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1.
BMC Complement Altern Med ; 19(1): 264, 2019 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-31590658

RESUMEN

BACKGROUND: Osteoarthritis (OA) is a common degenerative disease of synovial joints caused by inflammation. Acteoside (ACT), a major component and lipase inhibitor from the Chinese tea Ligustrum purpurascens kudingcha, has been reported to regulate the inflammation and immune response. The study aims to investigate the effects of ACT on inflammatory responses and joint protection in OA rats. METHODS: Cell proliferation was examined by MTT and colony formation assay. Apoptosis was analyzed using flow cytometry with Annexin V/PI staining. ELISA was employed to examine the concentration of inflammatory cytokines. OA rat model was established by surgery stimulation. RESULTS: ACT treatment significantly inhibited the upregulation of inflammatory cytokines induced by IL-1ß in primary chondrocytes, including IL-6, IL-12, TNF-α and IFN-γ. ACT stimulation also enhanced the cell proliferation, while inhibited cell apoptosis in IL-1ß-treated chondrocytes. Consistently, ACT treatment led to downregulation of cleaved-caspase-3 and apoptosis regulator Bax, and upregulation of Bcl-2. Furthermore, ACT treatment inhibited IL-1ß-induced activation of JAK/STAT pathway. The results were confirmed in surgery-induced OA rat model. Moreover, ACT treatment significantly inhibited synovial inflammation and articular chondrocyte apoptosis in OA rats. CONCLUSION: Our findings indicate that ACT has the potential therapeutic effect on OA through inhibiting the inflammatory responses via inactivating JAK/STAT signaling pathway.


Asunto(s)
Medicamentos Herbarios Chinos/administración & dosificación , Glucósidos/administración & dosificación , Ligustrum/química , Osteoartritis/tratamiento farmacológico , Fenoles/administración & dosificación , Animales , Proliferación Celular/efectos de los fármacos , Condrocitos , Modelos Animales de Enfermedad , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Quinasas Janus/genética , Quinasas Janus/inmunología , Masculino , Osteoartritis/genética , Osteoartritis/inmunología , Ratas , Ratas Sprague-Dawley , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
2.
Clin Exp Rheumatol ; 37 Suppl 120(5): 57-63, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31621560

RESUMEN

Although osteoarthritis (OA) was historically referred to as the non-inflammatory arthritis, it is now considered a condition involving persistent low-grade inflammation and activation of innate inflammatory pathways. Synovitis increases the risk of OA onset and progression and involves the recruitment of monocytes, lymphocytes, and other leukocytes. In particular, macrophages are important mediators of synovial inflammatory activity and pathologic cartilage and bone responses that are characteristic of OA. Advances in understanding how damage-associated molecular patterns (DAMPs) trigger monocyte/macrophage recruitment and activation in joints provide opportunities for disease-modifying therapies. However, the complexity and plasticity of macrophage phenotypes that exist in vivo have thus far prevented the successful development of macrophage-targeted treatments. Current studies show that synovial macrophages are derived from distinct cellular lineages, which correspond to unique functional roles for maintaining joint homeostasis. An improved understanding of the aetiology of synovial inflammation in specific OA-subtypes, such as with obesity or genetic risk, is a potential strategy for developing patient selection criteria for future precision therapies.


Asunto(s)
Macrófagos/inmunología , Osteoartritis , Sinovitis , Humanos , Inflamación , Monocitos , Osteoartritis/inmunología , Osteoartritis/patología , Sinovitis/inmunología , Sinovitis/patología
3.
Clin Exp Rheumatol ; 37 Suppl 120(5): 48-56, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31621566

RESUMEN

Osteoarthritis (OA) is the most common age-related chronic and disabling joint disease. Long considered to be a "wear and tear" disease, OA is now seen as a low-grade inflammation disease that affects all tissues of the joint, involving cartilage degradation, bone remodelling, osteophytes, and synovitis. The process, called inflammaging, is characterised by the association of low-grade inflammation, profound changes in intra-cellular mechanisms, and the decreased efficiency of the immune system with ageing. The activation of innate immunity plays a critical role in the development and progression of OA. Innate immunity, including inflammasome activation, is triggered by small endogenous molecules called alarmins or damage-associated molecular patterns (DAMPs). These molecules are released in the extracellular media after cell stress or damage, bind to pathogen-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and the receptor for advanced glycation end products (RAGE), and activate the secretion of pro-inflammatory factors, leading to joint inflammation. Moreover, such sterile inflammation triggers cell senescence, characterised by a senescence-associated secretory phenotype (SASP). Understanding the substantial age-related changes of joint tissues that influence the pathogenesis of OA is critical to improving the quality of life of elderly people in the context of increased life expectancy. This review will focus on age-related sterile inflammation in OA and highlight the various innovative and promising therapies targeting the mechanisms of aging.


Asunto(s)
Osteoartritis , Calidad de Vida , Anciano , Envejecimiento , Humanos , Inflamación/inmunología , Osteoartritis/inmunología , Osteoartritis/patología , Osteoartritis/terapia , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptores Toll-Like/metabolismo
4.
Clin Exp Rheumatol ; 37 Suppl 120(5): 130-134, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31621572

RESUMEN

From the time of their discovery in 1999, the aggrecanases, and ADAMTS-5 in particular, have been heavily investigated as targets for disease-modifying osteoarthritis drug (DMOAD) development. Here, we provide a brief narrative review of the discovery efforts to target these enzymes, and how this led to the current ongoing programmes that hold promise for the future. We discuss a comparison of inhibition of collagen breakdown versus inhibition of aggrecan breakdown. We then summarise existing programmes that target ADAMTS-5, including small molecule inhibitors, monoclonal neutralising antibodies and nanobodies, and gene editing technologies. We also briefly discuss the potential analgesic effects this strategy may offer in addition to its joint-protective effects.


Asunto(s)
Proteínas ADAM , Endopeptidasas/metabolismo , Osteoartritis/enzimología , Procolágeno N-Endopeptidasa , Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/inmunología , Proteína ADAMTS4 , Agrecanos/metabolismo , Humanos , Osteoartritis/tratamiento farmacológico , Osteoartritis/inmunología
5.
Medicina (Kaunas) ; 55(10)2019 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-31554310

RESUMEN

Background and objectives: Composition of the peripheral blood (PB) cell populations and their activation state reflect the immune status of a patient. Rheumatoid arthritis (RA) is characterized by abnormal B- and T-cell functions. The objective of this study was to assess the profiles of the PB mononuclear cell (PBMC) populations in patients with rheumatoid and osteoarthritis (OA) in comparison with healthy control (HC) subjects in order to evaluate the PBMC profiles as a potential diagnostic characteristic in RA. The second aim was to assess the CCR1 and CCR2 expression on PB lymphocytes and correlate it with the plasma levels of matrix metallopeptidase 9 (MMP-9), IL-17F, TNF-α, IL-6, and IL-10. Materials and Methods: The frequency and phenotype, including CCR1 and CCR2, of the PBMC populations (monocytes, CD19+B cells, and T/NK lymphocytes) in RA (n = 15) and OA (n = 10) patients and HC (n = 12) were analyzed by five-color flow cytometry. DNA of the viruses, HHV-6, HHV-7, and B19, in the whole blood and cell-free plasma, were assessed by nested-polymerase chain reaction (PCR). Results: Active persistent or acute infections, caused by HHV-6, HHV-7, or B19, were not detected in patients of this study. Both CCR1 and CCR2 were determined on the PB B and T/NK lymphocytes in several RA and OA patients and HCs. However, in patients, the frequency of the CCR1-positive T/NK lymphocytes showed a weak negative correlation with the IL-10 level, while the frequency of the CCR2-positive B cells correlated positively with the level of IL-6. Statistically significant differences in the proportions of the CD19-positive and CD19-negative lymphocyte and monocyte subsets within the PBMC set were determined between RA and OA patients and HC adults. Conclusions: We have shown in our pilot study with rather small cohorts of patients that the PBMC-population profiles were very consistent, and statistically significantly differed between RA and OA patients and HC subjects.


Asunto(s)
Antígenos CD19/análisis , Artritis Reumatoide/inmunología , Leucocitos Mononucleares/inmunología , Osteoartritis/inmunología , Adulto , Anciano , Artritis Reumatoide/sangre , Estudios de Casos y Controles , Citocinas/sangre , Femenino , Humanos , Recuento de Leucocitos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Osteoartritis/sangre , Proyectos Piloto , Valores de Referencia
6.
Food Funct ; 10(9): 6135-6146, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31497826

RESUMEN

Osteoarthritis (OA) is a degenerative joint disease, whose progression is closely related to the inflammatory environment. Urolithin A (UA), a natural metabolite of a class of compounds (ellagitannins and ellagic acid) found in pomegranates and other fruits and nuts, has been proved to exert anti-inflammatory effects in a variety of diseases. However, the exact role of UA in OA development is still unclear. In the present study, we examined the latent mechanism of UA and its protective role in the progression of OA by both in vitro and in vivo experiments. In vitro, UA inhibited the interleukin-1 beta (IL-1ß) induced over-production of nitric oxide (NO), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in a concentration-dependent manner in human OA chondrocytes. Furthermore, by downregulating the expression of metalloproteinase 13 (MMP13) and thrombospondin motifs 5 (ADAMTS5), UA attenuated the degradation of the extracellular matrix (ECM) induced by IL-1ß. Mechanistically, UA was found to suppress the activation of PI3K/Akt/NF-κB pathways. In vivo, in a surgically induced mouse OA model, UA-induced protective effects in OA development could be detected. In summary, this research suggested that UA may be adopted as a new therapeutic agent for the treatment of OA.


Asunto(s)
Cumarinas/administración & dosificación , Interleucina-1beta/inmunología , FN-kappa B/inmunología , Osteoartritis/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/inmunología , Proteínas Proto-Oncogénicas c-akt/inmunología , Animales , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Dinoprostona/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Óxido Nítrico/inmunología , Osteoartritis/genética , Osteoartritis/inmunología , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas c-akt/genética , Transducción de Señal/efectos de los fármacos
7.
Mol Med Rep ; 20(4): 3867-3873, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31485657

RESUMEN

Osteoarthritis (OA) is one of the most prevalent types of chronic joint diseases. Chondrocytes survival is closely associated with the destruction of joints in patients with OA. Long noncoding RNAs (lncRNAs) serve a critical role in OA. However, to the best of our knowledge, the role of lncRNAs NR024118 in OA has not been examined. In the present study, the expression levels of NR024118 in lipopolysaccharide (LPS)­induced chondrocytes was measured using reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and the apoptosis levels of cells was determined using flow cytometry. The levels of scavenged reactive oxygen species and expression levels of the antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and heme oxygenase­1 (HO­1) were measured using specialized detection kits. The expression of interleukin (IL)­1ß, IL­6 and IL­18 were measured using ELISA. Expression of the cell apoptosis markers Bcl­2, Bax, Bcl­2­like protein 11, NF­κB, phosphorylated (p)­NF­κB inhibitor ß (IκBß), IκBß, p­transcription factor p65 (p65) and p65, and nuclear factor erythroid­2 related factor 2 (Nrf2) signaling pathways­associated proteins, Nrf2, HO­1 and quinone oxidoreductase­1 were detected by western blot analysis and RT­qPCR. The results indicated that in ATDC5 cells, apoptosis, oxidative stress and inflammation were significantly increased and the expression level of NR024118 was significantly decreased by LPS­mediated induction. NR024118 overexpression significantly reversed the effects of LPS treatment in the ATDC5 cell line. In addition, the overexpression of NR024118 decreased NF­κB expression levels and activated the Nrf2 signaling pathways in LPS­induced ATDC5 cells. The present study demonstrated that NR024118 attenuated the effects of LPS­induction on ATDC5 cells. These results suggest that NR024118 may be a potential target for diagnosis and treatment of OA.


Asunto(s)
Apoptosis , Condrocitos/inmunología , Inflamación/genética , Factor 2 Relacionado con NF-E2/inmunología , FN-kappa B/inmunología , ARN Largo no Codificante/genética , Animales , Línea Celular , Condrocitos/metabolismo , Inflamación/inmunología , Lipopolisacáridos/inmunología , Ratones , Osteoartritis/genética , Osteoartritis/inmunología , Transducción de Señal , Regulación hacia Arriba
8.
Life Sci ; 234: 116786, 2019 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-31445934

RESUMEN

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.


Asunto(s)
Cartílago Articular/patología , Matriz Extracelular/patología , Metaloproteinasas de la Matriz/inmunología , Osteoartritis/patología , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/inmunología , Cartílago Articular/metabolismo , Descubrimiento de Drogas , Matriz Extracelular/efectos de los fármacos , Matriz Extracelular/inmunología , Matriz Extracelular/metabolismo , Humanos , Metaloproteinasa 13 de la Matriz/análisis , Metaloproteinasa 13 de la Matriz/inmunología , Metaloproteinasa 13 de la Matriz/metabolismo , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Metaloproteinasas de la Matriz/análisis , Metaloproteinasas de la Matriz/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/inmunología , Osteoartritis/metabolismo
9.
Food Funct ; 10(9): 5697-5706, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31435629

RESUMEN

Osteoarthritis (OA) is a common form of arthritis, which is characterized by the degeneration of articular cartilage, leading to joint dysfunction. Oral drug therapy seems to ameliorate some signs and symptoms of OA, but may be accompanied by side effects and does not appear to be effective long-term. Seaweed has received much attention for pharmacological application due to its various biomedical properties, including the anti-inflammation, antitumor, and antioxidant effects. This study investigated the ameliorative effects of a dietary polysaccharide from Eucheuma cottonii extract (ECE) on an anterior cruciate ligament transection with partial medial meniscectomy surgery (ACLT+MMx) to induce OA in high-fat diet (HFD)-induced obese rats. Male Sprague-Dawley rats were fed an HFD for 12 weeks before ACLT+MMx surgery, after which they were administered a daily oral gavage of saline (Sham, OB Sham, and OBOA) and either low-dose ECE (100 mg per kg body weight), high-dose ECE (400 mg per kg body weight), or glucosamine sulfate as a positive control (OBOAGS; 200 mg per kg body weight) for 5 weeks. Treatment with ECE decreased the body weight, triglyceride and total cholesterol (TC) levels, and the TC/high-density lipoprotein (HDL)-C ratio in the obese rats. Additionally, ECE downregulated the expression of proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, and leptin, and suppressed nuclear factor-kappa B and extracellular-signal-regulated kinase-1/2 expression, resulting in a decrease in the levels of matrix metalloproteinase (MMP)-1 and MMP-13 and prostaglandin-E2 and attenuated cartilage degradation. These results demonstrate that the dietary polysaccharide from ECE can suppress OA development in obese rats, suggesting its potential efficacy as a promising candidate for OA treatment.


Asunto(s)
Cartílago Articular/efectos de los fármacos , Citocinas/inmunología , Obesidad/complicaciones , Osteoartritis/tratamiento farmacológico , Extractos Vegetales/administración & dosificación , Polisacáridos/administración & dosificación , Rhodophyta/química , Algas Marinas/química , Animales , Ligamento Cruzado Anterior/efectos de los fármacos , Ligamento Cruzado Anterior/inmunología , Cartílago Articular/inmunología , Citocinas/genética , Modelos Animales de Enfermedad , Humanos , Masculino , Obesidad/metabolismo , Osteoartritis/etiología , Osteoartritis/genética , Osteoartritis/inmunología , Ratas , Ratas Sprague-Dawley
10.
Food Funct ; 10(9): 5873-5885, 2019 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-31464310

RESUMEN

Osteoarthritis (OA) is the most prevalent form of human arthritis which is characterized by the degradation of cartilage and inflammation. As a rare Sirt6 activator, cyanidin is the major component of anthocyanins commonly found in the Mediterranean diet, and increasing evidence has shown that cyanidin exhibits anti-inflammatory effects in a variety of diseases. However, the anti-inflammatory effects of cyanidin on OA have not been reported. In the present study, we identified that cyanidin treatment could strongly suppress the expression of NO, PGE2, TNF-α, IL-6, iNOs, COX-2, ADAMTS5 and MMP13, and reduce the degradation of aggrecan and collagen II in IL-1ß-induced human OA chondrocytes, indicating the anti-inflammatory effect of cyanidin. Further investigation of the mechanism involved revealed that cyanidin could upregulate the Sirt6 level in a dose-dependent manner and Sirt6 silencing abolished the effect of cyanidin in IL-1ß-stimulated human OA chondrocytes, indicating a stimulatory effect of cyanidin on Sirt6 activation. Meanwhile, we found that cyanidin could inhibit the NF-κB pathway in IL-1ß-stimulated human OA chondrocytes and its effect may to some extent depend on Sirt6 activation, suggesting that cyanidin may exert a protective effect through regulating the Sirt6/NF-κB signaling axis. Moreover, the in vivo study also proved that cyanidin ameliorated the development of OA in surgical destabilization of the medial meniscus (DMM) mouse OA models. In conclusion, these results demonstrate that cyanidin may have therapeutic potential for the treatment of OA.


Asunto(s)
Antocianinas/administración & dosificación , Antiinflamatorios/administración & dosificación , FN-kappa B/inmunología , Osteoartritis/tratamiento farmacológico , Sirtuinas/inmunología , Animales , Condrocitos/efectos de los fármacos , Condrocitos/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Humanos , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Metaloproteinasa 13 de la Matriz , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , Osteoartritis/genética , Osteoartritis/inmunología , Sirtuinas/genética
11.
J Immunol Res ; 2019: 4080735, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31428656

RESUMEN

Rheumatoid arthritis (RA) and osteoarthritis (OA) are common rheumatic disorders that primarily involve joints. The inflammation of the synovium can be observed in both of the two diseases. Synovial fibroblasts (SFs) play an important role in the inflammatory process of the synovium. The functional states of synovial fibroblasts are heterogeneous, and the detailed transition process of their functional states is still unclear. By using transcriptomic data of SFs at a single-cell level, we found a similar transition process for SFs in RA and OA. We also identified the potential regulatory effects of the WNT signaling pathway, the TGF-ß signaling pathway, the FcεRI signaling pathway, and the ERBB signaling pathway on modifying the SFs' functional state. These findings indicate potentially overlapped pathogenic mechanisms in these two diseases, which may help uncover new therapeutic targets to ameliorate disease progression.


Asunto(s)
Artritis Reumatoide/metabolismo , Fibroblastos/metabolismo , Osteoartritis/metabolismo , Membrana Sinovial/citología , Artritis Reumatoide/inmunología , Progresión de la Enfermedad , Fibroblastos/inmunología , Genes erbB , Humanos , Osteoartritis/inmunología , Análisis de la Célula Individual , Membrana Sinovial/inmunología , Membrana Sinovial/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Vía de Señalización Wnt
12.
Int Immunopharmacol ; 75: 105815, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31465913

RESUMEN

BACKGROUNDS: OA (Osteoarthritis) is a predominant degenerative disease, characterized by the synovial inflammation and cartilage destruction. The pathogenic mechanisms remain mostly unknown. There is an critical require for extra investigations to discover new therapeutic targets to prevent and treat OA disease, as there are currently no effective treatments except for the joint replacement. METHODS: The mRNA and protein levels of Metallothionein-1(MT-1) were quantified by qPCR and ELISA in peripheral blood mononuclear cells (PBMCs), serum and synovial cells (SCs) from erosive inflammatory OA (EIOA) and primary generalized OA (PGOA) patients. Age and sex matched healthy volunteers were recruited as healthy controls (HCs). The correlation between the MT-1 level and OA activity was assessed and the anti-inflammatory effects of MT-1 was determined in vitro. RESULTS: The mRNA and protein levels of MT-1 were significantly increased in the PBMCs and serum of EIOA patients compared with those of PGOA patients and HCs. Serum levels of MT-1 were positively correlated with VAS score, CRP, and ESR in OA patients. And the positive correlations were also identified between the MT-1 and IL-1ß, TNF-α or IL-6 in synovial cells. Furthermore, the recombinant MT-1 protein could significantly inhibit the expression of IL-1ß, TNF-α and IL-6 in PBMCs and SCs from EIOA patients in vitro. CONCLUSION: The data had shown that the MT-1 was up-regulated in EIOA patients and positively correlated with the disease activity. The recombinant MT-1 could suppress the expression of pro-inflammatory cytokines in both PBMCs and synovial cells from EIOA patients. Therefore, the MT-1 might become a novel therapeutic target for OA treatment.


Asunto(s)
Citocinas/inmunología , Metalotioneína/inmunología , Osteoartritis/inmunología , Sinoviocitos/inmunología , Anciano , Células Cultivadas , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Metalotioneína/genética , Persona de Mediana Edad , Dimensión del Dolor
13.
Biomed Pharmacother ; 118: 109186, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31302420

RESUMEN

Osteoarthritis is a degenerative joint disease, worldwide, and its underlying molecular mechanisms are still poorly understood. MicroRNAs are important regulators of diverse biological processes, including osteoarthritis. In this study, we showed that miR-103 was deregulated in osteoarthritis patients. We performed CCK8 and colony formation assay and found that miR-103 inhibited chondrocyte proliferation. We also found that miR-103 inhibited chondrocyte formation and maturation by RT-PCR, western blotting, and immunocytochemistry. Inhibition of miR-103 suppressed production of the catabolic factors and pro-inflammatory cytokines induced by IL-1ß in chondrocytes. Finally, we found that Sox6 was a direct target of miR-103 and participated in osteoarthritis development. In summary, we demonstrated that miR-103 contributed to osteoarthritis development by directly targeting and inhibiting the expression of Sox6. Regulation of miR-103 expression in human chondrocytes may be an effective treatment for osteoarthritis.


Asunto(s)
Cartílago Articular/patología , Proliferación Celular/genética , Regulación de la Expresión Génica , MicroARNs/genética , Osteoartritis/genética , Factores de Transcripción SOXD/genética , Cartílago Articular/metabolismo , Células Cultivadas , Regulación hacia Abajo , Humanos , Interleucina-1beta/biosíntesis , Persona de Mediana Edad , Osteoartritis/inmunología , Osteoartritis/patología , Cultivo Primario de Células , Transducción de Señal
14.
Food Funct ; 10(8): 5059-5069, 2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31359010

RESUMEN

As a chronic degenerative joint disease, osteoarthritis (OA) is clinically characterized by a high incidence, long-term pain, and limited joint activity but without effective preventative therapy. Troxerutin (Tx) is a natural flavonoid, also called vitamin P4, which is widely present in plants consumed as part of our daily diet, such as cereals, various fruits and vegetables, tea, and coffee, and possesses various biological activities, especially an anti-inflammatory effect. Here, we aimed to investigate the potential chondroprotection of Tx in experimental OA development. In in vitro studies, human chondrocytes were isolated and exposed in advanced glycation end-products (AGEs) to simulate OA development. It was found that Tx pretreatment inhibited the AGE-induced production of pro-inflammatory factors in chondrocytes, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Meanwhile, AGE-medicated extracellular matrix (ECM) degradation was decreased in Tx-pretreated chondrocytes. Furthermore, we found that Tx pretreatment suppressed the activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways in AGE-exposed chondrocytes. In vivo, Tx treatment prevented the narrowing of the joint space, the calcification of cartilage, and the loss of proteoglycans in the mouse OA model. In brief, Tx is considered as a potential therapeutic agent for OA.


Asunto(s)
Antiinflamatorios/administración & dosificación , Condrocitos/efectos de los fármacos , Productos Finales de Glicación Avanzada/efectos adversos , Hidroxietilrutósido/análogos & derivados , Osteoartritis/tratamiento farmacológico , Animales , Condrocitos/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/inmunología , Dinoprostona/inmunología , Modelos Animales de Enfermedad , Humanos , Hidroxietilrutósido/administración & dosificación , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Óxido Nítrico/inmunología , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/inmunología , Osteoartritis/etiología , Osteoartritis/genética , Osteoartritis/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
15.
Hum Immunol ; 80(10): 871-877, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31326139

RESUMEN

A subset of natural killer (NK) cells with CD56+/brightCD16dim/- expression is recently shown to present critical regulatory functions. Functional characteristics of CD56+/bright NK cells in osteoarthritis (OA) patients remains unknown. Here, we remedied this problem by comparing the NK cells from healthy controls and OA patients. Data showed that the CD56brightCD16- NK subset was significantly enriched in OA patients. These CD56brightCD16- NK cells from OA patients presented significantly higher IFNG transcription and IFN-γ protein secretion than those from healthy controls, both directly ex vivo and after activation via various stimulating reagents, including IL-2/IL-15, K562, and PMA/ionomycin. On the other hand, the transcription and secretion of granzyme A (Gzm-A), Gzm-B, and perforin were significantly lower in CD56brightCD16- NK cells from OA patients than in CD56brightCD16- NK cells from healthy controls. Also, the CD56brightCD16- NK cells from OA patients were less capable of suppressing the proliferation of autologous CD4+ T cells, in a manner that was dependent on the expression of Gzm-B and perforin. Interestingly, CD4+ T cells co-incubated with CD56brightCD16- NK cells were prone to express a higher level of IFNG, and the CD56brightCD16- NK cells from OA patients were more potent at stimulating IFNG than the CD56brightCD16- NK cells from healthy controls. Overall, our investigation demonstrated that CD56brightCD16- NK cells from osteoarthritis patients were shifted toward an IFN-γ-promoting phenotype and with reduced regulatory functions.


Asunto(s)
Antígeno CD56/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Células Asesinas Naturales/inmunología , Osteoartritis/inmunología , Fenotipo , Receptores de IgG/metabolismo , Anciano , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular , Técnicas de Cocultivo/métodos , Femenino , Proteínas Ligadas a GPI/metabolismo , Granzimas/genética , Granzimas/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Perforina/genética , Perforina/metabolismo
16.
Genes (Basel) ; 10(6)2019 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-31234442

RESUMEN

Osteoarthritis (OA) is a degenerative joint disease accompanied by pain and loss of function. Adipose tissue harbors mesenchymal stem/stromal cells (MSC), or medicinal signaling cells as suggested by Caplan (Caplan, 2017), used in autologous transplantation in many clinical settings. The aim of the study was to characterize a stromal vascular fraction from microfragmented lipoaspirate (SVF-MLA) applied for cartilage treatment in OA and compare it to that of autologous lipoaspirate (SVF-LA). Samples were first stained using a DuraClone SC prototype tube for the surface detection of CD31, CD34, CD45, CD73, CD90, CD105, CD146 and LIVE/DEAD Yellow Fixable Stain for dead cell detection, followed by DRAQ7 cell nuclear dye staining, and analyzed by flow cytometry. In SVF-LA and SVF-MLA samples, the following population phenotypes were identified within the CD45- fraction: CD31+CD34+CD73±CD90±CD105±CD146± endothelial progenitors (EP), CD31+CD34-CD73±CD90±CD105-CD146± mature endothelial cells, CD31-CD34-CD73±CD90+CD105-CD146+ pericytes, CD31-CD34+CD73±CD90+CD105-CD146+ transitional pericytes, and CD31-CD34+CD73highCD90+CD105-CD146- supra-adventitial-adipose stromal cells (SA-ASC). The immunophenotyping profile of SVF-MLA was dominated by a reduction of leukocytes and SA-ASC, and an increase in EP, evidencing a marked enrichment of this cell population in the course of adipose tissue microfragmentation. The role of EP in pericyte-primed MSC-mediated tissue healing, as well as the observed hormonal implication, is yet to be investigated.


Asunto(s)
Adventicia/inmunología , Cartílago/metabolismo , Inmunofenotipificación , Osteoartritis/tratamiento farmacológico , Adipocitos/efectos de los fármacos , Adipocitos/inmunología , Adventicia/efectos de los fármacos , Cartílago/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Femenino , Citometría de Flujo , Humanos , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/inmunología , Osteoartritis/inmunología , Osteoartritis/metabolismo , Pericitos/efectos de los fármacos , Pericitos/inmunología
17.
PLoS One ; 14(6): e0218740, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31251756

RESUMEN

Novel strategies have been proposed for articular cartilage damage occurring during osteoarthritis (OA) and -among these- Extracorporeal Shock Wave Therapy (ESWT), intra-articular injections of Platelet-Rich Plasma (PRP) or Hyaluronic Acid (HA) revealed encouraging results. To investigate the possible mechanisms responsible for those clinical benefits, we established primary cultures of human chondrocytes derived from cartilage explants and measured the in vitro effects of ESW, PRP and HA therapies. After molecular/morphological cell characterization, we assessed those effects on the functional activities of the chondrocyte cell cultures, at the protein and molecular levels. ESWT significantly prevented the progressive dedifferentiation that spontaneously occurs during prolonged chondrocyte culture. We then attested the efficiency of all such treatments to stimulate the expression of markers of chondrogenic potential such as SOX9 and COL2A, to increase the Ki67 proliferation index as well as to antagonize the traditional marker of chondrosenescence p16INK4a (known as Cdkn2a). Furthermore, all our samples showed an ESW- and HA-mediated enhancement of migratory and anti-inflammatory activity onto the cytokine-rich environment characterizing OA. Taken together, those results suggest a regenerative effect of such therapies on primary human chondrocytes in vitro. Moreover, we also show for the first time that ESW treatment induces the surface expression of major hyaluronan cell receptor CD44 allowing the increase of COL2A/COL1A ratio upon HA administration. Therefore, this work suggests that ESW-induced CD44 overexpression enhances the in vitro cell susceptibility of human chondrocytes to HA, presumably favouring the repair of degenerated cartilage.


Asunto(s)
Condrocitos/fisiología , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/administración & dosificación , Osteoartritis/terapia , Plasma Rico en Plaquetas/química , Regeneración , Anciano , Cartílago Articular/citología , Cartílago Articular/efectos de los fármacos , Cartílago Articular/fisiología , Células Cultivadas , Condrocitos/citología , Condrocitos/efectos de los fármacos , Técnicas de Cocultivo , Tratamiento con Ondas de Choque Extracorpóreas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Ácido Hialurónico/farmacología , Inyecciones Intraarticulares , Persona de Mediana Edad , Osteoartritis/inmunología
18.
APMIS ; 127(8): 588-593, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31233243

RESUMEN

Microfibrillar-associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) vs osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N = 6) and OA (N = 6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum vs healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/L (18.1-43.3) vs 17.7 U/L (13.7-21.2), p = 0.006 and p = 0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease.


Asunto(s)
Artritis Reumatoide/inmunología , Proteínas Portadoras/análisis , Proteínas de la Matriz Extracelular/análisis , Glicoproteínas/análisis , Osteoartritis/inmunología , Membrana Sinovial/inmunología , Anciano , Anticuerpos Monoclonales/inmunología , Biomarcadores/análisis , Proteínas Portadoras/inmunología , Estudios de Casos y Controles , Proteínas de la Matriz Extracelular/inmunología , Femenino , Glicoproteínas/inmunología , Humanos , Masculino , Persona de Mediana Edad , Líquido Sinovial/química , Membrana Sinovial/patología
19.
Life Sci ; 228: 258-265, 2019 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-30953645

RESUMEN

Diabetes is an independent risk factor for knee osteoarthritis (OA), and hyperglycaemia-induced inflammation is considered to play an important role in their connection. The Toll-like receptor 4 (TLR4) regulates inflammatory responses in several pathological conditions including diabetes and OA. However, its role in diabetes-associated OA is poorly understood. In this study, we found that TLR4 expression was higher in OA cartilage from patients with type 2 diabetes mellitus (T2DM) than that from non-T2DM patients. Similarly, its expression was induced in primary mouse chondrocytes treated with high glucose, which suggests that TLR4 upregulation in T2DM-associated OA cartilage may originate from hyperglycaemia stimulation. We further discovered that TLR4 promoted high glucose-induced catabolic and inflammatory responses in chondrocytes, and mechanistically, these effects could be explained by the exacerbated activation of the transcription factor nuclear factor kappa B (NF-κB) pathway, since its inhibition by Bay 11-7082 abrogated TLR4 effects on high glucose-treated chondrocytes. Taken together, these findings may reveal a promotive role of TLR4 in regulating hyperglycaemia-induced catabolism and inflammation in T2DM-associated OA, and also implicate that TLR4 inhibition might be of therapeutic significance in treating T2DM-associated OA.


Asunto(s)
Condrocitos/inmunología , Diabetes Mellitus Tipo 2/inmunología , Glucosa/inmunología , FN-kappa B/inmunología , Osteoartritis/inmunología , Receptor Toll-Like 4/inmunología , Animales , Células Cultivadas , Condrocitos/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Humanos , Inflamación/complicaciones , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones Endogámicos C57BL , Osteoartritis/complicaciones , Osteoartritis/patología
20.
Nat Commun ; 10(1): 1914, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-31015473

RESUMEN

Degradation of extracellular matrix (ECM) underlies loss of cartilage tissue in osteoarthritis, a common disease for which no effective disease-modifying therapy currently exists. Here we describe BNTA, a small molecule with ECM modulatory properties. BNTA promotes generation of ECM components in cultured chondrocytes isolated from individuals with osteoarthritis. In human osteoarthritic cartilage explants, BNTA treatment stimulates expression of ECM components while suppressing inflammatory mediators. Intra-articular injection of BNTA delays the disease progression in a trauma-induced rat model of osteoarthritis. Furthermore, we identify superoxide dismutase 3 (SOD3) as a mediator of BNTA activity. BNTA induces SOD3 expression and superoxide anion elimination in osteoarthritic chondrocyte culture, and ectopic SOD3 expression recapitulates the effect of BNTA on ECM biosynthesis. These observations identify SOD3 as a relevant drug target, and BNTA as a potential therapeutic agent in osteoarthritis.


Asunto(s)
Antiinflamatorios/farmacología , Benzamidas/farmacología , Cartílago Articular/efectos de los fármacos , Matriz Extracelular/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Factores Inmunológicos/farmacología , Osteoartritis/tratamiento farmacológico , Sulfonamidas/farmacología , Animales , Cartílago Articular/inmunología , Cartílago Articular/patología , Condrocitos/efectos de los fármacos , Condrocitos/inmunología , Condrocitos/patología , Citocinas/genética , Citocinas/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Matriz Extracelular/inmunología , Matriz Extracelular/patología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inyecciones Intraarticulares , Masculino , Osteoartritis/genética , Osteoartritis/inmunología , Osteoartritis/patología , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/genética , Superóxido Dismutasa/inmunología , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , Transcriptoma/inmunología
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