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1.
Life Sci ; 253: 117694, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32325132

RESUMO

AIMS: Chondrocyte degeneration is the main cause of osteoarthritis (OA) and increased evidence suggests that miRNAs could have vital roles in the pathology of various cartilage illnesses. miR-1236 has been found to contribute to inflammation in diseases such as pneumonia. However, the exact role of miR-1236 in OA is poorly understood. MATERIALS AND METHODS: H&E staining and saffron fixation experiments were employed to determine OA tissues. qRT-PCR and immunohistochemistry were used to detect the expression levels of miR-1236 and PIK3R3. Western blot was performed to detect the expression levels of proteins. Luciferase reporter assays were utilized to investigate the interaction between miR-1236 and PIK3R3. Cell counting assays and AO/EB were used to quantify cell growth and apoptosis. KEY FINDINGS: miR-1236 was up-regulated in OA knee cartilage compared to normal cartilage. Up-regulated expression of miR-1236 suppressed cell proliferation as well as induced apoptosis in chondrocytes. Bioinformatics identified PIK3R3 as a target of miR-1236. Co-transfection with miR-1236 and PIK3R3 could reverse cell apoptosis induced by the miR-1236 mimic. SIGNIFICANCE: These data enhance our understanding on the role of miR-1236 in OA and identifies miR-1236 as a potential biomarker or possible treatment target within OA.


Assuntos
Apoptose/genética , Condrócitos/patologia , MicroRNAs/genética , Osteoartrite do Joelho/patologia , Fosfatidilinositol 3-Quinases/genética , Cartilagem/patologia , Proliferação de Células/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/genética , Regulação para Cima
2.
Pathologe ; 41(2): 143-152, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-32060685

RESUMO

Cartilage tumors are a heterogeneous group of mesenchymal tumors whose common characteristic is the formation of a chondroblastic differentiated groundsubstance by the tumor cells. The basic features of their histological classification were already developed in the 1940s and supplemented by further entities in the following decades. Only in the past 10-15 years have fundamental new insights been gained through molecular genetic analysis. So, osteochondromas are characterized by alterations in the EXT1 and EXT2 genes. The description of mutations of isocitrate dehydrogenase 1 and 2 (IDH 1 and 2) in chondromas and chondrosarcomas is particularly important. The mesenchymal chondrosarcoma is characterized by a fusion of the HEY1-NCOA2 genes. The molecular genetic alterations characteristic for the individual tumor entities are first of all an essential supplement for the differential diagnosis of radiologically and histologically difficult cases. They also provide the basis for the establishment of molecular target therapies for malignant chondrogenic tumors. This applies in particular to conventional chondrosarcoma, for which all approaches to chemo- and radiotherapy have proven to be ineffective. However, the use of target therapies is still in its beginnings.


Assuntos
Neoplasias Ósseas , Cartilagem/patologia , Terapia de Alvo Molecular , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Humanos
3.
Sci Rep ; 10(1): 1441, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996703

RESUMO

Inflammation plays a critical role in osteoarthritis (OA). It stimulates catabolic events in articular chondrocytes and prevents chondrogenic precursor cells from repairing cartilage lesions, leading to accelerated cartilage degradation. Therefore, the identification of novel factors that reduce catabolic events in chondrocytes and enhances chondrogenic differentiation of precursor cells in an inflammatory environment may provide novel therapeutic strategies for the treatment of OA. The goal of this study was to determine whether a hyaluronan (HA)-binding peptide (P15-1), via interacting with high molecular weight (HMW)HA can enhance the anti-inflammatory properties of HMWHA and decrease catabolic events in interleukin-1beta (IL-1ß)-treated human articular chondrocytes. Treatment with P15-1 decreased catabolic events and stimulated anabolic events in articular chondrocytes cultured in an inflammatory environment. P15-1 pre-mixed with HMWHA was more effective in inhibiting catabolic events and stimulating anabolic events than P15-1 or HMWHA alone. Our findings suggest that P15-1 together with HMWHA inhibits catabolic events in articular chondrocytes via the inhibition of p38 mitogen-activated protein kinases (MAPK) and increasing the thickness of the pericellular matrix (PCM) around chondrocytes thereby decreasing catabolic signaling. Finally, conditioned medium from IL-1ß and P15-1-treated human articular chondrocytes was less inhibitory for chondrogenic differentiation of precursor cells than conditioned medium from chondrocytes treated with IL-1ß alone. In conclusion, P15-1 is proposed to function synergistically with HMWHA to enhance the protective microenvironment for chondrocytes and mesenchymal stem cells during inflammation and regeneration.


Assuntos
Cartilagem/patologia , Condrócitos/metabolismo , Receptores de Hialuronatos/metabolismo , Inflamação/metabolismo , Osteoartrite/metabolismo , Adulto , Diferenciação Celular , Células Cultivadas , Condrócitos/patologia , Condrogênese , Meios de Cultivo Condicionados/farmacologia , Matriz Extracelular/metabolismo , Humanos , Ácido Hialurônico/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Clin Exp Rheumatol ; 38(2): 203-211, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31140393

RESUMO

OBJECTIVES: Systemic inflammation is very closely linked to the increased risk of cardiovascular diseases (CVD) in rheumatoid arthritis (RA). We investigated the cardiac changes during the development of arthritis in collagen-induced arthritis (CIA) mice to explore the potential role of inflammation on cardiac dysfunction in RA. METHODS: Arthritis severity was evaluated using clinical indices, micro-computed tomography and histopathology. Cardiac function was determined by transthoracic echocardiography at weeks 5, 7, 9 and 11 after immunisation in mice. At week 7 (day 50), mice joints and hearts were removed for pathological study, and cardiomyocytes and cardiac fibroblasts were isolated using Langendorff perfusion method ex vivo to measure the expression of inflammatory and cardiac-related genes by real time PCR. The expression of key molecule in cardiac dysfunction (ß-MHC) was also tested in H9c2 cardiomyocyte treated with sera derived from CIA mice or RA patients. RESULTS: At day 50 after immunisation, cardiac function in CIA mice was prominently reduced as evidenced by decreased ejection fraction (EF) and fractional shortening (FS), increased left ventricular end-systolic volume (LVESV) and internal systolic diameter (LVIDs). Accordingly, enhanced inflammatory cell infiltration and fibrosis were identified in ventricular tissues pathologically, and increased inflammatory gene expression including TNF-α, IL-6, IL-17 and MMP3 was detected in isolated ventricular cardiomyocytes and cardiac fibroblasts from CIA mice. Furthermore, H9c2 cells treated with sera from CIA mice or RA patients exhibited high levels of ß-MHC. CONCLUSIONS: Joint inflammation is associated with an obvious cardiac dysfunction and enhanced inflammation infiltration and inflammatory cytokine production in cardiomyocytes and cardiac fibroblasts during CIA development. Our data provide the direct evidence that inflammation contributes to the development of cardiac diseases in RA patients.


Assuntos
Artrite Experimental , Cardiopatias , Inflamação/fisiopatologia , Animais , Artrite Experimental/patologia , Artrite Experimental/fisiopatologia , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Cartilagem/patologia , Modelos Animais de Doenças , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Cardiopatias/patologia , Humanos , Camundongos , Microtomografia por Raio-X
5.
Hum Genomics ; 13(1): 63, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31806011

RESUMO

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is characteristic of multiple skeletal anomalies comprising craniofacial anomalies/dysplasia, microcephaly, dysplastic ears, choanal atresia, and short stature. Heterozygous loss of function variants of EFTUD2 was previously reported in MFDM; however, the mechanism underlying EFTUD2-associated skeletal dysplasia remains unclear. RESULTS: We identified a novel frameshift variant of EFTUD2 (c.1030_1031delTG, p.Trp344fs*2) in an MFDM Chinese patient with craniofacial dysmorphism including ear canal structures and microcephaly, mild intellectual disability, and developmental delay. We generated a zebrafish model of eftud2 deficiency, and a consistent phenotype consisting of mandibular bone dysplasia and otolith loss was observed. We also showed that EFTUD2 deficiency significantly inhibited proliferation, differentiation, and maturation in human calvarial osteoblast (HCO) and human articular chondrocyte (HC-a) cells. RNA-Seq analysis uncovered activated TP53 signaling with increased phosphorylation of the TP53 protein and upregulation of five TP53 downstream target genes (FAS, STEAP3, CASP3, P21, and SESN1) both in HCO and in eftud2-/- zebrafish. Additionally, inhibition of p53 by morpholino significantly reduced the mortality of eftud2-/- larvae. CONCLUSIONS: Our results confirm a novel de novo variant of the EFTUD2 gene and suggest that EFTUD2 may participate in the maturation and differentiation of osteoblasts and chondrocytes, possibly via activation of the TP53 signaling pathway. Thus, mutations in this gene may lead to skeletal anomalies in vertebrates.


Assuntos
Diferenciação Celular , Condrócitos/patologia , Osteoblastos/patologia , Fatores de Alongamento de Peptídeos/deficiência , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/deficiência , Ribonucleoproteína Nuclear Pequena U5/genética , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo , Animais , Sequência de Bases , Osso e Ossos/embriologia , Osso e Ossos/patologia , Cartilagem/embriologia , Cartilagem/patologia , Linhagem Celular , Pré-Escolar , Condrócitos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Masculino , Mutação/genética , Osteoblastos/metabolismo , Linhagem , Fatores de Alongamento de Peptídeos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonucleoproteína Nuclear Pequena U5/metabolismo , Fatores de Tempo , Peixe-Zebra
6.
Int J Mol Sci ; 20(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847077

RESUMO

The unavailability of sufficient numbers of human primary cells is a major roadblock for in vitro repair of bone and/or cartilage, and for performing disease modelling experiments. Immortalized mesenchymal stromal cells (iMSCs) may be employed as a research tool for avoiding these problems. The purpose of this review was to revise the available literature on the characteristics of the iMSC lines, paying special attention to the maintenance of the phenotype of the primary cells from which they were derived, and whether they are effectively useful for in vitro disease modeling and cell therapy purposes. This review was performed by searching on Web of Science, Scopus, and PubMed databases from 1 January 2015 to 30 September 2019. The keywords used were ALL = (mesenchymal AND ("cell line" OR immortal*) AND (cartilage OR chondrogenesis OR bone OR osteogenesis) AND human). Only original research studies in which a human iMSC line was employed for osteogenesis or chondrogenesis experiments were included. After describing the success of the immortalization protocol, we focused on the iMSCs maintenance of the parental phenotype and multipotency. According to the literature revised, it seems that the maintenance of these characteristics is not guaranteed by immortalization, and that careful selection and validation of clones with particular characteristics is necessary for taking advantage of the full potential of iMSC to be employed in bone and cartilage-related research.


Assuntos
Regeneração Óssea , Osso e Ossos , Cartilagem , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Osso e Ossos/lesões , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cartilagem/lesões , Cartilagem/metabolismo , Cartilagem/patologia , Condrogênese , Humanos , Células-Tronco Mesenquimais/patologia , Osteogênese
7.
Int J Hyperthermia ; 36(1): 1189-1195, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884842

RESUMO

Purpose: To determine the size of the ablation zone after radiofrequency ablation (RFA) of atypical cartilaginous bone tumors (ACT) using temperature-controlled 20 and 30 mm RFA straight non-cooled electrodes.Materials and methods: Sixteen patients with ACT in their long bones, who had undergone a single-session single-application CT-guided temperature-controlled RFA, were included retrospectively in the study. Tumors with a diameter of 10-25 mm were treated with 20 mm electrodes (n = 10), and tumors of 25-35 mm, with 30 mm electrodes (n = 6). The ablated zone was measured after three months on MRI images.Results: All the tumors were within the ablated zone on the 3-month follow-up MRI scan. The mean ablation time with the electrode, at a target temperature of 90 °C, was 7.6 minutes (range 6-10). The median of the largest ablation diameters, on applying the 20 and 30 mm electrodes, were 42 mm (IQR 8.5, range 30-51 mm) and 44.5 mm (IQR 4.5, range 42-63 mm), respectively.Conclusions: All the retrospectively viewed tumors in the long bones of ACT patients treated with RFA were completely ablated. The ablation zone diameters in the bones were larger than expected, when compared to other tissues, such as the liver.


Assuntos
Neoplasias Ósseas/terapia , Cartilagem/patologia , Ablação por Cateter/métodos , Adulto , Idoso , Neoplasias Ósseas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
8.
Med Sci Monit ; 25: 10057-10066, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881548

RESUMO

BACKGROUND Magnetic resonance imaging (MRI) of osteoarthritis (OA) of the knee is a preoperative method of joint assessment. Histology of the joint is invasive and performed after surgery. T1rho/T2 MRI mapping is a new preoperative method of quantifying joint changes. This study aimed to analyze and compare the histological changes in the joint cartilage with the use of quantitative T1rho/T2 MRI mapping in patients with OA of the knee. MATERIAL AND METHODS Twenty patients with OA of the knee (20 knees) underwent preoperative MRI with T1rho mapping, T2 mapping, T1-weighted, and T2-weighted fat-suppressed MRI sequences. The degree of OA of the knee on MRI was graded according to the Osteoarthritis Research Society International (OARSI) criteria and the Kellgren-Lawrence grading system. Histological grading of OA used the OARSI criteria. Four tibiofemoral condyles were assessed histologically, and the degree of cartilage destruction was determined using the OARSI criteria. Two investigators performed cartilage segmentation for T1rho/T2 values. RESULTS Histology of the four knee joint condyles confirmed mild to severe OA. The histology of the cartilage thickness (P<0.001) and the MRI findings of the distal medial condyle (P<0.00) were significantly different from the other three knee joint condyles. The T2 and T1rho values of each condyle were significantly correlated with the histological grade (II-IV) of the joint condyles, including the cartilage volume, cartilage defects, thickness, and bone lesions (P<0.05). CONCLUSIONS In 20 patients with OA of the knee, preoperative T2/T1rho MRI identified Grade II-IV OA changes in the joint.


Assuntos
Imagem por Ressonância Magnética , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Idoso , Medula Óssea/diagnóstico por imagem , Medula Óssea/patologia , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Cartilagem/diagnóstico por imagem , Cartilagem/patologia , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Osteófito , Tíbia/patologia , Tíbia/cirurgia , Escala Visual Analógica
9.
J Comp Pathol ; 172: 58-61, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31690417

RESUMO

Congenital anomalies of the trachea are rare in cats. This article reports segmental absence of tracheal cartilage rings in a kitten. An 8-month-old female kitten was presented with a history of weight loss and respiratory distress for 2 months. Radiographs of the thorax demonstrated a large air-filled sac suggestive of pneumomediastinum. No cartilaginous structures were evident radiographically over the caudal portion of the trachea. At necropsy examination, approximately 2 cm from the carina, a 3 cm segment of the trachea lacked cartilaginous rings. The clinical and morphological features of this lesion were similar to those described in human and canine cases of congenital segmental absence of tracheal rings.


Assuntos
Doenças do Gato/diagnóstico , Anormalidades Congênitas/veterinária , Síndrome do Desconforto Respiratório do Adulto/veterinária , Traqueia/patologia , Animais , Cartilagem/embriologia , Cartilagem/patologia , Gatos , Feminino , Síndrome do Desconforto Respiratório do Adulto/diagnóstico , Traqueia/embriologia
10.
Int Immunopharmacol ; 77: 105928, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31711940

RESUMO

Osteoarthritis (OA), a common and severe disease, is predominantly characterized by cartilage destruction, which results in the degeneration of joint surfaces. Nowadays, it is accepted that TNFα plays a critical role in OA. Scutellarin, the main bioactive flavonoid glycoside extracted form Erigeron breviscapus, has been reported to exert positive effects on anti-inflammatory reactions. However, the effect of scutellarin in OA is still unknown. In this study, we isolated and cultured primary murine chondrocytes, stimulating TNF-α, in the presence or absence of scutellarin treatment. We found that the inflammatory response stimulated by TNF-α was significantly inhibited by the addition of scutellarin. Moreover, we established OA mouse models induced by surgery. In this mouse model, both inflammatory reaction and cartilage degeneration were markedly inhibited by oral administration of scutellarin. Furthermore, the cellular mechanism underlying the protective effect of scutellarin in OA was clearly associated with the NF-κB and PI3K/AKT signaling pathways. Collectively, this study proposes scutellarin as a potential therapeutic to treat joint degenerative diseases, including OA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Apigenina/uso terapêutico , Cartilagem/efeitos dos fármacos , Glucuronatos/uso terapêutico , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Apigenina/farmacologia , Cartilagem/metabolismo , Cartilagem/patologia , Glucuronatos/farmacologia , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Articulação do Joelho/efeitos dos fármacos , Articulação do Joelho/metabolismo , Articulação do Joelho/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Osteoartrite/metabolismo , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos
11.
PLoS One ; 14(11): e0224756, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31703078

RESUMO

Fibrin sealants are commonly used in cartilage repair surgeries to adhere cells or grafts into a cartilage defect. Both autologous and commercial allogeneic fibrin sealants are used in cartilage repair surgeries, yet there are no studies characterizing and comparing the mechanical properties of fibrin sealants from all-autologous sources. The objectives of this study were to investigate (i) the effect of fibrinogen and thrombin sources on failure mechanics of sealants, and (ii) how sealants affect the adhesion of particulated cartilage graft material (BioCartilage) to surrounding cartilage under physiological loading. Allogeneic thrombin and fibrinogen were purchased (Tisseel), and autologous sources were prepared from platelet-rich plasma (PRP) and platelet-poor plasma (PPP) generated from human blood. To compare failure characteristics, sealants were sandwiched between cartilage explants and pulled to failure. The effect of sealant on the adhesion of BioCartilage graft to cartilage was determined by quantifying microscale strains at the graft-cartilage interface using an in vitro cartilage defect model subjected to shear loading at physiological strains well below failure thresholds. Fibrinogen sources were not equivalent; PRP fibrinogen created sealants that were more brittle, failed at lower strains, and resulted in sustained higher strains through the graft-cartilage interface depth compared to PPP and allogeneic sources. PPP clotted slower compared to PRP, suggesting PPP may percolate deeper into the repair to provide more stability through the tissue depth. There was no difference in bulk failure properties or microscale strains at the graft-cartilage interface between the purely autologous sealant (autologous thrombin + PPP fibrinogen) and the commercial allogeneic sealant. Clinical Significance: All-autologous fibrin sealants fabricated with PPP have comparable adhesion strength as commercial allogeneic sealants in vitro, whereas PRP creates an inferior all-autologous sealant that sustains higher strains through the graft-cartilage interface depth.


Assuntos
Cartilagem/patologia , Adesivo Tecidual de Fibrina/farmacologia , Modelos Biológicos , Cicatrização/efeitos dos fármacos , Animais , Bovinos , Módulo de Elasticidade , Fibrinogênio/metabolismo , Plasma Rico em Plaquetas/metabolismo , Trombina/metabolismo , Transplante Autólogo , Transplante Homólogo
12.
EBioMedicine ; 50: 395-407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31735552

RESUMO

BACKGROUND: Epigenetic mechanisms have been reported to play key roles in osteoarthritis (OA) development. P300/CBP-associated factor (PCAF) is a member of the histone acetyltransferases, which exhibits a strong relationship with endoplasmic reticulum (ER) stress and transcription factor nuclear factor kappa B (NF-κB) signals. Salidroside, a natural histone acetylation inhibitor, showed its anti-inflammatory and anti-apoptotic effects in lipopolysaccharide (LPS)-stimulated microglia cells in our previous study. However, whether Sal has a protective effect against OA remains unknown, and its relationships to PCAF, NF-κB, and the ER stress pathway should be explored further. METHODS: We identified the role of PCAF in the pathogenesis of OA and determined the chondroprotective effect of Sal on both tumor necrosis factor alpha (TNF-α)-treated human chondrocytes and a destabilized medial meniscus (DMM) mouse OA model. FINDINGS: We found increased PCAF expression in human OA cartilage and TNF-α-driven chondrocytes. Meanwhile, silencing of PCAF attenuated nuclear p65 and C/EBP homologous protein levels in chondrocytes upon TNF-α stimulation. Furthermore, Sal was found to specifically bind to the inhibitory site of the PCAF protein structure, which subsequently reversed the TNF-α-induced activation of NF-κB signal and ER stress-related apoptosis in chondrocytes. In addition, the protective effect of Sal and its inhibitory effects on PCAF as well as inflammatory- and ER stress-related markers were also observed in the mouse DMM model. INTERPRETATION: Pharmacological blockade of PCAF by Sal ameliorates OA development via inhibition of inflammation and ER stress, which makes Sal a promising therapeutic agents for the treatment of OA.


Assuntos
Anti-Inflamatórios/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Osteoartrite/etiologia , Osteoartrite/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Apoptose/efeitos dos fármacos , Biomarcadores , Biópsia , Cartilagem/metabolismo , Cartilagem/patologia , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Osteoartrite/diagnóstico , Osteoartrite/tratamento farmacológico , Oxirredução , Ligação Proteica , Radiografia , Fatores de Transcrição de p300-CBP/química
13.
Wiad Lek ; 72(9 cz 1): 1671-1675, 2019.
Artigo em Polonês | MEDLINE | ID: mdl-31586981

RESUMO

Osteoarthritis is the disease connected with aging which is characterised by progressive degeneration of all elements building the joint but also influencing the muscles constituting motor unit with the affected joint. The effective and unified therapy has not been yet introduced despite the broad multi-site studies concentrating on metabolic pathways responsible for the development of the disease. The reason of which is probably its multifactorial aetiology. The treatment methods are based on decreasing of cartilage destruction activity, retardation of proinflammatory factors activity and fighting with pain. Physiotherapy, movement rehabilitation, painkillers, anti-inflammatory drugs, glucosamine sulphates and hyaluronic acids are used as therapeutic strategies. The methods recently introduced are platelet rich plasma concentrates and stem cells injected directly into the affected joint. The aim of this review article was the presentation of differential therapeutic options offered to patients in different stages of osteoarthritis.


Assuntos
Envelhecimento , Cartilagem/patologia , Osteoartrite/terapia , Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Glucosamina/uso terapêutico , Humanos , Ácido Hialurônico/uso terapêutico
14.
Med Sci Monit ; 25: 7488-7498, 2019 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-31587011

RESUMO

BACKGROUND Osteoarthritis (OA) is a joint disease characterized by articular cartilage degeneration and inflammation. We have previously clarified that a xanthan gum (XG) preparation exerts ameliorating effect on a rabbit OA model by regulating matrix metalloproteinase (MMP)-1 and MMP-3, which are critical proteins in the Wnt3a/ß-catenin pathway. Thus, it is reasonable to predict that the Wnt3a/ß-catenin pathway is involved in the treatment of OA with XG. MATERIAL AND METHODS The effect of XG in OA model animals were observed by hematoxylin and eosin staining (HE), Safranin O staining, and Fast Green staining. Articular cartilage degradation on the medial plateau sides was quantified using the modified Pritzker OARSI score. The levels of IL-6, TNF-alpha, and IL-1ß in synovial fluid were determined with ELISA. The protective effect of XG in rat chondrocytes was assessed by CCK8 assay. Moreover, activation of the Wnt3a/ß-catenin pathway and the expression of MMP13, ADAMTS5, aggrecan, and collagen II under the influence of XG was measured by Western blot and qRT-PCR. RESULTS Our results showed that XG reduced the OARSI score and the concentration of inflammatory cytokines in OA after intra-articular injection. XG acted on Wnt3a/ß-catenin in ATDC5 cells in a dose-dependent manner and exhibited a protective effect. XG also decreased the expression of MMP13 and ADAMTS5 and rescued the inhibition of aggrecan and collagen II expression in SNP-stimulated chondrocytes. CONCLUSIONS These results indicate that the effects of XG are related to the Wnt3a/ß-catenin pathway and XG suppresses matrix degradation by inhibiting the expression of MMPs and ADAMTS and promotes aggrecan and collagen II content in the ECM, indicating its favorable potential for use in OA therapy.


Assuntos
Osteoartrite/tratamento farmacológico , Polissacarídeos Bacterianos/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Proteína ADAMTS5/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Cartilagem/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Linhagem Celular , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Coelhos , Ratos , Ratos Sprague-Dawley , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/metabolismo , Proteína Wnt3A/metabolismo , beta Catenina/metabolismo
15.
EBioMedicine ; 48: 619-629, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31631036

RESUMO

BACKGROUND: Cartilaginous endplate (CEP) degeneration is considered as one of the major causes of intervertebral disc degeneration (IVDD) which causes low back pain. Recent studies have proved that epigenetic alteration is involved in a variety of diseases. This work explored the role of histone methyltransferase enhancer of zeste homologue 2 (EZH2) in CEP degeneration, as well as its underlying epigenetic mechanisms, and confirmed the effect of EZH2 knockdown on delaying IVDD development. METHODS: Western blotting, immunofluorescence staining, and ChIP assay were applied to demonstrate the molecular mechanism of EZH2 in CEP tissue. The therapeutic potential of EZH2 was investigated using puncture-induced rat models. FINDINGS: The EZH2 expression was upregulated in human and rat CEP tissue. It was also found that the overexpression of EZH2 suppressed the expression of Collagen II, aggrecan and Sox-9, and promoted the expression of ADTAMTS5 and MMP13 in rat endplate chondrocytes (EPCs), which could be reversed by EZH2 silencing. The correlation between EZH2 and Sox-9 was further explored, while overexpression of Sox-9 could reverse the effect of EZH2 in rat EPCs. Moreover, inhibition of EZH2 upregulated the level of Sox-9 by demethylating H3K27me3 at Sox-9 promoter sites, revealing the regulatory mechanism of EZH2 on Sox-9. Meanwhile, puncture-induced rat models showed that EZH2 knockdown exerted a protective effect on CEP and disc degeneration. INTERPRETATION: This study reveals that EZH2 inhibition is a promising strategy for mitigating the symptoms and progression of IVDD. FUNDING: This study was funded by the Natural Science Foundation of Zhejiang Province (Y16H060034). Authors declare that the funders had no involvement in the study design, data analysis and interpretation of the results.


Assuntos
Cartilagem/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Degeneração do Disco Intervertebral/etiologia , Degeneração do Disco Intervertebral/metabolismo , Fatores de Transcrição SOX9/metabolismo , Animais , Biomarcadores , Cartilagem/patologia , Desmetilação , Modelos Animais de Doenças , Progressão da Doença , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Degeneração do Disco Intervertebral/diagnóstico por imagem , Degeneração do Disco Intervertebral/patologia , Imagem por Ressonância Magnética , Masculino , Ratos
16.
Pharmacology ; 104(5-6): 216-225, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31514188

RESUMO

The present study evaluated the protective effects of pseurotin A against inflammation and the destruction of cartilage in a rat model of rheumatoid arthritis (RA). RA was induced by intradermal injections of Freund's complete adjuvant (1 mg/mL), and the treatment with pseurotin A (50 and 100 mg/kg, p.o.) was administered over 1 week. The effects of pseurotin A were assessed by estimating hind paw volume (HPV) and determining the levels of inflammatory mediators in the serum and synovial fluid of collagen-induced arthritis (CIA)-induced RA rats. Western blot and histopathological assays were performed to assess changes in synovial tissues. Additionally, in vitro analyses of receptor activator of nuclear factor-kappa-Β ligand (RANKL)-stimulated RAW264.7 cells treated with pseurotin A at different concentrations (1, 10, and 100 µg/mL) were conducted to assess the effects of pseurotin A on apoptosis ratio, real-time polymerase chain reaction data, and tartrate-resistant acid phosphatase staining. Compared to the RA group, treatment with pseurotin A significantly decreased HPV and reduced the levels of inflammatory mediators in the synovial fluid and blood. Additionally, pseurotin A ameliorated the protein expressions of osteoprotegerin, nuclear factor of activated T-cells, nuclear factor-kappa beta (NF-κB), IκBα, extracellular signal regulated kinase, and P38 as well as histopathological changes in the synovial tissue of CIA-induced RA rats. The in vitro findings revealed that pseurotin A treatment did not alter the apoptosis ratio in RANKL-stimulated RAW264.7 cells but significantly reduced the mRNA expressions of calcitonin receptor, NF-κB, and matrix metallopeptidase-9. The present findings suggest that pseurotin A ameliorated the differentiation of osteoclasts and the destruction of cartilage in RA rats via regulation of the mitogen-activated protein kinase/RANKL/NF-kB pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Substâncias Protetoras/uso terapêutico , Pirrolidinonas/uso terapêutico , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Experimental/prevenção & controle , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Dinoprostona/imunologia , Modelos Animais de Doenças , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/imunologia , Osteoclastos/efeitos dos fármacos , Osteoprotegerina/imunologia , Substâncias Protetoras/farmacologia , Pirrolidinonas/farmacologia , Ligante RANK/imunologia , Células RAW 264.7 , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
17.
Inflammation ; 42(6): 2278-2285, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31512108

RESUMO

Osteoarthritis (OA) is a common cause of joint pain and physical disability in the elderly. It is highly associated with local inflammatory reactions and cartilage degradation. Isorhapontigenin (ISO), a natural compound existing in various plants, has shown prominent anti-inflammatory and anti-oxidative properties in several inflammatory diseases. However, the effects of ISO on OA remain to be elucidated. Here, we investigated the effects of ISO on interleukin-1ß (IL-1ß)-treated rat chondrocytes and cartilage explants. Our results revealed that ISO could suppress the IL-1ß-induced elevated levels of nitric oxide (NO), inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and cyclooxygenase-2 (COX2). Besides, ISO could also inhibit the IL-1ß-induced up-regulation of cartilage matrix catabolic enzymes such as matrix metalloproteinases (MMPs) and aggrecanase-2 (ADAMTS5). Moreover, the IL-1ß-induced downregulation of collagen II and aggrecan could be reversed by ISO. Furthermore, ISO prevented rat cartilage explant damage induced by IL-1ß. Mechanistically, ISO worked partly by suppressing mitogen-activated protein kinase (MAPK)-associated ERK and p38 pathways. Taken together, our study indicated the anti-inflammatory potential of ISO on IL-1ß-treated rat chondrocytes, providing a new idea for OA treatment.


Assuntos
Cartilagem/patologia , Condrócitos/patologia , Inflamação/tratamento farmacológico , Estilbenos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Cartilagem/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-1beta/farmacologia , Metaloproteinases da Matriz/metabolismo , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Osteoartrite/tratamento farmacológico , Ratos
18.
ACS Appl Mater Interfaces ; 11(38): 34744-34754, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31475824

RESUMO

Here, kartogenin (KGN), an emerging stable nonprotein compound with the ability to promote differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes, was grafted onto the surface of modified ultrasmall superparamagnetic iron-oxide (USPIO) and then integrated into cellulose nanocrystal/dextran hydrogels. The hydrogels served as a carrier for the USPIO-KGN and a matrix for cartilage repair. We carried out in vitro and in vivo studies, the results of which demonstrated that KGN undergoes long-term stable sustained release, recruits endogenous host cells, and induces BMSCs to differentiate into chondrocytes, thus enabling in situ cartilage regeneration. Meanwhile, the USPIO-incorporated theranostic hydrogels exhibited a distinct magnetic resonance contrast enhancement and maintained a stable relaxation rate, with almost no loss, both in vivo and in vitro. According to noninvasive in vivo observation results and immunohistochemistry analyses, the regenerated cartilage tissue was very similar to natural hyaline cartilage. This innovative diagnosis and treatment system increases the convenience and effectiveness of chondrogenesis.


Assuntos
Anilidas , Cartilagem , Hidrogéis , Nanopartículas de Magnetita , Ácidos Ftálicos , Regeneração/efeitos dos fármacos , Anilidas/química , Anilidas/farmacologia , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Cartilagem/lesões , Cartilagem/patologia , Cartilagem/fisiologia , Diferenciação Celular/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Hidrogéis/química , Hidrogéis/farmacologia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Ácidos Ftálicos/química , Ácidos Ftálicos/farmacologia , Coelhos , Nanomedicina Teranóstica
19.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 91-95, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31472053

RESUMO

Osteoarthritis (OA) is a degenerative joint disease usually seen in the elderly, which incidence increases with age. Its pathogenesis and underlying mechanism are still unclear. The disease severely affects the physical health and life quality of patients, thereby constituting a huge economic burden to family and society. Luteolin (LUT) is a natural flavonoid with multiple pharmacological properties. Many plants containing LUT have been applied in the treatment of several inflammation-related diseases due the relatively strong anti-inflammatory effects of LUT. The present study investigated the influence of LUT on cell apoptosis and inflammatory reactions in cartilage of OA guinea pigs, and its underlying mechanism. It was found that LUT effectively inhibited proliferation of OA cartilage cells, down-regulated the expressions of JNK and p38MAPK in cartilage cells of OA, and downregulated NO, TNF-α and IL-6. Thus, it alleviated inflammatory reactions, protected cartilage cells, and delayed cartilage degeneration.


Assuntos
Apoptose/efeitos dos fármacos , Condrócitos/enzimologia , Condrócitos/patologia , Luteolina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoartrite/enzimologia , Osteoartrite/patologia , Animais , Osso e Ossos/patologia , Cartilagem/patologia , Proliferação de Células/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Cobaias , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Articulações/patologia , Lipopolissacarídeos , Luteolina/química
20.
Med Sci Monit ; 25: 6649-6659, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31484919

RESUMO

BACKGROUND Chondrocyte dysfunction and apoptosis are 2 major features during the progression of osteoarthritis. Catalpol, an iridoid glycoside isolated from the root of Rehmannia, is a valuable medication with anti-inflammatory, anti-oxidative, and anti-apoptotic effects in various diseases. However, whether catalpol protects against osteoarthritis has not been investigated. MATERIAL AND METHODS To assess the role of catalpol in osteoarthritis and the potential mechanism of action, chondrocytes were treated with interleukin (IL)-1ß and various concentrations of catalpol. Catabolic metabolism, apoptotic level and relative signaling pathway were measured by western blot, real-time polymerase chain reaction and immunofluorescence staining. Meanwhile, we assess the cartilage degeneration in an experimental rat model using Safranin O fast green staining and cartilage was graded according to the Osteoarthritis Research Society International (OARSI) system. RESULTS The results showed that catalpol prevented chondrocyte apoptotic level triggered by IL-1ß, suppressed the release of catabolic enzymes, and inhibited the degradation of extracellular matrix induced by IL-1ß. Catalpol also inhibited the nuclear factor kappa B (NF-kappaB) pathway, reduced the production of inflammatory cytokines (IL-6, tumor necrosis factor-alpha) in IL-1ß-treated chondrocytes, and partially reversed cartilage degeneration in the knee joint in animal model of osteoarthritis. CONCLUSIONS Our work suggested that catalpol treatment attenuates IL-1ß-induced inflammatory response and catabolism in rat chondrocytes by inhibiting the NF-kappaB pathway, suggesting the therapeutic potential of catalpol for the treatment of osteoarthritis.


Assuntos
Apoptose/efeitos dos fármacos , Cartilagem/patologia , Condrócitos/patologia , Matriz Extracelular/metabolismo , Inflamação/patologia , Interleucina-1beta/farmacologia , Glucosídeos Iridoides/farmacologia , Proteínas ADAMTS/metabolismo , Animais , Cartilagem/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Mediadores da Inflamação/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
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