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1.
Int J Mol Sci ; 22(19)2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34638736

RESUMO

In rheumatoid arthritis (RA), inflammatory cytokines play a pivotal role in triggering abnormal osteoclastogenesis leading to articular destruction. Recent studies have demonstrated enhanced levels of interleukin-9 (IL-9) in the serum and synovial fluid of patients with RA. In RA, strong correlation has been observed between tissue inflammation and IL-9 expression in synovial tissue. Therefore, we investigated whether IL-9 influences osteoclastogenesis in patients with RA. We conducted the study in active RA patients. For inducing osteoclast differentiation, mononuclear cells were stimulated with soluble receptor activator of NF-kB ligand (sRANKL) and macrophage-colony-stimulating factor (M-CSF) in the presence or absence of recombinant (r) IL-9. IL-9 stimulation significantly enhanced M-CSF/sRANKL-mediated osteoclast formation and function. Transcriptome analysis revealed differential gene expression induced with IL-9 stimulation in the process of osteoclast differentiation. IL-9 mainly modulates the expression of genes, which are involved in the metabolic pathway. Moreover, we observed that IL-9 modulates the expression of matrix metalloproteinases (MMPs), which are critical players in bone degradation. Our results indicate that IL-9 has the potential to influence the structural damage in the RA by promoting osteoclastogenesis and modulating the expression of MMPs. Thus, blocking IL-9 pathways might be an attractive immunotherapeutic target for preventing bone degradation in RA.


Assuntos
Artrite Reumatoide/metabolismo , Regulação da Expressão Gênica , Interleucina-9/biossíntese , Osteoclastos/metabolismo , Membrana Sinovial/metabolismo , Adulto , Artrite Reumatoide/patologia , Colagenases/biossíntese , Feminino , Humanos , Fator Estimulador de Colônias de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Osteoclastos/patologia , Ligante RANK/metabolismo , Membrana Sinovial/patologia
2.
Am J Cardiol ; 160: 96-98, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34620488

RESUMO

Cardiac amyloidosis is often preceded by orthopedic manifestations such as carpal tunnel syndrome, and 10% of patients who underwent idiopathic carpal tunnel release surgery will have biopsy-confirmed amyloid deposits in the tenosynovial sheath. Trigger finger is also commonly reported in patients with amyloidosis and involves the same tendon sheath as carpal tunnel syndrome, but the prevalence of amyloid deposition is unclear. This prospective cross-sectional study enrolled 100 patients aged ≥50 years at the time of surgery for idiopathic trigger finger. Patients underwent release surgery, and a sample of the tenosynovium of the affected finger was excised, stained with Congo red, and subtyped with mass spectrometry if amyloid was demonstrated. Further cardiac evaluation was performed in patients with amyloid deposition. Of the 100 patients (mean age 65.5 ± 8.1 years) enrolled, only 2 demonstrated amyloid deposits on Congo red staining. One patient with previous proteinuric kidney disease had fibrinogen A α-chain amyloidosis, and the other patient had untyped amyloidosis. Neither patient had cardiac involvement. A total of 13 of the 100 patients underwent concomitant carpal tunnel release surgery, and 2 of these patients had amyloid deposits in the carpal tunnel with "false-negative" samples from the trigger finger tenosynovium. In conclusion, biopsy during trigger finger release surgery demonstrated a 2% yield for amyloidosis, which is significantly lower than the previously published yield of 10% during carpal tunnel release surgery. This observation has important implications for the development of diagnostic algorithms to screen patients for amyloidosis during orthopedic operations.


Assuntos
Amiloidose/diagnóstico , Cardiomiopatias/diagnóstico , Membrana Sinovial/patologia , Dedo em Gatilho/cirurgia , Idoso , Amiloidose/complicações , Amiloidose/metabolismo , Amiloidose/patologia , Cardiomiopatias/complicações , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Síndrome do Túnel Carpal/etiologia , Síndrome do Túnel Carpal/metabolismo , Síndrome do Túnel Carpal/patologia , Síndrome do Túnel Carpal/cirurgia , Feminino , Fibrinogênio/metabolismo , Humanos , Masculino , Programas de Rastreamento , Espectrometria de Massas , Pessoa de Meia-Idade , Membrana Sinovial/metabolismo , Dedo em Gatilho/etiologia , Dedo em Gatilho/metabolismo , Dedo em Gatilho/patologia
3.
Int J Mol Sci ; 22(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34502442

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive synovitis. It is significantly associated with disability, impaired quality of life, and premature mortality. Recently, the development of biological agents (including tumor necrosis factor-α and interleukin-6 receptor inhibitors) and Janus kinase inhibitors have advanced the treatment of RA; however, it is still difficult to predict which drug will be effective for each patient. To break away from the current therapeutic approaches that could be described as a "lottery," there is an urgent need to establish biomarkers that stratify patients in terms of expected therapeutic responsiveness. This review deals with recent progress from multi-faceted analyses of the synovial tissue in RA, which is now bringing new insights into diverse features at both the cellular and molecular levels and their potential links with particular clinical phenotypes.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Humanos , Membrana Sinovial/patologia
4.
Sci Rep ; 11(1): 16956, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417523

RESUMO

Osteoarthritis (OA), a most common and highly prevalent joint disease, is closely associated with dysregulated expression and modification of RXRα. However, the role of RXRα in the pathophysiology of OA remains unknown. The present study aimed to investigate whether RXRα modulator, such as K-80003 can treat OA. Experimental OA was induced by intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats. Articular cartilage degeneration was assessed using Safranin-O and fast green staining. Synovial inflammation was measured using hematoxylin and eosin (H&E) staining and enzyme-linked immunosorbent assay (ELISA). Expressions of MMP-13, ADAMTS-4 and ERα in joints were analyzed by immunofluorescence staining. Western blot, RT-PCR and co-Immunoprecipitation (co-IP) were used to assess the effects of K-80003 on RXRα-ERα interaction. Retinoid X receptor α (RXRα) modulator K-80003 prevented the degeneration of articular cartilage, reduced synovial inflammation, and alleviated osteoarthritic pain in rats. Furthermore, K-80003 markedly inhibited IL-1ß-induced p65 nuclear translocation and IκBα degradation, and down-regulate the expression of HIF-2α, proteinases (MMP9, MMP13, ADAMTS-4) and pro-inflammatory factors (IL-6 and TNFα) in primary chondrocytes. Additionally, knockdown of ERα with siRNA blocked these effects of K-80003 in chondrocytes. In conclusion, RXRα modulators K-80003 suppresses inflammatory and catabolic responses in OA, suggesting that targeting RXRα-ERα interaction by RXRα modulators might be a novel therapeutic approach for OA treatment.


Assuntos
Inflamação/complicações , Inflamação/metabolismo , Osteoartrite/complicações , Osteoartrite/metabolismo , Receptor X Retinoide alfa/metabolismo , Sulindaco/análogos & derivados , Animais , Cartilagem/diagnóstico por imagem , Cartilagem/patologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Modelos Animais de Doenças , Receptor alfa de Estrogênio/metabolismo , Células HEK293 , Humanos , Inflamação/diagnóstico por imagem , Articulações/efeitos dos fármacos , Articulações/patologia , Masculino , NF-kappa B/metabolismo , Osteoartrite/diagnóstico por imagem , Dor/complicações , Substâncias Protetoras/farmacologia , Ligação Proteica/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Sulindaco/farmacologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Sinovite/complicações , Sinovite/patologia , Regulação para Cima
5.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208719

RESUMO

Synovitis of the knee synovium is proven to be a precursor of knee osteoarthritis (OA), leading to a radiologically advanced stage of the disease. This study was conducted to elucidate the expression pattern of different inflammatory factors-NF-kB, iNOS, and MMP-9 in a subpopulation of synovial cells. Thirty synovial membrane intra-operative biopsies of patients (ten controls, ten with early OA, and ten with advanced OA, according to the Kellgren-Lawrence radiological score) were immunohistochemically stained for NF-kB, iNOS, and MMP9, and for different cell markers for macrophages, fibroblasts, leukocytes, lymphocytes, blood vessel endothelial cells, and blood vessel smooth muscle cells. The total number of CD68+/NF-kB+ cells/mm2 in the intima of early OA patients (median = 2359) was significantly higher compared to the total number of vimentin+/Nf-kB+ cells/mm2 (median = 1321) and LCA+/NF-kB+ cells/mm2 (median = 64) (p < 0.001 and p < 0.0001, respectively). The total number of LCA+/NF-kB+ cells/mm2 in the subintima of advanced OA patients (median = 2123) was significantly higher compared to the total number of vimentin+/NF-kB+ cells/mm2 (median = 14) and CD68+/NF-kB+ cells/mm2 (median = 29) (p < 0.0001). The total number of CD68+/iNOS+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/iNOS+ cells/mm2 and LCA+/iNOS+ cells/mm2 (p < 0.0001 and p < 0.001, respectively). The total number of CD68+/MMP-9+ cells/mm2 in the intima of both early and advanced OA patients was significantly higher compared to the total number of vimentin+/MMP-9+ cells/mm2 and CD5+/MMP-9+ cells/mm2 (p < 0.0001). Macrophages may have a leading role in OA progression through the NF-kB production of inflammatory factors (iNOS and MMP-9) in the intima, except in advanced OA, where leukocytes could have a dominant role through NF-kB production in subintima. The blocking of macrophageal and leukocyte NF-kB expression is a possible therapeutic target as a disease modifying drug.


Assuntos
NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Osteoartrite do Joelho/metabolismo , Osteoartrite do Joelho/patologia , Adulto , Biomarcadores , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinases da Matriz/metabolismo , Osteoartrite do Joelho/etiologia , Índice de Gravidade de Doença , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Adulto Jovem
6.
Isr Med Assoc J ; 23(7): 412-415, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34251122

RESUMO

BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease characterized by different phenotypes in terms of joint involvement. The so-called oligoarticular pattern involves fewer than five active joints at a different time points. The evaluation of disease activity in this subset of patients is an unmet need due to the lack of specific indices able to capture modifications over time. OBJECTIVES: To evaluate the ability of musculoskeletal ultrasound to monitor the response to apremilast treatment in oligoarticular PsA patients. METHODS: We evaluated 24 oligoarticular patients (19 women, 5 men; median age 56 years, interquartile range (IQR) 19; median disease duration 5 years, IQR 5.75). All patients were assessed at baseline (T0), and after 6 (T1), 12 (T2), and 24 (T3) weeks. Clinical assessment included evaluation of 66 swollen joints and patient global health assessment. All the patients underwent ultrasound assessment of the clinically involved joints. Synovial effusion/hypertrophy and power Doppler were scored with a semi-quantitative scale (0-3). The total inflammatory score was the sum of the scores. RESULTS: We found a reduction in the ultrasound inflammatory score at all time points, with a significant improvement at 6 and 12 weeks of treatment compared with baseline: T0 median 8.5 (IQR 5.0); T1 3.5 (3.0); T2 2.0 (3.5); P = 0.01. We observed a significant reduction of patient global health assessment after 24 weeks (T0 median 50 (32.5); T3 40 (57.5); P = 0.01). CONCLUSIONS: Musculoskeletal ultrasound could be useful in the assessment of treatment response in PsA patients with oligoarticular subset.


Assuntos
Artrite Psoriásica , Monitoramento de Medicamentos/métodos , Membrana Sinovial , Talidomida/análogos & derivados , Ultrassonografia/métodos , Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/fisiopatologia , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Tamanho do Órgão , Gravidade do Paciente , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Líquido Sinovial/diagnóstico por imagem , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Talidomida/administração & dosagem
7.
Front Immunol ; 12: 665442, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248943

RESUMO

Background: Pigmented villonodular synovitis (PVNS) is a rare condition that involves benign proliferation of the synovial tissue and is characterized by severe joint destruction and high recurrence even after surgical resection. However, poor understanding of the pathogenesis limits its effective therapy. Method: In this study, gene expression profiles of six patients with PVNS, 11 patients with osteoarthritis (OA), nine patients with rheumatoid arthritis (RA) (E-MTAB-6141), and three healthy subjects (GSE143514) were analyzed using integrating RNA sequencing (RNA-seq) and microarray to investigate the PVNS transcriptome. Gene ontology, string, and cytoscape were used to determine the gene functional enrichment. Cell functional molecules were detected using flow cytometry or immunohistochemical test to identify the cell subset and function. CD14+ cells were isolated and induced to osteoclast to evaluate the monocyte/macrophage function. Results: The most obvious local manifestations of PVNS were inflammation, including increased immune cells infiltration and cytokine secretion, and tumor phenotypes. High proportion of inflammatory cells, including T cells, natural killer (NK) cells, NKT cells, and B cells were recruited from the blood. Th17 and monocytes, especially classical monocytes but not nonclassical monocytes, increased in PVNS synovium. An obvious increase in osteoclastogenesis and macrophage activation was observed locally. Elevated expression of MMP9, SIGLEC 15, and RANK were observed in myeloid cell of PVNS than OA. When compared with RA, osteoclast differentiation and myeloid cell activation are PVNS-specific characters, whereas T cell activation is shared by PVNS and RA. Conclusion: The transcriptional expression characteristics of PVNS showed increased immune response, cell migration, and osteoclastogenesis. Osteoclast differentiation is only observed in PVNS but not RA, whereas T-cell activation is common in inflammatory arthritis.


Assuntos
Osteogênese/genética , Osteogênese/imunologia , Membrana Sinovial/patologia , Sinovite Pigmentada Vilonodular/genética , Sinovite Pigmentada Vilonodular/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Proliferação de Células , Humanos , Imuno-Histoquímica , Análise em Microsséries , Osteoartrite/genética , Osteoartrite/imunologia , Osteoclastos/metabolismo , Análise de Sequência de RNA , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Sinovite Pigmentada Vilonodular/patologia , Transcriptoma
8.
Front Immunol ; 12: 655477, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220809

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Joint inflammation of RA is closely related to infiltration of immune cells, synovium hyperplasia, and superfluous secretion of proinflammatory cytokines, which lead to cartilage degradation and bone erosion. The joint synovium of RA patients contains a variety of immune cellular types, among which monocytes/macrophages and T cells are two essential cellular components. Monocytes/macrophages can recruit and promote the differentiation of T cells into inflammatory phenotypes in RA synovium. Similarly, different subtypes of T cells can recruit monocytes/macrophages and promote osteoblast differentiation and production of inflammatory cytokines. In this review, we will discuss how T cell-monocyte/macrophage interactions promote the development of RA, which will provide new perspectives on RA pathogenesis and the development of targeted therapy.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Membrana Sinovial/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Artrite Reumatoide/patologia , Biomarcadores , Comunicação Celular/imunologia , Suscetibilidade a Doenças , Humanos , Imunomodulação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
9.
Lab Invest ; 101(10): 1353-1362, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34282280

RESUMO

Synovial hyperplasia, a profound alteration in the structure of synovial tissue, is the basis for cumulative joint destruction in rheumatoid arthritis (RA). It is generally accepted that controlling synovial hyperplasia can delay the progression of RA. As one of the most intensively studied isoforms of acid-sensing ion channels (ASICs), ASIC1a contributes to various physiopathologic conditions, including RA, due to its unique property of being permeable to Ca2+. However, the role and the regulatory mechanisms of ASIC1a in synovial hyperplasia are poorly understood. Here, rats induced with adjuvant arthritis (AA) and human primary synovial fibroblasts were used in vivo and in vitro to investigate the role of ASIC1a in the proliferation of RA synovial fibroblasts (RASFs). The results show that the expression of ASIC1a was significantly increased in synovial tissues and RASFs obtained from patients with RA as well as in the synovium of rats with AA. Moreover, extracellular acidification improved the ability of RASFs colony formation and increased the expression of proliferation cell nuclear antigen (PCNA) and Ki67, which was abrogated by the specific ASIC1a inhibitor psalmotoxin-1 (PcTX-1) or ASIC1a-short hairpin RNA (ASIC1a-shRNA), suggesting that extracellular acidification promotes the proliferation of RASFs by activating ASIC1a. In addition, the activation of c-Raf and extracellular signal-regulated protein kinases (ERKs) signaling was blocked with PcTX-1 or ASIC1a-shRNA and the proliferation of RASFs was further inhibited by the ERK inhibitor (U0126), indicating that ERK/MAPK signaling contributes to the proliferation process of RASFs promoted by the activation of ASIC1a. These findings gave us an insight into the role of ASIC1a in the proliferation of RASFs, which may provide solid foundation for ASIC1a as a potential target in the treatment of RA.


Assuntos
Canais Iônicos Sensíveis a Ácido/metabolismo , Artrite Experimental/metabolismo , Proliferação de Células/fisiologia , Fibroblastos/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Animais , Células Cultivadas , Humanos , Ratos , Membrana Sinovial/química , Membrana Sinovial/citologia , Membrana Sinovial/patologia
10.
Cells ; 10(6)2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201243

RESUMO

Alphaviruses are a group of arboviruses that generate chronic inflammatory rheumatisms in humans. Currently, no approved vaccines or antiviral therapies are available to prevent or treat alphavirus-induced diseases. The aim of this study was to evaluate the repositioning of the anti-cancer molecule irinotecan as a potential modulator of the antiviral and inflammatory responses of primary human synovial fibroblasts (HSF), the main stromal cells of the joint synovium. HSF were exposed to O'nyong-nyong virus (ONNV) and polyinosinic-polycytidylic acid (PIC) to mimic, respectively, acute and chronic infectious settings. The cytokine IL-1ß was used as a major pro-inflammatory cytokine to stimulate HSF. Quantitative RT-PCR analysis revealed that irinotecan at 15 µM was able to amplify the antiviral response (i.e., interferon-stimulated gene expression) of HSF exposed to PIC and reduce the expression of pro-inflammatory genes (CXCL8, IL-6 and COX-2) upon IL-1ß treatment. These results were associated with the regulation of the expression of several genes, including those encoding for STAT1, STAT2, p53 and NF-κB. Irinotecan did not modulate these responses in both untreated cells and cells stimulated with ONNV. This suggests that this drug could be therapeutically useful for the treatment of chronic and severe (rather than acute) arthritis due to viruses.


Assuntos
Infecções por Alphavirus/tratamento farmacológico , Antivirais/farmacologia , Artrite Reumatoide/tratamento farmacológico , Inflamação/tratamento farmacológico , Irinotecano/farmacologia , Citocinas/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Cultura Primária de Células , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
11.
Biochem Biophys Res Commun ; 570: 26-34, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34271433

RESUMO

Hydroxysafflor yellow A (HSYA) from safflower (Carthamus tinctorius L.) possesses several medicinal properties. However, it is unknown whether HSYA is effective in the treatment of rheumatoid arthritis (RA). Hence, we investigated the effects of HSYA on the inflammation and synovial damage in rats with collagen-induced arthritis (CIA) by subjecting them to treatment with different doses of HSYA. Our results revealed that HSYA could significantly reduce paw swelling, pathological manifestations, and serum cytokine levels in rats with CIA. The HSYA-treated groups showed increased antioxidant enzyme activity in the serum and decreased expression of inflammatory mediators in the synovial tissues. Furthermore, HSYA treatment inhibited extracellular signal-regulated kinase (ERK) signalling pathway activation. Notably, the highest dose of HSYA (20 mg/kg) exhibited the best effects against RA symptoms. Therefore, our findings suggest that HSYA alleviates the inflammatory response and synovial damage in rats with CIA by inhibiting the ERK signalling pathway.


Assuntos
Artrite Experimental/tratamento farmacológico , Chalcona/análogos & derivados , Quinonas/uso terapêutico , Animais , Artrite Experimental/sangue , Artrite Experimental/patologia , Bovinos , Chalcona/farmacologia , Chalcona/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Citocinas/sangue , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , Oxirredução , Quinonas/farmacologia , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
12.
Arch Biochem Biophys ; 708: 108962, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34116007

RESUMO

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. But, changes in the metabolism of normal synovial membranes or synovial cells during the early stages of inflammation remains unknown. Moreover, there are still many aspects of inflammatory signaling pathways altered by glycolysis inhibitors, that remain unclear. In this study we found that, in normal, non-pathological bovine synovial cells, most of ATP synthesis was generated by mitochondrial respiration. However, during the early of stages inflammation, initiated by lipopolysaccharide (LPS) exposure, synovial cells shifted to glycolysis for ATP production. The glycolysis inhibitor 2-deoxyglucose (2DG) reversed LPS induced increases in glycolysis for ATP production and suppressed the expression of inflammatory cytokines and proteolytic enzymes. 2DG suppressed the phosphorylation of the transcription factor cAMP response element binding protein (CREB) enhanced by LPS. Treatment with a CREB inhibitor reversed the expression of LPS-stimulated inflammatory cytokines and proteolytic enzymes. This study showed that changes in metabolism occur during the early stages of inflammation of synovial cells and can be reversed by 2DG and signaling pathways associated with CREB phosphorylation.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Desoxiglucose/farmacologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Animais , Bovinos , Citocinas/metabolismo , Glicólise/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos
13.
Sci Rep ; 11(1): 12455, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127696

RESUMO

Adult onset Still's disease (AOSD) is a rare systemic autoinflammatory disease, characterised by fever, arthritis, and skin rash, and joint involvement is one of its clinical manifestations. The aims of this work were to assess joint involvement, to describe main patterns of involvement, and associated clinical characteristics. In this work, we aimed at assessing the joint involvement in AOSD by using MRI, to describe main patterns and associated clinical characteristics. In addition, we aimed at assessing the global transcriptomic profile of synovial tissues in AOSD to elucidate possible pathogenic pathways involved. We also evaluated the global transcriptomic profile of synovial tissues to elucidate possible pathogenic pathways involved in the disease. Thus, AOSD patients, who underwent to MRI exam on joints, were assessed to describe patterns of joint involvement and associated clinical characteristics. Some synovial tissues were collected for RNA-sequencing purposes. The most common MRI finding was the presence of synovitis on 60.5%, mainly in peripheral affected joints, with low to intermediate signal intensity on T1-weighted images and intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. Bone oedema and MRI-bone erosions were reported on 34.9% and 25.6% MRI exams, respectively. Patients with MRI-bone erosions showed a higher prevalence of splenomegaly, a more frequent chronic disease course, lower levels of erythrocyte sedimentation rate, and ferritin. In AOSD synovial tissues, a hyper-expression of interleukin (IL)-1, IL-6, and TNF pathways was shown together with ferritin genes. In conclusion, in AOSD patients, the most common MRI-finding was the presence of synovitis, characterised by intermediate to high signal intensity on T2-fat-saturated weighted and STIR images. MRI-bone erosions and bone oedema were also observed. In AOSD synovial tissues, IL-1, IL-6, and TNF pathways together with ferritin genes resulted to be hyper-expressed.


Assuntos
Regulação da Expressão Gênica/imunologia , Doença de Still de Início Tardio/complicações , Membrana Sinovial/diagnóstico por imagem , Sinovite/imunologia , Adulto , Feminino , Humanos , Interleucina-1/genética , Interleucina-1/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RNA-Seq , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Doença de Still de Início Tardio/genética , Doença de Still de Início Tardio/imunologia , Doença de Still de Início Tardio/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/genética , Sinovite/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
J Bone Joint Surg Am ; 103(14): 1284-1294, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34097669

RESUMO

BACKGROUND: As carpal tunnel syndrome often precedes other signs of systemic amyloidosis, tenosynovial biopsy at the time of carpal tunnel release may facilitate early diagnosis and treatment. However, evidence-based guidelines for amyloidosis screening during carpal tunnel release have not been established. We sought to develop a predictive model for amyloidosis after carpal tunnel release to inform screening efforts. METHODS: We performed a retrospective cohort study of adults without known amyloidosis undergoing at least 1 carpal tunnel release from 2000 to 2019 with use of the national Veterans Health Administration database. After estimating the cumulative incidence of amyloidosis after carpal tunnel release, we identified risk factors, constructed a predictive nomogram based on a multivariable subdistribution-hazard competing-risks model, and performed cross-validation. RESULTS: Among 89,981 patients undergoing at least 1 carpal tunnel release, 310 were subsequently diagnosed with amyloidosis at a median interval of 4.5 years, corresponding to a cumulative incidence of 0.55% (95% confidence interval [CI]: 0.47% to 0.63%) at 10 years. Amyloidosis diagnosis following carpal tunnel release was associated with an increased hazard of heart failure (hazard ratio [HR], 4.68; 95% CI: 4.26 to 5.55) and death (HR, 1.27; 95% CI: 1.07 to 1.51) after adjustment for potential confounders. Age, male sex, Black race, monoclonal gammopathy of undetermined significance or multiple myeloma, rheumatoid arthritis, atrial fibrillation, spinal stenosis, and bilateral carpal tunnel syndrome were independently associated with increased risk of amyloidosis diagnosis and were included in the risk nomogram. CONCLUSIONS: Amyloidosis diagnosis after carpal tunnel release is rare but is associated with poor outcomes. We present an amyloidosis-risk nomogram to help guide tenosynovial biopsy at time of carpal tunnel release. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Assuntos
Amiloidose/diagnóstico , Síndrome do Túnel Carpal/etiologia , Nomogramas , Sinovectomia , Idoso , Amiloidose/complicações , Amiloidose/epidemiologia , Biópsia , Síndrome do Túnel Carpal/diagnóstico , Síndrome do Túnel Carpal/cirurgia , Diagnóstico Precoce , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Membrana Sinovial/patologia , Tendões/patologia
15.
Front Immunol ; 12: 651475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968050

RESUMO

In this study, we sought to characterize synovial tissue obtained from individuals with arthralgia and disease-specific auto-antibodies and patients with established rheumatoid arthritis (RA), by applying an integrative multi-omics approach where we investigated differences at the level of DNA methylation and gene expression in relation to disease pathogenesis. We performed concurrent whole-genome bisulphite sequencing and RNA-Sequencing on synovial tissue obtained from the knee and ankle from 4 auto-antibody positive arthralgia patients and thirteen RA patients. Through multi-omics factor analysis we observed that the latent factor explaining the variance in gene expression and DNA methylation was associated with Swollen Joint Count 66 (SJC66), with patients with SJC66 of 9 or more displaying separation from the rest. Interrogating these observed differences revealed activation of the immune response as well as dysregulation of cell adhesion pathways at the level of both DNA methylation and gene expression. We observed differences for 59 genes in particular at the level of both transcript expression and DNA methylation. Our results highlight the utility of genome-wide multi-omics profiling of synovial samples for improved understanding of changes associated with disease spread in arthralgia and RA patients, and point to novel candidate targets for the treatment of the disease.


Assuntos
Artralgia/imunologia , Artrite Reumatoide/complicações , Metilação de DNA/imunologia , Epigênese Genética/imunologia , Membrana Sinovial/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artralgia/genética , Artralgia/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artroscopia , Biópsia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA-Seq , Índice de Gravidade de Doença , Membrana Sinovial/imunologia , Sequenciamento Completo do Genoma , Adulto Jovem
16.
Nat Commun ; 12(1): 2174, 2021 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-33846342

RESUMO

Insufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvß3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.


Assuntos
Apoptose , Artrite Reumatoide/patologia , Inflamação/patologia , Articulações/patologia , Macrófagos/patologia , Osteoclastos/patologia , Animais , Artrite Reumatoide/diagnóstico por imagem , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Endocitose/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Articulações/diagnóstico por imagem , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/ultraestrutura , Oligopeptídeos/química , Ratos , Membrana Sinovial/diagnóstico por imagem , Membrana Sinovial/patologia , Distribuição Tecidual , Triterpenos , Microtomografia por Raio-X
17.
Mol Immunol ; 135: 36-44, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857817

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS: The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-ß expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-ß expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS: hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.


Assuntos
Artrite Experimental/terapia , Vesículas Extracelulares/metabolismo , Imunomodulação/imunologia , Células-Tronco Mesenquimais/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Animais , Artrite Experimental/induzido quimicamente , Células Cultivadas , Colágeno/toxicidade , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Imunossupressores/farmacologia , Interleucina-10/imunologia , Interleucina-17/imunologia , Metotrexato/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ratos , Ratos Wistar , Membrana Sinovial/patologia , Fator de Crescimento Transformador beta/metabolismo
18.
Front Immunol ; 12: 619392, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841401

RESUMO

Objectives: Mounting evidence has demonstrated that microRNAs (miRNAs) participate in rheumatoid arthritis (RA). The role of highly conserved miR-15/107 family in RA has not been clarified yet, and hence investigated in this study. Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to evaluate the expression of miRNAs and genes. Cell counting kit 8 (CCK-8) and FACS were used to detect proliferation and apoptosis. Protein expression was detected by using Western blotting. mRNA deep sequencing and cytokine antibody array were used to analyze differentially expressed genes, signaling pathways and cytokines. Results: The expression of miR-15a, miR-103, miR-497, and miR-646 was found decreased, while miR-424 increased in RA patients. MiR-424 and miR-497 were further investigated and the results showed that they could regulate the expression of multiple genes in rheumatoid arthritis synovial fibroblast (RASF) and affect signaling pathways. At the protein level, miR-497 mimic altered all the selected inflammation-related genes while miR-424 inhibitor only affected part of genes. MiR-497 mimic, rather than miR-424 inhibitor, had significant effects on proliferation and apoptosis of RASF. DICER1 was found to positively regulate the expression of miR-424 and miR-497, while DICER1 was also negatively regulated by miR-424. The increase of miR-424 could reduce miR-497 expression, thus forming a loop, which facilitated explaining the dysregulated miR-424 and miR-497 in RA. Conclusion: The miR-424 and miR-497 of miR-15/107 family affect cell proliferation and apoptosis in RA, and the proposed miR-424-DICER1-miR-497 feedback loop provides a novel insight into regulating miRNA expression and a candidate target for controlling RA.


Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Membrana Sinovial/metabolismo , Apoptose/genética , Artrite Reumatoide/patologia , Biomarcadores , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Citocinas/metabolismo , Suscetibilidade a Doenças , Matriz Extracelular , Humanos , Transdução de Sinais , Membrana Sinovial/patologia
19.
Nat Commun ; 12(1): 2343, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879788

RESUMO

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.


Assuntos
Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Ácidos Siálicos/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Animais , Artrite Experimental/patologia , Artrite Reumatoide/imunologia , Linhagem Celular , Citocinas/metabolismo , Regulação para Baixo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Glicosilação , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Endogâmicos DBA , Fenótipo , RNA-Seq , Sialiltransferases/genética , Sialiltransferases/metabolismo , Membrana Sinovial/imunologia , Transcriptoma
20.
Eur J Immunol ; 51(8): 2062-2073, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33864383

RESUMO

MicroRNA-147 (miR-147) had been previously found induced in synoviocytes by inflammatory stimuli derived from T cells in experimental arthritis. This study was designed to verify whether loss of its function might alleviate inflammatory events in joints of experimental and rheumatoid arthritis (RA). Dark Agouti (DA) rats were injected intradermally with pristane to induce arthritis, and rno-miR-147 antagomir was locally administrated into individual ankle compared with negative control or rno-miR-155-5p antagomir (potential positive control). Arthritis onset, macroscopic severity, and pathological changes were monitored. While in vitro, gain or loss function of hsa-miR-147b-3p/hsa-miR-155-5p and ZNF148 was achieved in human synovial fibroblast cell line SW982 and RA synovial fibroblasts (RASF). The expression of miRNAs and mRNAs was detected by using RT-quantitative PCR, and protein expression was detected by using Western blotting. Anti-miR-147 therapy could alleviate the severity, especially for the synovitis and joint destruction in experimental arthritis. Gain of hsa-miR-147b-3p/hsa-miR-155-5p function in TNF-α stimulated SW982 and RASF cells could upregulate, in contrast, loss of hsa-miR-147b-3p/hsa-miR-155-5p function could downregulate the gene expression of TNF-α, IL-6, MMP3, and MMP13. Hence, such alteration could participate in synovial inflammation and joint destruction. RNAi of ZNF148, a miR-147's target, increased gene expression of TNF-α, IL-6, MMP3, and MMP13 in SW982 and RASF cells. Also, mRNA sequencing data showed that hsa-miR-147b-3p mimic and ZNF148 siRNA commonly regulated the gene expression of CCL3 and DEPTOR as well as some arthritis and inflammation-related pathways. Taken together, miR-147b-3p contributes to synovial inflammation through repressing ZNF148 in RA and experimental arthritis.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Ligação a DNA/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/imunologia , Membrana Sinovial/patologia , Fatores de Transcrição/imunologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Inflamação , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Ratos , Fatores de Transcrição/metabolismo
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