein Receptor-Related Protein-1); 9007-34-5 (Collagen); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (Collagenases); EC 3.4.24.- (MMP13 protein, human); EC 3.4.24.- (Matrix Metalloproteinase 13); EC 3.4.24.80 (MMP14 protein, human); EC 3.4.24.80 (Matrix Metalloproteinase 14); EC 3.4.24.86 (ADAM17 Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1002/art.40080


  10 / 302 MEDLINE  
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[PMID]:28099917
[Au] Autor:Fontanil T; Álvarez-Teijeiro S; Villaronga MÁ; Mohamedi Y; Solares L; Moncada-Pazos A; Vega JA; García-Suárez O; Pérez-Basterrechea M; García-Pedrero JM; Obaya AJ; Cal S
[Ad] Endereço:Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Asturias Spain.
[Ti] Título:Cleavage of Fibulin-2 by the aggrecanases ADAMTS-4 and ADAMTS-5 contributes to the tumorigenic potential of breast cancer cells.
[So] Source:Oncotarget;8(8):13716-13729, 2017 Feb 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fibulin-2 participates in the assembly of extracellular matrix components through interactions with multiple ligands and promotes contacts between cells and their surrounding environment. Consequently, identification of processes that could lead to an altered Fibulin-2 could have a major impact not only in the maintenance of tissue architecture and morphogenesis but also in pathological situations including cancer. Herein, we have investigated the ability of the secreted metalloproteases ADAMTS-4 and ADAMTS-5 to digest Fibulin-2. Using in vitro approaches and cultured breast cancer cell lines we demonstrate that Fibulin-2 is a better substrate for ADAMTS-5 than it is for ADAMTS-4. Moreover, Fibulin-2 degradation is associated to an enhancement of the invasive potential of T47D, MCF-7 and SK-BR-3 cells. We have also found that conditioned medium from MCF-7 cells that simultaneously overexpress Fibulin-2 and ADAMTS-5 significantly induced the migratory and invasive ability of normal breast fibroblasts using 3D collagen matrices. Immunohistochemical analysis highlights the close proximity or partial overlap of both Fibulin-2 and ADAMTS-5 in breast tumor samples. Additionally, proteolytic products derived from a potential degradation of Fibulin-2 by ADAMTS-5 were also identified in these samples. Finally, we also show that the cleavage of Fibulin-2 by ADAMTS-5 is counteracted by ADAMTS-12, a metalloprotease that interacts with Fibulin-2. Overall, our results provide direct evidence indicating that Fibulin-2 is a novel substrate of ADAMTS-5 and that this proteolysis could alter the cellular microenvironment affecting the balance between protumor and antitumor effects associated to both Fibulin-2 and the ADAMTSs metalloproteases.
[Mh] Termos MeSH primário: Proteína ADAMTS4/metabolismo
Proteína ADAMTS5/metabolismo
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Proteínas de Ligação ao Cálcio/metabolismo
Proteínas da Matriz Extracelular/metabolismo
[Mh] Termos MeSH secundário: Neoplasias da Mama/enzimologia
Carcinogênese
Linhagem Celular Tumoral
Feminino
Fibroblastos/patologia
Seres Humanos
Células MCF-7
Esferoides Celulares
Transfecção
Microambiente Tumoral
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Extracellular Matrix Proteins); 0 (fibulin 2); EC 3.4.24.- (ADAMTS5 Protein); EC 3.4.24.- (ADAMTS5 protein, human); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14627



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