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1.
Medicine (Baltimore) ; 99(44): e22892, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126340

RESUMO

T cell immunoglobulin and mucin domain-3 (TIM-3) is a surface molecule expressed on immune cells which play a role in immune regulation. The aims of the present study were to determine whether circulating soluble T cell immunoglobulin domain and mucin-3 (sTIM-3) are elevated in rheumatoid arthritis (RA) patients, and investigate the relationships between sTIM-3 and clinical features of RA.The study included 116 patients with established RA and 27 healthy control subjects. Serum levels of sTIM-3 were measured via the enzyme-linked immunosorbent assays (ELISA). Correlations between serum sTIM-3 and a range of parameters including anti-citrullinated peptide antibody (ACPA) titer, erythrocyte sedimentation rate (ESR), and matrix metalloproteinase-3 (MMP-3) were assessed.Serum sTIM-3 was significantly elevated in RA patients compared with those in healthy subjects, and it was positively correlated with ACPA titer (r = 0.27 P = .005), ESR (r = 0.27, P = .004) and MMP-3 (r = 0.35, P < .001). In RA patients with high ACPA titers (≥200 U/mL), sTIM-3 was not correlated with ESR or MMP-3. Whereas, sTIM-3 was significantly correlated with ESR and MMP-3 in RA patients with low ACPA titers (<200 U/mL).Serum sTIM-3 was increased in RA patients, and it was associated with proinflammatory markers and disease activity in RA patients under a particular ACPA status. Our data suggest that circulating sTIM-3 may be a useful biomarker for the determination of disease activity in RA patients.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide , Receptor Celular 2 do Vírus da Hepatite A/sangue , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Sedimentação Sanguínea , Correlação de Dados , Progressão da Doença , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Metaloproteinase 3 da Matriz/sangue , Pessoa de Meia-Idade , Monitorização Imunológica/métodos , Gravidade do Paciente
2.
Nat Med ; 26(8): 1295-1306, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32601335

RESUMO

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKposTREM2high and MerTKposLYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.


Assuntos
Artrite Reumatoide/metabolismo , Inflamação/metabolismo , Macrófagos/imunologia , Líquido Sinovial/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Biópsia , Linhagem da Célula/genética , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/patologia , Articulações/imunologia , Articulações/metabolismo , Articulações/patologia , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/metabolismo , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/imunologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Líquido Sinovial/imunologia , Membrana Sinovial
3.
Rinsho Shinkeigaku ; 60(8): 554-559, 2020 Aug 07.
Artigo em Japonês | MEDLINE | ID: mdl-32641626

RESUMO

A 42-year-old man with a history of two previous coronary embolisms was referred to our hospital. He had been experiencing muscle weakness since he was around 40 years old. He had muscle atrophy of the scapula, upper arm, and lower extremities, and electromyography revealed myogenic changes in the limb muscles. Histopathological analysis of the muscle biopsy specimen revealed a complete deficiency of emerin protein, and genetic examination revealed a mutation in the emerin (EMD) gene, resulting in a diagnosis of Emery-Dreifuss muscular dystrophy (EDMD). EDMD is a muscular disorder with three symptoms: joint contracture at early onset, muscle weakness and atrophy, and cardiac dysfunction. Although this patient showed no obvious joint contracture, the course and clinical symptoms vary among patients. Therefore, in patients in whom clinical diagnosis is difficult, muscle biopsy and genetic testing should be performed for EDMD in order to prevent sudden death due to this disease.


Assuntos
Contratura , Articulações , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Adulto , Contratura/patologia , Humanos , Articulações/patologia , Masculino , Proteínas de Membrana/genética , Debilidade Muscular/patologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/patologia , Mutação , Proteínas Nucleares/genética
4.
Proc Natl Acad Sci U S A ; 117(22): 12029-12040, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404427

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a uniformly fatal condition that is especially prevalent in skin, cardiovascular, and musculoskeletal systems. A wide gap exists between our knowledge of the disease and a promising treatment or cure. The aim of this study was to first characterize the musculoskeletal phenotype of the homozygous G608G BAC-transgenic progeria mouse model, and to determine the phenotype changes of HGPS mice after a five-arm preclinical trial of different treatment combinations with lonafarnib, pravastatin, and zoledronic acid. Microcomputed tomography and CT-based rigidity analyses were performed to assess cortical and trabecular bone structure, density, and rigidity. Bones were loaded to failure with three-point bending to assess strength. Contrast-enhanced µCT imaging of mouse femurs was performed to measure glycosaminoglycan content, thickness, and volume of the femoral head articular cartilage. Advanced glycation end products were assessed with a fluorometric assay. The changes demonstrated in the cortical bone structure, rigidity, stiffness, and modulus of the HGPS G608G mouse model may increase the risk for bending and deformation, which could result in the skeletal dysplasia characteristic of HGPS. Cartilage abnormalities seen in this HGPS model resemble changes observed in the age-matched WT controls, including early loss of glycosaminoglycans, and decreased cartilage thickness and volume. Such changes might mimic prevalent degenerative joint diseases in the elderly. Lonafarnib monotherapy did not improve bone or cartilage parameters, but treatment combinations with pravastatin and zoledronic acid significantly improved bone structure and mechanical properties and cartilage structural parameters, which ameliorate the musculoskeletal phenotype of the disease.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Modelos Animais de Doenças , Lamina Tipo A/genética , Progéria , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Cartilagem/efeitos dos fármacos , Cartilagem/patologia , Fêmur/efeitos dos fármacos , Fêmur/patologia , Glicosaminoglicanos/análise , Articulações/efeitos dos fármacos , Articulações/patologia , Lamina Tipo A/metabolismo , Camundongos , Camundongos Transgênicos , Mutação , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Fenótipo , Piperidinas/uso terapêutico , Pravastatina/uso terapêutico , Progéria/tratamento farmacológico , Progéria/genética , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/uso terapêutico , Microtomografia por Raio-X , Ácido Zoledrônico/uso terapêutico
5.
PLoS Pathog ; 16(5): e1008516, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32413091

RESUMO

Lyme disease, caused by Borrelia burgdorferi, B. afzelii and B. garinii, is a chronic, multi-systemic infection and the spectrum of tissues affected can vary with the Lyme disease strain. For example, whereas B. garinii infection is associated with neurologic manifestations, B. burgdorferi infection is associated with arthritis. The basis for tissue tropism is poorly understood, but has been long hypothesized to involve strain-specific interactions with host components in the target tissue. OspC (outer surface protein C) is a highly variable outer surface protein required for infectivity, and sequence differences in OspC are associated with variation in tissue invasiveness, but whether OspC directly influences tropism is unknown. We found that OspC binds to the extracellular matrix (ECM) components fibronectin and/or dermatan sulfate in an OspC variant-dependent manner. Murine infection by isogenic B. burgdorferi strains differing only in their ospC coding region revealed that two OspC variants capable of binding dermatan sulfate promoted colonization of all tissues tested, including joints. However, an isogenic strain producing OspC from B. garinii strain PBr, which binds fibronectin but not dermatan sulfate, colonized the skin, heart and bladder, but not joints. Moreover, a strain producing an OspC altered to recognize neither fibronectin nor dermatan sulfate displayed dramatically reduced levels of tissue colonization that were indistinguishable from a strain entirely deficient in OspC. Finally, intravital microscopy revealed that this OspC mutant, in contrast to a strain producing wild type OspC, was defective in promoting joint invasion by B. burgdorferi in living mice. We conclude that OspC functions as an ECM-binding adhesin that is required for joint invasion, and that variation in OspC sequence contributes to strain-specific differences in tissue tropism displayed among Lyme disease spirochetes.


Assuntos
Borrelia burgdorferi/metabolismo , Dermatan Sulfato/metabolismo , Matriz Extracelular/metabolismo , Artropatias/metabolismo , Articulações/metabolismo , Doença de Lyme/metabolismo , Animais , Antígenos de Bactérias , Aderência Bacteriana , Proteínas da Membrana Bacteriana Externa , Borrelia burgdorferi/genética , Borrelia burgdorferi/patogenicidade , Dermatan Sulfato/genética , Matriz Extracelular/genética , Matriz Extracelular/microbiologia , Matriz Extracelular/patologia , Feminino , Fibronectinas/genética , Fibronectinas/metabolismo , Artropatias/genética , Artropatias/microbiologia , Artropatias/patologia , Articulações/microbiologia , Articulações/patologia , Doença de Lyme/genética , Doença de Lyme/microbiologia , Doença de Lyme/patologia , Camundongos , Camundongos SCID , Mutação , Especificidade de Órgãos
6.
Exp Mol Pathol ; 115: 104454, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32422132

RESUMO

The pleiotropic effects of statins, including an antiarthritic potential, have been noted. This study aimed to determine the efficacy of statins on rheumatoid arthritis (RA) and clarify how statins affect its pathogenesis. Fluvastatin (500 µg/kg/day) or vehicle was given per os to env-pX rats, which carry the human T-cell leukemia virus type I env-pX gene and spontaneously develop destructive arthritis mimicking RA, for 30 days. Blood sampling and ultrasonography (US) of the ankle joints were conducted on days 0, 10, 20, and 30. On day 30, all rats were euthanized, and the ankle joints were subjected to histological analysis. To clarify how fluvastatin affects the pathogenesis of RA, comprehensive serum exosomal microRNA (miRNA) analysis was performed. Gene expression in the primary culture of synovial fibroblasts derived from arthritic rat and human and non-arthritic rat periarticular tissues was determined quantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). As a result, the development of arthritis in env-pX rats was significantly suppressed by fluvastatin, which was evident from the viewpoints of serology, US imaging, and histology. Comprehensive serum exosomal miRNA analysis suggested that the expression of Rho GTPase-activating protein 12 (Arhgap12) was decreased in arthritic env-pX rats but increased with the administration of fluvastatin. Corresponding results were obtained by quantitative RT- PCR using primary culture of synovial fibroblasts. The collective findings suggest that fluvastatin prevents the development of arthritis in env-pX rats via the up-regulation of ARHGAP12. This study suggests that ARHGAP12 can be a possible therapeutic target of RA.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/prevenção & controle , Fluvastatina/uso terapêutico , Proteínas Ativadoras de GTPase/metabolismo , Regulação para Cima , Animais , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/patologia , Exossomos/efeitos dos fármacos , Exossomos/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fluvastatina/farmacologia , Proteínas Ativadoras de GTPase/genética , Humanos , Inflamação/patologia , Articulações/diagnóstico por imagem , Articulações/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Membrana Sinovial/patologia , Regulação para Cima/efeitos dos fármacos
7.
Lab Invest ; 100(8): 1068-1079, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32341517

RESUMO

Increased permeability and growth (angiogenesis) of blood vessels play a key role in joint swelling and pannus formation in inflammatory arthritis, a family of diseases influenced by reproductive hormones. The hormone prolactin (PRL) protects against joint inflammation, pannus formation, and bone destruction in adjuvant-induced arthritis and these effects may involve its proteolytic conversion to vasoinhibin, a PRL fragment that inhibits angiogenesis and vasopermeability. Here, we show that the intra-articular injection of an adeno-associated virus type-2 (AAV2) vector encoding vasoinhibin reduced joint inflammation, the hyperplasia, vascular density, and vasopermeability of the pannus, and the loss of bone in mice subjected to antigen-induced arthritis. In agreement, the AAV2 vasoinhibin vector reduced the expression of proinflammatory cytokines (interleukin-1ß, interleukin-6), an endothelial cell marker (platelet endothelial cell-adhesion molecule 1), and proangiogenic molecules [vascular endothelial growth factor (VEGF), VEGF receptor 2, and hypoxia-inducible factor 1α] in the arthritic joint. Also, vasoinhibin reduced the synovial vasopermeability induced by the intra-articular injection of VEGF in healthy mice. Finally, vasoinhibin signals by blocking the phosphorylation/activation of endothelial nitric oxide synthase (eNOS) at Ser1179 and the AAV2 vasoinhibin vector inhibited the enhanced phosphorylation of eNOS Ser1179 in the arthritic joint. We conclude that vasoinhibin reduces joint inflammation and bone loss in arthritis by inhibiting pannus angiogenesis and vasopermeability via the blockage of VEGF-induced eNOS activation. These findings suggest the potential therapeutic benefit of AAV2-mediated vasoinhibin gene delivery in arthritis.


Assuntos
Artrite Experimental/terapia , Permeabilidade Capilar/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Osteíte/prevenção & controle , Osteoporose/prevenção & controle , Prolactina/farmacologia , Animais , Antígenos , Artrite Experimental/induzido quimicamente , Artrite Experimental/genética , Proteínas de Ciclo Celular/genética , Dependovirus/genética , Terapia Genética/métodos , Vetores Genéticos/genética , Humanos , Articulações/patologia , Masculino , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Osteíte/genética , Osteíte/terapia , Osteoporose/genética , Osteoporose/terapia
8.
Am J Surg Pathol ; 44(5): 633-640, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32294062

RESUMO

Abnormal accumulation of neutrophils in a subarticular bone usually raises the concern for osteomyelitis or septic arthritis, a disabling and potentially life-threatening medical condition. At the pathology department of a specialized orthopedic institute, we observed a distinct pattern of subarticular inflammation mimicking infection characterized by collections of neutrophils, macrophages, and fibrin in pseudocystic spaces of variable size and extent in the superficial subarticular bone not accompanied by granulation tissue or necrosis. We coined the term "inflammatory pseudoabscess" to describe these accumulations. From 1997-2015, we reported inflammatory pseudoabscesses in 157 primary arthroplasty/osteotomy specimens from 143 patients without penetrating trauma or hardware in the affected joint. The predominant gross and histologic features were those of destructive/inflammatory joint disease, including lymphoplasmacytic synovitis (95.3%), subchondral osseous chronic inflammation (80.3%), exudative synovitis (58.0%), synovial pannus (52.0%), and marginal erosions of articular cartilage and/or subarticular bone (43.3%). Clinical information was available in 137 (95.8%) patients, 107 (overall: 74.8%) of whom had preoperatively or postoperatively diagnosed inflammatory arthropathy, most commonly rheumatoid arthritis. The remaining 30 (overall: 21.0%) patients had no documented inflammatory disorders, but some had bilateral or multijoint arthropathy, hands/feet involvement, lymphoplasmacytic synovitis, ulcerative colitis, or family history of inflammatory arthropathy. There was no documented infection-associated implant failure. We believe that inflammatory pseudoabscess represents an intraosseous manifestation of noninfectious inflammatory disorders of joints. This feature should be recognized by pathologists and used to suggest further clinical evaluation for undiagnosed inflammatory joint diseases.


Assuntos
Abscesso/patologia , Osso e Ossos/patologia , Articulações/patologia , Neutrófilos/patologia , Sinovite/patologia , Abscesso/imunologia , Abscesso/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/cirurgia , Biópsia , Osso e Ossos/imunologia , Osso e Ossos/cirurgia , Criança , Diagnóstico Diferencial , Feminino , Humanos , Articulações/imunologia , Articulações/cirurgia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Valor Preditivo dos Testes , Estudos Retrospectivos , Sinovite/imunologia , Sinovite/cirurgia , Adulto Jovem
9.
PLoS One ; 15(4): e0231904, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32320449

RESUMO

Detection of lameness in cats can be very time-consuming and frustrating. Feline studies have shown that the success of treatment can be evaluated by measurement of the ground reaction force (GRF). However, the possibility of multiple limb involvement or the presence of a compensatory mechanism has not been investigated. Furthermore, there has been no research in cats on possible differences in GRFs between those with stifle problems and those with hip problems, as reported in dogs. In this study, we compared temporospatial parameters and GRFs in 20 lame cats after femoral head and neck ostectomy (FHO) or stifle disease to those in 15 healthy cats. An orthopedic examination was performed in all cats and radiographs were obtained to confirm the disease. GRFs, including peak vertical force (PFz), vertical impulse (IFz), time to PFz, and temporospatial parameters, including step length, paw contact area, and stance phase duration, were calculated. We also calculated the symmetry index (SI) in the forelimbs and hind limbs. The GRFs were normalized to total force (% TF). We found that the IFz (% TF) and PFz (% TF) were lower in the affected limb than in the other limbs in the lame cats. When the lame cats were compared with the sound cats, this difference was only significant for IFz (% TF). The SI values for the PFz and IFz were significantly higher in the hind limbs than in the forelimbs in the lame cats group but there was no difference in the SI according to whether the problem was in the hip or stifle. There were also differences in stance phase duration and paw contact area in both the forelimbs and hind limbs between the sound group and the lame group. There was no difference in PFZ (% TF) or IFZ (% TF) in the affected limb between the lame cats with stifle and those after FHO; however, there were changes in time to PFz and step length. In conclusion, mild to moderate lameness can be detected and measured in cats using pressure plates. The compensatory mechanisms in cats at a walk appear to involve shifting the weight to the other three legs without favoring either the contralateral or the diagonal limb.


Assuntos
Membro Posterior , Coxeadura Animal/diagnóstico , Pressão , Animais , Fenômenos Biomecânicos , Gatos , Feminino , Membro Posterior/patologia , Membro Posterior/fisiopatologia , Articulações/patologia , Articulações/fisiopatologia , Coxeadura Animal/patologia , Coxeadura Animal/fisiopatologia , Masculino
10.
Am J Trop Med Hyg ; 102(6): 1316-1318, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32228782

RESUMO

Deformities of bones of the face and extremities are markers of leprosy (Hansen's disease) which contribute to stigma associated with this disease. Among these deformities are articular alterations that can mimic rheumatoid arthritis (RA). In this case, a 64-year-old man presented with a history of having been treated for lepromatous leprosy and erythema nodosum leprosum episodes, which evolved with joint alterations similar to those of RA. Most cases of leprosy-related arthritis are associated with reactional episodes, of which a large number do not respond to conventional therapy for leprosy reactions. In cases of chronic arthritis not associated with leprosy reactions, although patients show considerable relief with anti-leprosy therapy, arthritis is not completely resolved. This emphasizes the need for early diagnosis and treatment of leprosy to prevent the development of osteoarticular alterations.


Assuntos
Artrite Reumatoide/patologia , Articulações/patologia , Hanseníase Virchowiana/diagnóstico , Hanseníase Virchowiana/patologia , Humanos , Masculino , Pessoa de Meia-Idade
11.
Int J Nanomedicine ; 15: 1517-1535, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189966

RESUMO

Purpose: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. Methods: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. Results: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. Conclusion: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.


Assuntos
Benzilaminas/uso terapêutico , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Naftalenos/uso terapêutico , Febre Reumática/tratamento farmacológico , Administração Cutânea , Animais , Benzilaminas/farmacocinética , Varredura Diferencial de Calorimetria , Feminino , Humanos , Articulações/diagnóstico por imagem , Articulações/patologia , Nanopartículas/ultraestrutura , Naftalenos/farmacocinética , Ligante RANK/metabolismo , Ratos Wistar , Febre Reumática/induzido quimicamente , Febre Reumática/diagnóstico por imagem , Febre Reumática/patologia , Testes de Irritação da Pele
12.
Am J Sports Med ; 48(3): 624-634, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32004084

RESUMO

BACKGROUND: Lubricin, a mucinous glycoprotein, plays a chondroprotective role as a constituent of synovial fluid. Structural analogs have been synthesized to mimic the structure and function of native lubricin in an effort to recapitulate this effect with the goal of delaying progression of osteoarthritis (OA). PURPOSE: To investigate the efficacy of intra-articular injections of lubricin mimetics in slowing or preventing the progression of posttraumatic OA by using a rat anterior cruciate ligament transection model. STUDY DESIGN: Controlled laboratory design. METHODS: Four lubricin mimetics were investigated, differing from one another in their binding orientations and steric interactions. Eighty skeletally mature Sprague-Dawley rats underwent bilateral anterior cruciate ligament transections and were randomly allocated to receive intra-articular injections (50 µL/injection) of 1 of the 4 mimetics in the right knee and equal volumes of saline injection in the contralateral knee (control). All rats were euthanized 8 weeks postoperatively and assessed via biomechanical analysis, which evaluated comparative friction coefficients across the 4 groups, and histological evaluation of articular cartilage, osteophytes, and synovitis. The Osteoarthritis Research Society International (OARSI) histopathological assessment system was used to evaluate the degree of articular cartilage degeneration and osteophytes, while synovitis was assessed through a semiquantitative scoring system. Binding efficacy of the 4 mimetics was assessed in vitro and in vivo through the immunohistochemical localization of polyethylene glycol. Articular cartilage degeneration and synovitis scoring data analyses were performed with generalized estimating equation modeling. RESULTS: Injection of the group 3 mimetic (random 24 + 400 + 30) directly correlated with improved OARSI scores for femoral articular cartilage degeneration when compared with saline-injected contralateral control knees (P = .0410). No lubricin mimetic group demonstrated statistically significant differences in OARSI scores for tibial articular cartilage degeneration. Injection of the group 4 mimetic (AB 24 + 400 + 30) led to a statistically significant difference in osteophyte OARSI score (P = .0019). None of the 4 lubricin mimetics injections incited an additive synovial inflammatory response. Immunohistochemical staining substantiated the binding capacity of all 4 mimetics, while in vivo experimentation revealed that the group 1 and 3 mimetics were still retained within the joint 4 weeks after injection. There were no differences in friction coefficients between any pair of groups and no significant trends based on lubricin mimetic structure. CONCLUSION: We demonstrated that the tribosupplementation of a traumatically injured knee with a specific lubricin structural analog may attenuate the natural progression of OA. CLINICAL RELEVANCE: The current lack of efficacious clinical options to counter the onset and subsequent development of OA suggests that further investigation into the synthesis and behavior of lubricin analogs could yield novel translational applications.


Assuntos
Ligamento Cruzado Anterior/fisiopatologia , Proteoglicanas de Sulfatos de Condroitina/administração & dosagem , Glicoproteínas/administração & dosagem , Articulações/patologia , Osteoartrite do Joelho/tratamento farmacológico , Animais , Cartilagem Articular , Proteoglicanas de Sulfatos de Condroitina/uso terapêutico , Modelos Animais de Doenças , Glicoproteínas/uso terapêutico , Injeções Intra-Articulares , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
13.
JAMA Netw Open ; 3(2): e200032, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32101306

RESUMO

Importance: Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for an ever-increasing number of cancers. However, their use has also led to the emergence of immune-related adverse events, such as ICI-induced inflammatory arthritis. A reproducible, reliable, and accessible modality is needed to assess and distinguish early ICI-induced inflammatory arthritis and help in management. Magnetic resonance imaging (MRI) of joints may be helpful for early diagnosis, guiding therapeutic decision-making, and identifying patients at high risk for erosive disease. Objective: To assess the role of MRI of joints in patients with ICI-induced inflammatory arthritis. Design, Setting, and Participants: This retrospective case series included patients enrolled at the National Institutes of Health Clinical Center in Bethesda, Maryland. Patients were evaluated by the rheumatology consultation service between December 27, 2016, and May 28, 2019. A retrospective health record review was performed to determine demographic characteristics, clinical characteristics of inflammatory arthritis and malignant tumors, and imaging findings. Inclusion criteria were patients who were enrolled on various institutional review board-approved protocols of ICIs, developed joint-related symptoms, and had MRI data for at least 1 joint. Data were analyzed from June 1, 2019, to September 1, 2019. Exposures: Undergoing MRI of at least 1 joint. Main Outcomes and Measures: All MRIs were reviewed for synovitis, tenosynovitis, bone marrow edema, and soft tissue conditions. Results: A total of 8 patients (mean [SD] age, 58.8 [5.2] years; 6 women and 2 men) between the ages of 50 and 65 years who were undergoing ICI therapy for a variety of malignant tumors were included in this study. Only 1 patient was receiving combined ICI therapy. The results of 13 separate MRI examinations were reviewed. The most commonly performed MRIs were of the hands and wrists (9 MRIs), followed by knee examinations (3 MRIs). Tenosynovitis and synovitis were frequently seen in the hands and wrists. Bone marrow edema and erosions were also found in 3 patients, suggesting early damage. In larger joints (ie, knees and ankles), joint effusions and synovial thickening were characteristic. Most patients (5 patients) were treated with corticosteroids and had good responses. In patients with high-risk features on MRI imaging (eg, bone marrow edema, erosions), disease-modifying antirheumatic drug therapy was also discussed as a treatment option. Conclusions and Relevance: These findings suggest that advanced imaging may help to distinguish ICI-induced inflammatory arthritis from other causes of joint pain, aid in identifying patients at increased risk of joint damage, and provide utility in monitoring inflammatory arthritis treatment response in patients receiving ICI therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Artrite Reumatoide/diagnóstico , Imunoterapia/efeitos adversos , Articulações/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Idoso , Artrite Reumatoide/induzido quimicamente , Diagnóstico Precoce , Feminino , Humanos , Articulações/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
14.
J Vis Exp ; (156)2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32091008

RESUMO

Neutrophils are a major member of the innate immune system and play pivotal roles in host defense against pathogens and pathologic inflammatory reactions. Neutrophils can be recruited to inflammation sites via the guidance of cytokines and chemokines. Overwhelming infiltration of neutrophils can lead to indiscriminate tissue damage, such as in rheumatoid arthritis (RA). Neutrophils isolated from peritoneal exudate respond to a defined chemoattractant, N-formyl-Met-Leu-Phe (fMLP), in vitro in Transwell or Zigmond chamber assays. The air pouch experiment can be used to evaluate the chemotaxis of neutrophils towards lipopolysaccharide (LPS) in vivo. The adjuvant-induced arthritis (AA) mouse model is frequently used in RA research, and immunohistochemical staining of joint sections with anti-myeloperoxidase (MPO) or anti-neutrophil elastase (NE) antibodies is a well-established method to measure neutrophil infiltration. These methods can be used to discover promising therapies targeting neutrophil migration.


Assuntos
Movimento Celular , Neutrófilos/citologia , Animais , Artrite Experimental/imunologia , Artrite Experimental/patologia , Movimento Celular/efeitos dos fármacos , Separação Celular , Modelos Animais de Doenças , Articulações/patologia , Camundongos Endogâmicos C57BL , N-Formilmetionina Leucil-Fenilalanina/análogos & derivados , N-Formilmetionina Leucil-Fenilalanina/farmacologia , Infiltração de Neutrófilos/efeitos dos fármacos , Infiltração de Neutrófilos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia
15.
Int J Pharm ; 576: 119001, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-31893540

RESUMO

The conventional medications are still facing a huge challenge for the treatment of rheumatoid arthritis (RA). Thus, looking for an effective therapy of RA has became an urgent issue nowadays. In this study, a novel thermosensitive liposome loaded with sinomenine hydrochloride (SIN-TSL) was developed by a pH gradient method. The SIN-TSL had a mean particle size of around 100 nm, and an high entrapment efficiency and drug loading capacity. The results also suggested that SIN-TSL had a thermosensitive drug release behaviour, with the drug release rate at 43 °C was much faster than the one at 37 °C. The SIN-TSL could be effectively taken up by lipopolysaccharide-activated HUVECs, without any cytotoxicity was observed. In addition, both in vitro and in vivo studies indicated that the SIN-TSL combined with microwave hyperthermia exhibited superior anti-rheumatoid arthritis effect. Overall, these results suggest that SIN-loaded thermosensitive liposomes combined with microwave hyperthermia could provide an optional strategy for alleviating the clinical symptoms of RA.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/terapia , Hipertermia Induzida , Articulações/efeitos dos fármacos , Lipídeos/química , Micro-Ondas , Morfinanos/administração & dosagem , 1,2-Dipalmitoilfosfatidilcolina/química , Animais , Antirreumáticos/química , Antirreumáticos/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Células Cultivadas , Colesterol/química , Terapia Combinada , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Articulações/metabolismo , Articulações/patologia , Lipossomos , Morfinanos/química , Morfinanos/metabolismo , Tamanho da Partícula , Ratos Wistar , Solubilidade
17.
Med Sci Monit ; 26: e920346, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31978040

RESUMO

BACKGROUND Osteoarthritis is a chronic degenerative disease of the joints that is common in older people worldwide. The characteristic features of osteoarthritis include cartilage degradation, synovitis, and remodelling of subchondral bone. The present study investigated the effect of 2-aminoquinoline on knee articular cartilage degradation in an osteoarthritis rat model. MATERIAL AND METHODS The rat model of osteoarthritis was established in Wistar rats by intra-articular injection of monosodium iodoacetate. The rats were randomly divided into 6 groups of 10 rats each: a normal control group, an untreated group, and 4 (5, 10, 15 and 20 mg/kg) treatment groups. The rats in treatment groups received 5, 10, 15, or 20 mg/kg doses of 2-aminoquinoline on day 2 of monosodium iodoacetate injection. RESULTS The 2-aminoquinoline treatment of monosodium iodoacetate-injected rats markedly decreased weight-bearing asymmetry, inhibited edema formation, and improved paw withdrawal thresholds. The expression of inflammatory cytokines was markedly higher in the osteoarthritis rats. Treatment with 2-aminoquinoline led to a significant reduction in inflammatory cytokine expression in osteoarthritis rats in a dose-dependent manner. In osteoarthritis rats, the expressions of prostaglandin E2 (PGE2), matrix metalloproteinase-13 (MMP-13), and substance P were also higher in comparison to the control group. The 2-aminoquinoline treatment supressed PGE2, MMP-13, and substance P levels in osteoarthritis rats. Moreover, the expression of phosphorylated nuclear factor kappaB (p-NF-kappaB) was markedly higher in the untreated rats. However, activation of NF-kappaB was downregulated in the osteoarthritis rats by treatment with 2-aminoquinoline. CONCLUSIONS The present study demonstrated that 2-aminoquinoline prevents articular cartilage damage in osteoarthritis rats through inhibition of inflammatory factors and downregulation of NF-kappaB activation, suggesting that 2-aminoquinoline would be effective in treatment of osteoarthritis.


Assuntos
Aminoquinolinas/farmacologia , Cartilagem Articular/patologia , NF-kappa B/metabolismo , Osteoartrite/patologia , Animais , Citocinas/biossíntese , Dinoprostona/metabolismo , Edema/patologia , Extremidades/patologia , Articulações/patologia , Masculino , Metaloproteinase 13 da Matriz/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Wistar , Receptores Purinérgicos P2X7/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/metabolismo
18.
Arthritis Rheumatol ; 72(1): 57-66, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31350812

RESUMO

OBJECTIVE: To evaluate the antiinflammatory and analgesic effects of sepiapterin reductase (SPR) inhibition in a mouse model of inflammatory joint disease, and to determine whether urinary sepiapterin levels, as measured in mice and healthy human volunteers, could be useful as a noninvasive, translational biomarker of SPR inhibition/target engagement. METHODS: The collagen antibody-induced arthritis (CAIA) model was used to induce joint inflammation in mice. The effects of pharmacologic inhibition of SPR on thresholds of heat-, cold-, and mechanical-evoked pain sensitivity and on signs of inflammation were tested in mice with CAIA. In addition, mice and healthy human volunteers were treated with SPR inhibitors, and changes in urinary sepiapterin levels were analyzed by high-performance liquid chromatography. RESULTS: CAIA in mice was characterized by 2 phases: in the acute inflammation (early) phase, joint inflammation and heat-, mechanical-, and cold-induced pain hypersensitivity were present, while in the postinflammation (late) phase, no joint inflammation was observed but heat- and mechanical-induced hypersensitivity, but not cold hypersensitivity, were present. Inhibition of SPR in mice with CAIA significantly attenuated the heat-induced hyperalgesia in both phases, and the mechanical allodynia in the late phase. Signs of inflammation were unaffected by SPR inhibition. Urinary tetrahydrobiopterin levels, as a marker of inflammatory pain, were increased during inflammation in mice with CAIA (2-fold increase over controls; P < 0.05) and significantly reduced by SPR inhibition (P < 0.05 versus vehicle-treated mice). Increased urinary sepiapterin levels in the presence of SPR inhibition in both mice and healthy human volunteers were associated with high sensitivity (70-85%) and high specificity (82-88%) for the prediction of SPR inhibition/target engagement. CONCLUSION: SPR inhibition reduces the pain associated with joint inflammation, thus showing its potential utility as an analgesic strategy for inflammatory joint pain. In addition, SPR inhibition increases urinary sepiapterin levels, indicating the potential of this measurement as a noninvasive biomarker of target engagement of SPR inhibitors, such as sulfasalazine, a disease-modifying antirheumatic drug that is currently used as a first-line treatment for rheumatoid arthritis.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antirreumáticos/farmacologia , Artrite Experimental/fisiopatologia , Hiperestesia/fisiopatologia , Articulações/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Pterinas/urina , Sulfassalazina/farmacologia , Adulto , Animais , Artrite Experimental/patologia , Biomarcadores/urina , Biopterina/análogos & derivados , Biopterina/urina , Cromatografia Líquida de Alta Pressão , Temperatura Baixa , Feminino , Membro Posterior , Temperatura Alta , Humanos , Articulações/patologia , Masculino , Camundongos
19.
Cell Mol Life Sci ; 77(7): 1387-1399, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31342120

RESUMO

In rheumatoid arthritis (RA), synovial tissue abundantly expresses CCL21, a chemokine strongly associated with RA susceptibility. In this study, we aimed to characterize the functional significance of CCL21/CCR7 signaling in different phases of RA pathogenesis. We determined that CCR7 is a hallmark of RA M1 synovial fluid (SF) macrophages, and its expression in RA monocytes and in vitro differentiated macrophages is closely associated with disease activity score (DAS28). In early stages of RA, monocytes infiltrate the synovial tissue. However, blockade of SF CCL21 or CCR7 prevents RA SF-mediated monocyte migration. CCR7 expression in the newly migrated macrophages can be accentuated by LPS and IFNγ and suppressed by IL-4 treatment. We also uncovered that CCL21 stimulation increases the number of M1-polarized macrophages (CD14+CD86+), resulting in elevated transcription of IL-6 and IL-23. These CCL21-induced M1 cytokines differentiate naïve T cells to Th17 cells, without affecting Th1 cell polarization. In the erosive stages of disease, CCL21 potentiates RA osteoclastogenesis through M1-driven Th17 polarization. Disruption of this intricate crosstalk, by blocking IL-6, IL-23, or IL-17 function, impairs the osteoclastogenic capacity of CCL21. Consistent with our in vitro findings, we establish that arthritis mediated by CCL21 expands the joint inflammation to bone erosion by connecting the differentiation of M1 macrophages with Th17 cells. Disease progression is further exacerbated by CCL21-induced neovascularization. We conclude that CCL21 is an attractive novel target for RA therapy, as blockade of its function may abrogate erosive arthritis modulated by M1 macrophages and Th17 cell crosstalk.


Assuntos
Artrite Reumatoide/imunologia , Quimiocina CCL21/metabolismo , Inflamação/patologia , Articulações/patologia , Macrófagos/metabolismo , Osteoclastos/patologia , Receptores CCR7/metabolismo , Células Th17/imunologia , Animais , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Biomarcadores/metabolismo , Diferenciação Celular , Polaridade Celular , Quimiotaxia , Feminino , Humanos , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Monócitos/patologia , Células Mieloides/metabolismo , Osteogênese , Receptores CCR7/sangue , Transdução de Sinais , Líquido Sinovial/metabolismo , Regulação para Cima
20.
Ann Rheum Dis ; 79(1): 112-122, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662319

RESUMO

OBJECTIVES: This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis. METHODS: Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and µCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis. RESULTS: R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice. CONCLUSIONS: Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis.


Assuntos
Cartilagem Articular/patologia , Quimiocina CXCL12/metabolismo , Macrófagos/metabolismo , Osteoartrite/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores CXCR/genética , Sinovite/genética , Animais , Quimiotaxia/genética , Marcha , Regulação da Expressão Gênica , Humanos , Articulações/metabolismo , Articulações/patologia , Camundongos , Camundongos Knockout , Monócitos/metabolismo , Células Mieloides , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores CXCR/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Sinovite/patologia
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