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1.
Rev Prat ; 69(5): 507-509, 2019 May.
Artigo em Francês | MEDLINE | ID: mdl-31626453

RESUMO

"Osteoarthritis (OA) is one of the most common disorders of joints. The joints most frequently affected are the hip, knee and the hand, notably the base of the thumb. Use of imaging to diagnose OA, whatever its localization should be limited to plain X-Rays in the majority of cases. It is particularly useful for the diagnosis, the assessment of the severity of structural changes and follow-up. The four main radiographic features of OA are joint space narrowing, subchondral sclerosis, subchondral cyst formation and osteophyte. MRI, CT scanner and Ultrasound have no role in the diagnosis of OA in the vast majority of OA patients. However, US is useful to guide intra-articular injection, mostly in the hip, and to diagnose a baker cyst. There is no blood or urine biomarker validated at the individual level for the diagnosis of OA."


Assuntos
Biomarcadores/análise , Cartilagem Articular/diagnóstico por imagem , Osteoartrite , Osteófito , Humanos , Imagem por Ressonância Magnética , Osteoartrite/diagnóstico por imagem , Osteoartrite/metabolismo , Radiografia
2.
Clin Exp Rheumatol ; 37 Suppl 120(5): 73-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621570

RESUMO

Osteoarthritis (OA) is a disease of the whole joint, including synovium, bone and cartilage. OA is a slow degenerative and very heterogeneous disease, with both varying levels of disease activity and progression. Biomarkers are urgently needed to assist drug developers in selecting and developing the projects with the highest chance of success. Biomarkers for enrichment of clinical studies, early efficacy as well as other diagnostic tools are needed. Osteoporosis and OA have many similarities. In osteoporosis an armamentarium of treatments are now available with high clinical efficacy and well-described effects on biomarkers. Possibly, lessons learned from the osteoporosis field in the use of biomarkers may be applied in the OA field, from both technical and scientific perspectives. To help guide the way, the FDA has recently published the BEST guidelines, to facilitate obtaining a common vocabulary to assist biomarker researchers. In the current review, we will review the biomarkers of OA, with emphasis on bone, cartilage and synovial biomarkers, and draw clear perspectives to the use of biomarkers for drug development and clinical practice in the osteoporosis field.


Assuntos
Biomarcadores/análise , Cartilagem Articular , Osteoartrite , Biomarcadores/metabolismo , Cartilagem Articular/metabolismo , Humanos , Osteoartrite/metabolismo , Osteoporose/metabolismo , Membrana Sinovial
3.
Clin Exp Rheumatol ; 37 Suppl 120(5): 40-47, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31621575

RESUMO

MicroRNAs are small double-stranded RNAs, which negatively regulate gene expression and have been shown to have key roles in both chondrocyte development and cartilage homeostasis with age. Deletion of all microRNAs in chondrocytes leads to skeletal growth defects in mice, whilst deletion of specific microRNAs, e.g. miR-140, leads to premature articular cartilage degradation and increased susceptibility to posttraumatic osteoarthritis. Studies comparing microRNA expression in normal human articular cartilage compared to osteoarthritic cartilage show differential expression, but varying sample groups make interpretation difficult. MicroRNAs have been proposed as circulating biomarkers of osteoarthritis, but again, this differs amongst patient cohorts. Many micro-RNAs have been shown to have roles in chondrocyte phenotype via signalling pathways, apoptosis, autophagy and senescence. Modulating microRNAs in the joint has been shown to reduce osteoarthritis in animal models and translating this to man as a novel therapeutic strategy will be key.


Assuntos
Autofagia , Cartilagem Articular , MicroRNAs , Osteoartrite , Animais , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Humanos , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/fisiologia , Osteoartrite/genética , Osteoartrite/metabolismo
4.
Orv Hetil ; 160(44): 1727-1734, 2019 Nov.
Artigo em Húngaro | MEDLINE | ID: mdl-31657254

RESUMO

Authors discuss the musculoskeletal aspects of obesity by applying a novel approach. Biochemical changes associated with obesity and especially metabolic syndrome, may have a great impact on the function of bones, joints and muscles. Therefore we need a new view and new strategies in rheumatic diseases. Obesity-associated metabolic changes should be considered during the progress of as well as the selection of treatment in inflammatory rheumatic diseases. Individualised treatment is necessary due to associated comorbidities as well. Orv Hetil. 2019; 160(44): 1727-1734.


Assuntos
Artropatias/etiologia , Artropatias/fisiopatologia , Síndrome Metabólica , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/fisiopatologia , Obesidade/complicações , Obesidade/fisiopatologia , Doenças Reumáticas , Adipocinas/metabolismo , Artrite , Humanos , Artropatias/metabolismo , Leptina/metabolismo , Doenças Musculoesqueléticas/metabolismo , Obesidade/metabolismo , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Doenças Reumáticas/etiologia , Doenças Reumáticas/metabolismo , Doenças Reumáticas/fisiopatologia
5.
Acta Cir Bras ; 34(6): e201900604, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31432995

RESUMO

PURPOSE: In view of the principal role of Toll-like receptor 4 (TLR4) in mediating sterile inflammatory response contributing to osteoarthritis (OA) pathogenesis, we used lipopolysaccharide (LPS), a known TLR4 activator, to clarify whether modulation of TLR4 contributed to the protective actions of intra-articular administration of curcumin in a classical rat OA model surgically induced by anterior cruciate ligament transection (ACLT). METHODS: The rats underwent ACLT and received 50µl of curcumin at the concentration of 1 mg mL-1 and 10 µg LPS by intra-articular injection once a week for 8 weeks. Morphological changes of the cartilage and synovial tissues were observed. Apoptotic chondrocytes were detected using TUNEL assay. The concentrations of IL-1ß and TNF-ɑ in synovial fluid were determined using ELISA kits. The mRNA and protein expression levels of TLR4 and NF-κB p65 were detected by real-time PCR and Western blotting, respectively. RESULTS: Intra-articular administration of curcumin significantly improved articular cartilage injury, suppressed synovial inflammation and down-regulated the overexpression of TLR4 and its downstream NF-κB caused by LPS-induced TLR4 activation in rat osteoarthritic knees. CONCLUSION: The data suggested that the inhibition of TLR4 signal might be an important mechanism underlying a protective effect of local curcumin administration on OA.


Assuntos
Ligamento Cruzado Anterior/cirurgia , Curcumina/farmacologia , Osteoartrite/prevenção & controle , Receptor 4 Toll-Like/metabolismo , Animais , Ligamento Cruzado Anterior/patologia , Western Blotting , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Injeções Intra-Articulares , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Masculino , NF-kappa B/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/metabolismo , Reação em Cadeia da Polimerase , Ratos , Receptor 4 Toll-Like/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
6.
Life Sci ; 234: 116786, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445934

RESUMO

Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA results in the loss of joint function, usually accompanied by severe pain, and are the most common type of arthritis, affecting more than 10% of adults. The characteristic signs of OA are progressive cartilage destruction and, eventually, complete loss of chondrocytes. A key enzyme responsible for these degenerative changes in cartilage is matrix metalloproteinase-13 (MMP-13), which is thought to be a major contributor to the degenerative process occurring during OA pathogenesis. The aim of the present review is to shed light on the general role of MMPs, with special emphasis on MMP-13, in the induction of OA and the general basis of OA treatment. The pathogenic mechanism of this highly prevalent disease is not clear, and no effective disease-modifying treatment is currently available. Any updated information about OA treatment in human patients will also benefit companion animals such as horses and dogs, which also suffer from OA. Selective inhibition of MMP-13 seems to be an attractive therapeutic strategy.


Assuntos
Cartilagem Articular/patologia , Matriz Extracelular/patologia , Metaloproteinases da Matriz/imunologia , Osteoartrite/patologia , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Cartilagem Articular/metabolismo , Descoberta de Drogas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Humanos , Metaloproteinase 13 da Matriz/análise , Metaloproteinase 13 da Matriz/imunologia , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Metaloproteinases da Matriz/análise , Metaloproteinases da Matriz/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/imunologia , Osteoartrite/metabolismo
7.
Orthop Clin North Am ; 50(4): 529-537, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31466668

RESUMO

Ankle osteoarthritis affects a significant portion of the global adult population. Unlike other joints, arthritis of the ankle often develops as a response to traumatic injury (intra-articular fracture) of the ankle joints. The full mechanism leading to posttraumatic osteoarthritis of the ankle (PTOAA) is poorly understood. These deficits in knowledge pose challenges in the management of the disease. Adequate surgical reduction of fractured ankle joints remains the gold standard in prevention. The purpose of this review is to thoroughly delineate the known pathogenesis of PTOAA, and provide critical updates on this pathology and new avenues to provide therapeutic management of the disease.


Assuntos
Fraturas do Tornozelo/complicações , Fraturas do Tornozelo/cirurgia , Osteoartrite/patologia , Fraturas do Tornozelo/metabolismo , Fenômenos Biomecânicos , Gerenciamento Clínico , Fixação Interna de Fraturas/instrumentação , Humanos , Metabolismo dos Lipídeos , Osteoartrite/metabolismo , Resultado do Tratamento
8.
Cell Mol Life Sci ; 76(22): 4493-4502, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31317206

RESUMO

The human chondromodulin-1 (Chm-1, Chm-I, CNMD, or Lect1) gene encodes a 334 amino acid type II transmembrane glycoprotein protein with characteristics of a furin cleavage site and a putative glycosylation site. Chm-1 is expressed most predominantly in healthy and developing avascular cartilage, and healthy cardiac valves. Chm-1 plays a vital role during endochondral ossification by the regulation of angiogenesis. The anti-angiogenic and chondrogenic properties of Chm-1 are attributed to its role in tissue development, homeostasis, repair and regeneration, and disease prevention. Chm-1 promotes chondrocyte differentiation, and is regulated by versatile transcription factors, such as Sox9, Sp3, YY1, p300, Pax1, and Nkx3.2. Decreased expression of Chm-1 is implicated in the onset and progression of osteoarthritis and infective endocarditis. Chm-1 appears to attenuate osteoarthritis progression by inhibiting catabolic activity, and to mediate anti-inflammatory effects. In this review, we present the molecular structure and expression profiling of Chm-1. In addition, we bring a summary to the potential role of Chm-1 in cartilage development and homeostasis, osteoarthritis onset and progression, and to the pathogenic role of Chm-1 in infective endocarditis and cancers. To date, knowledge of the Chm-1 receptor, cellular signalling, and the molecular mechanisms of Chm-1 is rudimentary. Advancing our understanding the role of Chm-1 and its mechanisms of action will pave the way for the development of Chm-1 as a therapeutic target for the treatment of diseases, such as osteoarthritis, infective endocarditis, and cancer, and for potential tissue regenerative bioengineering applications.


Assuntos
Cardiopatias/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/metabolismo , Osteoartrite/metabolismo , Animais , Cartilagem/metabolismo , Homeostase/fisiologia , Humanos
9.
Medicine (Baltimore) ; 98(28): e16355, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305428

RESUMO

Osteoarthritis (OA) has a multifactorial etiology that includes oxidative stress. Oxidative balance score (OBS) is a well-known indicator of oxidative stress. However, the association between OBS and OA has not been assessed. Thus, this study aimed to investigate the associations of OBS with OA and quality of life (QOL) in patients with OA.By using data from the Korea National Health and Nutrition Examination Survey VI, patients previously diagnosed and/or treated by a physician were considered to have OA regardless of the affected joints. The control group was defined as participants without any form of chronic arthritis. OBS was calculated by combining 10 pro-oxidant and antioxidant factors through a baseline nutritional and lifestyle assessment. Higher OBS scores indicated a predominance of antioxidant exposure. Multivariable logistic regression was used to estimate the adjusted odds ratios (ORs) for OA, and the EuroQoL five-dimensional questionnaire (EQ5D) was used in patients with OA after adjusting for demographic factors and comorbidities.Among the 14,930 participants, 296 patients with OA, and 1,309 controls were included in the analysis. In the age- and sex-adjusted model, the OR of the total OBS for OA was significant. In the full model adjusted for age, sex, education, income, and comorbidities, the total OBS for OA was not significant. Only the non-dietary pro-oxidant OBS had a significant inverse association with OA. The patients with OA who had a high EQ5D score had a higher total OBS than those with a low EQ5D score. The OR of the total OBS for a high EQ5D score was 1.14 in the multivariable logistic regression model. As we analyzed the OBS as a categorical variable (reference = Q1), the ORs of the Q2, Q3, and Q4 (highest) total OBS were 1.43, 2.71, and 2.22, respectively.In the fully adjusted model, the total OBS was not associated with OA. However, a positive association was observed between the total OBS and QOL in the patients with OA, indicating that antioxidative status was associated with better QOL in patients with OA.


Assuntos
Osteoartrite/metabolismo , Estresse Oxidativo , Qualidade de Vida , Idoso , Dieta , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Osteoartrite/epidemiologia , República da Coreia
10.
Toxicol Lett ; 314: 18-26, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31299270

RESUMO

Epidemiological investigations indicate that effects related to prenatal adverse environments on the organs of the offspring could continue to adulthood. This study intends to confirm that prenatal nicotine exposure (PNE) increases the susceptibility of osteoarthritis (OA) in the male offspring, and to explore the potential intrauterine programming mechanism. During pregnancy, rats were divided into a PNE group and a control group. After birth, rats were given a high-fat diet for 6 months and long-distance running for 6 weeks. The rats were euthanized at 18 months after birth (PM18) and on gestational day 20 (GD20), respectively. Knee joints were collected for histochemistry, immunohistochemistry, and quantitative polymerase chain reaction (qPCR) assays. Histological analyses and the Mankin's score showed increased cartilage destruction and accelerated OA progression in adult offspring from the PNE group. Immunohistochemistry results showed decreased expression of transforming growth factor beta (TGFß) signaling pathway. Furthermore, the expression of apoptosis factors (caspase-3 and caspase-8), inflammatory factors [interleukin (IL)-1, IL-6] and matrix degradation enzymes [matrix metalloproteinase (MMP)-3, MMP-13] were also significantly increased. Traced back to the intrauterine period, it was found that the number of chondrocytes and the contents of Col2A1 and aggrecan in the matrix in the PNE group were decreased. And, the expression of the TGFß signaling pathway was inhibited. These results suggested that PNE enhanced the susceptibility of OA in male elderly offspring rats by down-regulating TGFß signaling, which increased articular cartilage local inflammation, matrix degradation, and cell apoptosis. This study confirmed the developmental origin of OA, and clarified the congenital and the living environment impact on the occurrence and development of OA. Our findings provide a theoretical and experimental basis for OA early prevention.


Assuntos
Articulações/efeitos dos fármacos , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Osteoartrite/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fatores Etários , Agrecanas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 8/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Feminino , Idade Gestacional , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Articulações/metabolismo , Articulações/patologia , Masculino , Exposição Materna , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Gravidez , Ratos Wistar , Fatores de Risco , Fatores Sexuais
11.
Biomed Res Int ; 2019: 4328219, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179322

RESUMO

High molecular weight hyaluronan (H-HA) has a pivotal role in the maintenance of normal functions of synovial fluid and structure of the articular joint, but it has been shown that its concentration is reduced in patients affected by degenerative cartilage diseases, such as osteoarthritis (OA). The aim of this study was to investigate the anti-inflammatory effects and properties of hybrid cooperative complexes based on high and low molecular weight hyaluronan (HCC) compared to H-HA on human primary cells derived by pathological joints. In addition, the rheological behavior of HCC was evaluated in order to define their potential as viscosupplement gel in degenerated joints. The experiments were performed using an in vitro model of OA based on human chondrocytes and synoviocytes isolated from degenerated joints of patients hospitalized for surgical replacement. In order to assess the anti-inflammatory effects of HCC, we evaluated NF-kB, COMP-2, IL-6, and IL-8 as specific markers at the transcriptional and/or protein level. Moreover, the proliferative properties of HCC were assessed using time lapse video microscopy. We showed that chondrocytes and synoviocytes clearly presented an altered cytokine profile compatible with a severe ongoing inflammation status. H-HA and, above all, HCC significantly reduced levels of the specific biomarkers evaluated and improved cartilage healing. The rheological profile indicated HCC suitability for intra-articular injection in joint diseases. HCC viscoelastic properties and the protective/anti-inflammatory effect on human chondrocytes and synoviocytes suggest the novel HCC-based gels as a valid support for OA management.


Assuntos
Proliferação de Células/efeitos dos fármacos , Condrócitos/metabolismo , Ácido Hialurônico , Modelos Biológicos , Osteoartrite/tratamento farmacológico , Sinoviócitos/metabolismo , Condrócitos/patologia , Géis , Humanos , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Peso Molecular , Osteoartrite/metabolismo , Osteoartrite/patologia , Sinoviócitos/patologia
12.
Vet Surg ; 48(5): 780-785, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31155740

RESUMO

OBJECTIVE: To evaluate the relationship between serum and synovial fluid (SF) leptin concentrations and body condition score (BCS) in healthy and osteoarthritic dogs. STUDY DESIGN: Controlled, prospective, clinical study. ANIMALS: Nineteen healthy dogs and 29 dogs with osteoarthritis (OA) secondary to cranial cruciate ligament injury. METHODS: Synovial fluid was obtained from the femorotibial joint under sedation (healthy dogs) or during surgery (OA dogs). Serum and SF leptin and interleukin (IL)-1ß concentrations were measured via enzyme-linked immunosorbent assay. Dogs were classified as optimal weight (BCS 4-5/9) or overweight (BCS >5/9). Radiographs were scored for OA severity by a radiologist. Owners completed the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire. RESULTS: Mean (± SD) SF leptin (4.09 ± 4 ng/mL) was lower than serum leptin (6.88 ± 5.52 ng/mL, P < .0001). Synovial fluid leptin was higher in overweight (5.28 ± 4.21) than in optimal body weight dogs (1.54 ± 1.72 ng/mL, P < .0001). Serum (P < .001) and SF leptin (P = .004) concentrations were associated with BCS. Concentration of SF leptin did not differ between healthy (2.4 ± 2.04 ng/mL) and OA (4.9 ± 4.3 ng/mL, P = .25) dogs. Synovial fluid leptin and LOAD scores were weakly associated (P = .03). No association was detected between SF leptin and radiographic score or IL-1ß (P = .73). CONCLUSION: Serum and SF leptin correlated with BCS in this population. Synovial fluid leptin was weakly associated with LOAD scores but not with radiographic severity of OA or IL-1ß. CLINICAL SIGNIFICANCE: Serum and SF leptin concentrations do not predict radiographic severity of canine OA but contribute to joint pain and dysfunction.


Assuntos
Composição Corporal , Doenças do Cão/metabolismo , Leptina/sangue , Osteoartrite/veterinária , Líquido Sinovial/química , Animais , Lesões do Ligamento Cruzado Anterior/sangue , Lesões do Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/veterinária , Doenças do Cão/sangue , Cães , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Leptina/análise , Leptina/metabolismo , Masculino , Osteoartrite/sangue , Osteoartrite/metabolismo , Estudos Prospectivos , Radiografia
13.
Artif Cells Nanomed Biotechnol ; 47(1): 2139-2145, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31146598

RESUMO

Osteoarthritis (OA) is a common joint disease for which a safe and reliable treatment has yet to be developed. Here, we demonstrated the potential benefit of treatment with paeonol, a derivative of Paeonia suffruticosa, in the treatment and prevention of OA. Chondrogenic cell line ATDC5 cells were cultured with IL-1ß and the effects of paeonol were assessed through qRT-PCR, western blot analysis, MTT, ELISA, and NF-κB luciferase reporter gene assay. Our findings demonstrate a novel ability of paeonol to inhibit numerous factors of OA, including expressions of IL-6, TNF-α, NOX2, PTGS2, NUCB2/nesfatin-1, ICAM-1, VCAM-1, MMP-3/13, degradation of type II collagen, and NF-κB activation through the rescue of IκBα. Additionally, we assessed the effects of paeonol on cell viability to confirm its safety. These findings implicate a valuable potential role of paeonol in the treatment and prevention of OA.


Assuntos
Acetofenonas/farmacologia , Condrócitos/efeitos dos fármacos , Colágeno Tipo II/metabolismo , Interleucina-1beta/farmacologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Proteólise/efeitos dos fármacos , Acetofenonas/uso terapêutico , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NADPH Oxidase 2/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Osteoartrite/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
14.
Artif Cells Nanomed Biotechnol ; 47(1): 1971-1977, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31155960

RESUMO

Objective: Cyclin D1 was an important molecular involved in the pathological process of osteoarthritis (OA). The purpose of this study was to identify the effect and potential mechanism of Cyclin D1 for the proliferation and apoptosis of OA chondrocytes. Methods: We used polymerase chain reaction (PCR) method to identify the expression levels of Cyclin D1 and down-stream Wnt/ß-catenin pathway-related genes in OA chondrocytes according to the grade of OA. Small interfering RNA (siRNA) or overexpression of Cyclin D1 were used to identify the role of Cyclin D1 in cell proliferation and apoptosis. Next, we used XAV-939 to inhibit the Wnt/ß-catenin pathway and explore the relevant mechanism. Results: Cyclin D1 was significantly decreased with OA grade (p < .05). After siCyclin D1 transfection, the expression level of WNT3 and nuclear ß-catenin were significantly increased, while Wnt10a and total ß-catenin were not obviously changed. Co-cultured with XAV-939 and siCyclin D1 abolished the effects of siCyclin D1 on proliferation and apoptosis of OA chondrocytes (p < .05). Conclusions: Cyclin D1 regulated chondrocyte proliferation and apoptosis through Wnt3/ß-catenin instead of Wnt10a/ß-catenin signalling pathway.


Assuntos
Apoptose , Condrócitos/patologia , Ciclina D1/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Via de Sinalização Wnt , Proteína Wnt3/metabolismo , Estudos de Casos e Controles , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Condrócitos/metabolismo , Ciclina D1/genética , Regulação da Expressão Gênica , Humanos , Osteoartrite/genética
15.
Nat Commun ; 10(1): 2876, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253842

RESUMO

Osteoarthritis (OA) is a common, painful disease. Currently OA is incurable, and its etiology largely unknown, partly due to limited understanding of OA as a whole-joint disease. Here we report that two homologous microRNAs, miR-204 and miR-211, maintain joint homeostasis to suppress OA pathogenesis. Specific knockout of miR-204/-211 in mesenchymal progenitor cells (MPCs) results in Runx2 accumulation in multi-type joint cells, causing whole-joint degeneration. Specifically, miR-204/-211 loss-of-function induces matrix-degrading proteases in articular chondrocytes and synoviocytes, stimulating articular cartilage destruction. Moreover, miR-204/-211 ablation enhances NGF expression in a Runx2-dependent manner, and thus hyper-activates Akt signaling and MPC proliferation, underlying multiplex non-cartilaginous OA conditions including synovial hyperplasia, osteophyte outgrowth and subchondral sclerosis. Importantly, miR-204/-211-deficiency-induced OA is largely rescued by Runx2 insufficiency, confirming the miR-204/-211-Runx2 axis. Further, intraarticular administration of miR-204-expressing adeno-associated virus significantly decelerates OA progression. Collectively, miR-204/-211 are essential in maintaining healthy homeostasis of mesenchymal joint cells to counteract OA pathogenesis.


Assuntos
Células-Tronco Mesenquimais/fisiologia , MicroRNAs/metabolismo , Osteoartrite/metabolismo , Animais , Condrócitos/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , Osteoartrite/etiologia , Osteoartrite/patologia , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Sinoviócitos/metabolismo
16.
Nat Commun ; 10(1): 2429, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160553

RESUMO

The WW domain-containing protein 2 (Wwp2) gene, the host gene of miR-140, codes for the Wwp2 protein, which is an HECT-type E3 ubiquitin ligases abundantly expressed in articular cartilage. However, its function remains unclear. Here, we show that mice lacking Wwp2 and mice in which the Wwp2 E3 enzyme is inactivated (Wwp2-C838A) exhibit aggravated spontaneous and surgically induced osteoarthritis (OA). Consistent with this phenotype, WWP2 expression level is downregulated in human OA cartilage. We also identify Runx2 as a Wwp2 substrate and Adamts5 as a target gene, as similar as miR-140. Analysis of Wwp2-C838A mice shows that loss of Wwp2 E3 ligase activity results in upregulation of Runx2-Adamts5 signaling in articular cartilage. Furthermore, in vitro transcribed Wwp2 mRNA injection into mouse joints reduces the severity of experimental OA. We propose that Wwp2 has a role in protecting cartilage from OA by suppressing Runx2-induced Adamts5 via Runx2 poly-ubiquitination and degradation.


Assuntos
Proteína ADAMTS5/metabolismo , Cartilagem Articular/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Osteoartrite/genética , Ubiquitina-Proteína Ligases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Artrite Experimental/genética , Artrite Experimental/metabolismo , Cartilagem Articular/diagnóstico por imagem , Modelos Animais de Doenças , Humanos , Articulação do Joelho/diagnóstico por imagem , Meniscos Tibiais/cirurgia , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Osteoartrite/metabolismo , RNA Mensageiro/farmacologia , Transdução de Sinais , Crânio/diagnóstico por imagem , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Microtomografia por Raio-X , Adulto Jovem
17.
Life Sci ; 228: 158-166, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31055086

RESUMO

AIMS: Chondrocyte apoptosis is the most common pathological feature of cartilage in osteoarthritis (OA). Excessive mechanical stress can induce chondrocyte apoptosis and destroy cartilage tissue. Transient receptor potential channel vanilloid 4 (TRPV4) is a mechanosensitive ion channel that mediates chondrocyte response to mechanical stress. Here, we investigated the potential role of TRPV4 in chondrocyte apoptosis induced by excessive mechanical stress. MAIN METHODS: Using a rat OA anterior cruciate-ligament transection (ALCT) model, we detected immunolocalization of calmodulin protein and mRNA and protein levels of TRPV4, calmodulin, and cleaved caspase-8 in articular cartilage. Primary chondrocytes were isolated and cultured in vitro, and Fluo-4AM staining was used to assess intracellular Ca2+ levels in order to evaluate TRPV4-mediated Ca2+ influx. Flow cytometry and western blot were performed to detect apoptosis and apoptosis-related protein levels in chondrocytes, respectively. KEY FINDINGS: TRPV4 was upregulated in ALCT-induced OA articular cartilage, and we found that administration of a TRPV4 inhibitor attenuated cartilage degeneration. Additionally, TRPV4 specifically mediated extracellular Ca2+ influx, leading to chondrocyte apoptosis in vitro, which was inhibited by transfection of TRPV4 small-interfering RNA or administration of a TRPV4 inhibitor. Moreover, increased Ca2+ influx triggered apoptosis by upregulating FAS-associated protein with death domain and cleaved caspase-3, -6, -7, and -8 levels, with these effects abolished by TRPV4 knockdown or TRPV4 inhibition. SIGNIFICANCE: These results indicated that TRPV4 was upregulated in OA articular cartilage, and that excessive mechanical stress might induce chondrocyte apoptosis via TRPV4-mediated Ca2+ influx, suggesting TRPV4 as a potential drug target in OA.


Assuntos
Ligamento Cruzado Anterior/patologia , Apoptose , Condrócitos/patologia , Osteoartrite/patologia , Estresse Mecânico , Canais de Cátion TRPV/metabolismo , Animais , Ligamento Cruzado Anterior/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Modelos Animais de Doenças , Masculino , Osteoartrite/genética , Osteoartrite/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/análise , Canais de Cátion TRPV/genética , Regulação para Cima
18.
Life Sci ; 228: 242-250, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075235

RESUMO

AIMS: Osteoarthritis (OA) is a leading cause of deformity in aging people. Emerging evidence suggests that microRNAs and Wnt signaling pathway are associated with its pathogenesis. We aimed to determine whether microRNA-320c inhibits the development of osteoarthritis by suppressing Wnt signaling pathway. MATERIALS AND METHODS: MiR-320c and ß-catenin expression was assessed in human adipose derived stem cells (hADSCs) model of chondrogenesis and in normal and OA primary human chondrocytes. OA chondrocytes were transfected with miR-320c or its antisense inhibitor and ß-catenin siRNA respectively. Direct interaction between miR-320c and ß-catenin mRNA as well as activity of ß-catenin/TCF complex were confirmed by luciferase reporter assay. Mmu-miR-320-3p agomir was intra-articularly injected in collagenase-induced OA mouse model. OA progression was evaluated histologically and immunohistochemically. KEY FINDINGS: MiR-320c was decreased and ß-catenin was increased in OA chondrocytes and late stage of hADSCs chondrogenesis. Overexpression of miR-320c and knockdown of ß-catenin had similar effects that the cartilage-specific genes were elevated and hypertrophy-related genes were down-regulated in OA chondrocytes. Luciferase reporter assay confirm that miR-320c regulated the expression of ß-catenin by directly targeting 3'UTR of ß-catenin mRNA and decreased the relative transcriptional activity of the ß-catenin/TCF complex. Injection of mmu-miR-320-3p attenuated OA progression in the OA mouse model. SIGNIFICANCE: Our results supports that miR-320c can inhibits the degeneration of osteoarthritis chondrocytes via suppressing the canonical Wnt signaling pathway and indicates the potential of miR-320c as a novel therapeutic agent for osteoarthritis treatment.


Assuntos
Regulação para Baixo , MicroRNAs/genética , Osteoartrite/genética , Via de Sinalização Wnt , beta Catenina/genética , Adolescente , Adulto , Idoso , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Condrogênese , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/metabolismo , Adulto Jovem , beta Catenina/metabolismo
19.
Bratisl Lek Listy ; 120(5): 386-391, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113203

RESUMO

AIM: To discuss the effects and mechanism of microRNA-34a in cell apoptosis induced by osteoarthritis. METHODS: Collection of the normal and osteoarthritis synovial tissues and measurements of the miRNA-34a and TGIF2 gene expression. In the cell experiment, the cells were divided into Control, Blank and miRNA inhibitor group. The cell proliferation and apoptosis of the different groups were measured by MTT and flow cytometry and the TGIF2 protein expression in the different groups was evaluated by WB assay. The correlation between TGIF2 and miRNA-34a was analyzed by Double luciferase experiment. RESULTS: Compared with normal synovial tissues, the miRNA-34a gene expression was significantly up-regulated and TGIF2 gene expression was significantly suppressed in osteoarthritis synovial tissues (p < 0.001, respectively). The cell proliferation was significantly depressed and the cell apoptosis rate was significantly increased in miRNA inhibitor group compared with the Control group (p < 0.001, respectively). Using the WB assay it was shown that the TGIF2 protein expression of miRNA inhibitor group was significantly suppressed compared with that of Control group (p < 0.01). By Double luciferase assay, TGIF2 gene was one target gene of miRNA-34a. CONCLUSION: miRNA-34a could induce osteoarthritis synovial cell apoptosis via regulation of TGIF2 in vitro (Fig. 6, Ref. 29).


Assuntos
Apoptose , Proteínas de Homeodomínio , MicroRNAs , Osteoartrite , Proteínas Repressoras , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/fisiologia , Humanos , MicroRNAs/fisiologia , Osteoartrite/metabolismo , Proteínas Repressoras/fisiologia
20.
BMB Rep ; 52(5): 336-341, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31068249

RESUMO

The cGAS-STING pathway plays an important role in pathogen-induced activation of the innate immune response. The 29-kDa amino-terminal fibronectin fragment (29-kDa FN-f) found predominantly in the synovial fluid of osteoarthritis (OA) patients increases the expression of catabolic factors via the toll-like receptor-2 (TLR-2) signaling pathway. In this study, we investigated whether 29-kDa FN-f induces inflammatory responses via the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway in human primary chondrocytes. The levels of cGAS and STING were elevated in OA cartilage compared with normal cartilage. Long-term treatment of chondrocytes with 29-kDa FN-f activated the cGAS/STING pathway together with the increased level of gamma-H2AX, a marker of DNA breaks. In addition, the expression of pro-inflammatory cytokines, including granulocytemacrophage colony-stimulating factor (GM-CSF/CSF-2), granulocyte colony-stimulating factor (G-CSF/CSF-3), and type I interferon (IFN-α), was increased more than 100-fold in 29-kDa FN-f-treated chondrocytes. However, knockdown of cGAS and STING suppressed 29-kDa FN-f-induced expression of GM-CSF, G-CSF, and IFN-α together with the decreased activation of TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), and inhibitor protein κBα (IκBα). Furthermore, NOD2 or TLR-2 knockdown suppressed the expression of GM-CSF, G-CSF, and IFN-α as well as decreased the activation of the cGAS/STING pathway in 29-kDa FN-f-treated chondrocytes. These data demonstrate that the cGAS/STING/TBK1/IRF3 pathway plays a critical role in 29-kDa FN-f-induced expression of pro-inflammatory cytokines. [BMB Reports 2019; 52(5): 336-341].


Assuntos
Citocinas/biossíntese , Fibronectinas/metabolismo , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismo , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Citocinas/metabolismo , DNA/metabolismo , Humanos , Fator Regulador 3 de Interferon/metabolismo , Interferon beta/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Líquido Sinovial/metabolismo , Receptor 2 Toll-Like/metabolismo
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