RESUMEN
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.
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Osteogénesis/genética , Osteogénesis/inmunología , Membrana Sinovial/patología , Sinovitis Pigmentada Vellonodular/genética , Sinovitis Pigmentada Vellonodular/inmunología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Proliferación Celular , Humanos , Inmunohistoquímica , Análisis por Micromatrices , Osteoartritis/genética , Osteoartritis/inmunología , Osteoclastos/metabolismo , Análisis de Secuencia de ARN , Membrana Sinovial/citología , Membrana Sinovial/inmunología , Sinovitis Pigmentada Vellonodular/patología , TranscriptomaRESUMEN
Rationale: Pigmented villonodular synovitis (PVNS) is a destructive benign tumor-like hyperplastic disease that occurs in synovial tissue. Fibroblast-like synoviocytes (FLS) are the predominant cell type comprising the structure of the PVNS synovial lining layer. Due to a high recurrence rate, high invasion, migration, and cartilage destruction ability, PVNS causes substantial damage to patients and the efficacy of surgical resection is not satisfactory. Therefore, exploring the pathogenesis and identifying novel therapeutic targets for PVNS are urgently required. Currently, the pathogenesis of PVNS remains unclear, and there is uncertainty and controversy regarding whether PVNS is an inflammatory or a neoplastic disease. Cadherin-11 is a classical molecule that mediates hemophilic cell-to-cell adhesion in FLS and plays an important role in the normal synovium lining layer formation. This study aimed to explore the role of inflammation and cadherin-11 in PVNS pathogenesis and determine the effects of cadherin-11 as a molecular target for PVNS treatment. Methods: FLS were primarily cultured from PVNS patients during arthroscopic synovectomy. The level of cytokines in the PVNS synovial fluid was evaluated using a human antibody array. Cadherin-11 expression of PVNS FLS was detected by qPCR, Western blots, tissue immunohistochemistry, and cell immunofluorescence. Cadherin-11 was down-regulated by siRNA or up-regulated with a plasmid, with or without inflammatory factor stimulation, and PI3K/Akt was inhibited with LY294002. The capacity of migration and invasion of PVNS FLS was tested using Transwell and wound-healing assays. Activation of the nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways was detected by Western blots. Chondrocyte damage by PVNS FLS was assessed with a co-culture assay. Results: Inflammatory factors (IL-1ß and TNF-α) in the synovial fluid of PVNS patients were significantly up-regulated. Cadherin-11 was highly expressed in the FLS of PVNS patients, and positively correlated with recurrence, extra-articular migration, and cartilage destruction of PVNS. Knocking down of cadherin-11 inhibited the migration and invasion of PVNS FLS. Moreover, inflammatory factors up-regulated the expression of cadherin-11, which activated the NF-κB and MAPK signaling pathways and led to cartilage destruction. Inhibition of cadherin-11 blocked IL-1ß- and TNF-α-induced activation of the above pathways, migration and invasion of PVNS FLS, and damage of chondrocyte. In addition, the elevation of cadherin-11 expression, together with the migration and invasion, of PVNS FLS was down-regulated by the inhibition of the PI3K/Akt signaling pathway. Conclusions: Cadherin-11 plays an important role in the pathogenesis of PVNS and forms a positive feedback loop with inflammatory factors, which further activates the NF-κB and MAPK pathways to trigger an inflammatory cascade. Cadherin-11-mediated inflammation results in PVNS with high recurrence, invasiveness, and strong cartilage destruction ability, and eventually promotes the transformation of PVNS from the initial inflammatory disease to neoplastic disease. Thus, inhibition of cadherin-11 together with its related inflammatory reaction, represents a new therapeutic strategy for PVNS.
Asunto(s)
Cadherinas/metabolismo , Mediadores de Inflamación/metabolismo , Membrana Sinovial/patología , Sinoviocitos/metabolismo , Sinovitis Pigmentada Vellonodular/inmunología , Adenilato Quinasa/metabolismo , Adulto , Artroscopía , Cadherinas/genética , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Células Cultivadas , Cromonas/farmacología , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Sistema de Señalización de MAP Quinasas/inmunología , Masculino , Persona de Mediana Edad , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Cultivo Primario de Células , Sinovectomía/métodos , Membrana Sinovial/citología , Membrana Sinovial/inmunología , Sinoviocitos/inmunología , Sinovitis Pigmentada Vellonodular/patología , Sinovitis Pigmentada Vellonodular/cirugía , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaRESUMEN
PURPOSE OF REVIEW: Colony-stimulating factor 1 receptor (CSF-1R) and its ligands, CSF-1 and interleukin 34 (IL-34), regulate the function and survival of tumor-associated macrophages, which are involved in tumorigenesis and in the suppression of antitumor immunity. Moreover, the CSF-1R/CSF-1 axis has been implicated in the pathogenesis of pigmented villonodular synovitis (PVNS), a benign tumor of the synovium. As advanced or metastatic malignant solid tumors and relapsed/refractory PVNS remain unresolved therapeutic problems, new approaches are needed to improve the outcome of patients with these conditions. RECENT FINDINGS: In solid tumors, targeting CSF-1R via either small molecules or antibodies has shown interesting results in vitro but limited antitumor activity in vivo. Concerning PVNS, clinical trials assessing CSF-1R inhibitors have revealed promising initial outcomes. Blocking CSF-1/CSF-1R signaling represents a promising immunotherapy approach and several new potential combination therapies for future clinical testing.
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Carcinogénesis/genética , Factor Estimulante de Colonias de Macrófagos/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Sinovitis Pigmentada Vellonodular/tratamiento farmacológico , Anticuerpos/uso terapéutico , Humanos , Inmunoterapia , Interleucinas/antagonistas & inhibidores , Interleucinas/genética , Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Macrófagos/metabolismo , Macrófagos/patología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Sinovitis Pigmentada Vellonodular/genética , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/patologíaRESUMEN
Tenosynovial giant cell tumour (TSGCT; synonym, pigmented villonodular synovitis (PVNS)) is a rare low-grade mesenchymal neoplasm of either intra-articular or extra-articular origin. The etiopathogenesis of TSGCT is still uncertain, but recent studies showed a translocation involving colony-stimulating factor 1 (CSF-1) gene in a subset of cases. Histological features mimicking TSGCT can sometimes be encountered in periprosthetic interface membranes. To investigate the frequency and morphologic spectrum of this phenomenon, we conducted a systematic analysis of 477 periprosthetic interface membranes and performed immunohistochemical analysis on a subset of lesions compared to genuine TSGCT. In 26 of 477 periprosthetic membrane samples (5 %), at least some TSGCT-like features were found and 18 cases (4 %) strongly resembled it. Wear particles were detected in 100 % of the TSGCT-like lesions but only in 63.3 % of the whole cohort of periprosthetic membranes (p value <0.001). Immunohistochemistry comparing true TSGCT and TSGCT-like membranes showed similar inflammatory infiltrates with slightly elevated CD3+/CD8+ T lymphocytes and a slightly higher proliferation index in TSGCT samples. In conclusion, TSGCT-like changes in periprosthetic membranes likely represent exuberant fibrohistiocytic inflammatory response induced by wear particles and should be distinguished from genuine (neoplastic) TSGCT. Although TSGCT and TSGCT-like periprosthetic membranes represent different entities, their comparable morphology might reflect analogous morphogenesis.
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Antígenos CD/inmunología , Tumores de Células Gigantes/patología , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/patología , Linfocitos T/citología , Adulto , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Proliferación Celular/fisiología , Femenino , Tumores de Células Gigantes/diagnóstico , Humanos , Inmunohistoquímica/métodos , Inflamación/inmunología , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Conejos , Sinovitis Pigmentada Vellonodular/diagnóstico , Linfocitos T/inmunología , Translocación Genética/genéticaRESUMEN
BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Tumores de Células Gigantes/tratamiento farmacológico , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Sinovitis Pigmentada Vellonodular/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/efectos adversos , Esquema de Medicación , Femenino , Tumores de Células Gigantes/inmunología , Tumores de Células Gigantes/metabolismo , Tumores de Células Gigantes/patología , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Receptor de Factor Estimulante de Colonias de Macrófagos/inmunología , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de los Tejidos Blandos/inmunología , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/metabolismo , Sinovitis Pigmentada Vellonodular/patología , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Giant cell tumor of tendon sheath and pigmented villonodular synovitis are synovial-based diseases that are generally treated by surgery. For aggressive and recurrent tumors, treatment alternatives are needed. This review explores a targeted therapeutic strategy. RECENT FINDINGS: Imatinib, a tyrosine kinase inhibitor, blocks expression of colony stimulating factor 1 (CSF1) by a small subpopulation of tumor cells that recruit CSF1-bearing nonneoplastic cells. Limited clinical data support the efficacy and side effect profile of imatinib in stabilizing disease in most patients. SUMMARY: Imatinib along with other such inhibitors and monoclonal antibodies to CSF1R are putative drugs that may play an important role in the treatment of these tumors.
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Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Sinovitis Pigmentada Vellonodular/tratamiento farmacológico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Benzamidas , Humanos , Mesilato de Imatinib , Factor Estimulante de Colonias de Macrófagos/inmunología , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Receptor de Factor Estimulante de Colonias de Macrófagos/inmunología , Sinovitis Pigmentada Vellonodular/inmunologíaRESUMEN
Pigmented villonodular synovitis (PVNS) is a synovial tumour-like lesion that frequently causes osteolysis. PVNS contains numerous macrophages and osteoclast-like giant cells. In this study, we have analysed the cytochemical and functional characteristics of mononuclear and multinucleated cells in PVNS and determined the cellular and humoral mechanisms underlying giant cell formation and resorption in PVNS. Giant cells and CD14(+) and CD14(-) mononuclear cell populations were isolated from PVNS synovial tissue and cultured alone or in the presence and absence of the osteoclastogenic factors, RANKL and M-CSF. Osteoclast formation and activity was assessed by expression of TRAP and evidence of lacunar resorption. Giant cells in PVNS expressed an osteoclast-phenotype (CD51(+) , TRAP(+) , CD14(-) , HLA-DR(-) ) and were formed only in cultures of mononuclear cells that expressed the macrophage marker CD14. Osteoclast formation required RANKL and occurred in both the presence and absence of exogenous M-CSF. CD14(-) cells in PVNS expressed RANKL. Lacunar resorption by PVNS-derived giant cells was abolished by the addition of the bisphosphonate, zoledronate. Our findings indicate that osteoclasts form by a RANKL-dependent mechanism from CD14(+) mononuclear phagocytes in PVNS. Osteoclast formation occurred even in the absence of exogenous M-CSF, a finding which is in keeping with over-expression of M-CSF playing a pathogenic role in this condition. Anti-osteoclast resorptive treatment may be useful to control osteolysis in PVNS.
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Osteoclastos/fisiología , Sinovitis Pigmentada Vellonodular/patología , Adolescente , Adulto , Resorción Ósea/etiología , Células Cultivadas , Femenino , Células Gigantes/fisiología , Humanos , Inmunofenotipificación , Articulación de la Rodilla/patología , Receptores de Lipopolisacáridos/análisis , Factor Estimulante de Colonias de Macrófagos/metabolismo , Masculino , Osteoclastos/metabolismo , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Sinovitis Pigmentada Vellonodular/complicaciones , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/metabolismo , Adulto JovenRESUMEN
Diffuse-type tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, are unique mesenchymal lesions that arise from the synovial tissue of the joints. They are predominantly intraarticular, aggressive, infiltrative processes, characterized by both inflammatory or neoplastic properties and local destructive progression. The pattern of synovial gene and protein expressions in pigmented villonodular synovitis, similar to those in activated macrophages in rheumatoid arthritis, and the phenotype of multinucleated giant cells, characteristic of osteoclasts, suggest that there is a common autocrine mechanism in osteoclast differentiation in both diseases and indicate the potential utility of tumor necrosis factor (TNF)-alpha blockade. High synovial colony stimulating factor 1 (CSF1) messenger RNA (m RNA) expression in pigmented villonodular synovitis, unrelated to a chromosomal translocation involving CSF1 locus, may indicate that there is a synergic paracrine loop mediated by TNF-alpha and CSF1, as shown in both inflammatory and neoplastic conditions. The effects of a new therapeutic approach consisting in intraarticular TNF-alpha blockade were studied in four pigmented villonodular synovitis knees. Knee injections produced a rapid reduction in clinical and sonographic indexes and immunohistological alterations, confirmed by arthroscopic synovectomy. A delayed relapse in one of the four knees and unaltered synovial CSF1 expression were other important findings. In the light of these observations, CSF1/CSF1R interaction probably represents a more sensible therapeutic target than TNF-alpha blockade in the diffuse form of pigmented villonodular synovitis.
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Articulación de la Rodilla , Factor Estimulante de Colonias de Macrófagos/metabolismo , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto , Artritis/tratamiento farmacológico , Artritis/inmunología , Artritis/metabolismo , Artritis/patología , Células del Tejido Conectivo , Femenino , Expresión Génica , Tumores de Células Gigantes/inmunología , Tumores de Células Gigantes/patología , Células Gigantes/metabolismo , Células Gigantes/patología , Humanos , Articulación de la Rodilla/patología , Factor Estimulante de Colonias de Macrófagos/biosíntesis , Factor Estimulante de Colonias de Macrófagos/genética , Masculino , Persona de Mediana Edad , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal , Líquido Sinovial/metabolismo , Sinovitis Pigmentada Vellonodular/tratamiento farmacológico , Sinovitis Pigmentada Vellonodular/patologíaRESUMEN
AIM: Haemosiderotic synovitis (HS) is caused by excessive bleeding into a joint. It occurs secondary to a variety of conditions and needs to be distinguished from pigmented villonodular synovitis (PVNS) for the purposes of treatment. The histopathological distinction between these conditions, particularly in biopsy specimens, can be problematic. METHODS: Immunophenotypic findings in 20 cases of PVNS and 20 cases of HS were analysed using monoclonal antibodies against proliferation (Ki-67), apoptosis (bcl2), macrophage (CD14, CD68, HLA-DR) and osteoclast (CD51) antigens. RESULTS: Macrophages in PVNS and HS expressed CD14 and HLA-DR. The giant cells in PVNS, but not those in HS, expressed CD51 and were negative for CD14 and HLA-DR, indicating that these cells had an osteoclast phenotype. Considerably more CD51-expressing mononuclear cells were noted in PVNS compared with HS. The Ki-67 proliferation index was higher in PVNS than in HS. CONCLUSIONS: The findings indicate that there are immunophenotypic differences in giant cells between PVNS and HS, and that expression of CD51 and a high Ki-67 index effectively distinguishes between these two conditions.
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Hemosiderosis/complicaciones , Sinovitis/diagnóstico , Sinovitis/inmunología , Adolescente , Adulto , Anticuerpos Monoclonales/inmunología , Apoptosis , Biomarcadores/metabolismo , Proliferación Celular , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Integrina alfaV/metabolismo , Antígeno Ki-67/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Persona de Mediana Edad , Músculo Liso/metabolismo , Músculo Liso/patología , Osteoclastos/metabolismo , Osteoclastos/patología , Sinovitis/etiología , Sinovitis/patología , Sinovitis Pigmentada Vellonodular/diagnóstico , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/patología , Adulto JovenRESUMEN
Pigmented villonodular synovitis (PVNS) is a destructive proliferative tumoroid disease of the synovial sheath of the joints, bursae, and tendon. The microscopic pattern of PVNS is characterized by mosaicism: compact cell zones alternate with loose few-celled fields. The synovial sheath is hyperplastic; its stroma exhibits hemosiderin and siderophages, as well as histiocytes, lymphocytes, multinucleated giant osteoclasts, foamy and synoviocyte-like cells. Proliferation with destructive growth was noted in PVNS. A distinction is made between focal and diffuse, intraarticular and extraarticular forms of the disease. Early diagnosis of the disease favors effective treatment and prevention of soft tissue and bone destruction and reduces the risk of recurrences.
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Sinovitis Pigmentada Vellonodular/patología , Humanos , Sinovitis Pigmentada Vellonodular/inmunologíaRESUMEN
OBJECTIVE: To determine the expression of bcl-2, p53, and caspase 3, and measure the Ki-67 proliferation index as well as DNA content and DNA fragmentation in a case of diffuse pigmented villonodular synovitis (PVNS) of the knee with aggressive clinical behaviour. METHODS: Expression of p53, Bcl-2 and Ki-67 was investigated using immunohistochemistry. In addition, multiparametric flow cytometry was performed for expression of p53, bcl-2, and caspase 3, as well as analysis of DNA content and distribution of cell cycle phases. DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL). RESULTS: A strong cytoplasmic positivity for Bcl-2 protein, a key factor in regulation of apoptosis, was found in the majority of proliferating synovial cells. No apoptotic cell fraction was found by analysis of DNA content. DNA fragmentation was observed in 6.8% of cells. No elevated expression of p53 and caspase 3 was detected. CONCLUSION: Our results indicate a possible role of dysregulation of apoptosis in this case of PVNS. This aspect in the pathogenesis of PVNS should be clarified in further studies.
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Fragmentación del ADN , Genes bcl-2 , Sinovitis Pigmentada Vellonodular/metabolismo , Adulto , Apoptosis/genética , Caspasa 3 , Caspasas/metabolismo , Citometría de Flujo , Humanos , Inmunohistoquímica , Etiquetado Corte-Fin in Situ , Antígeno Ki-67/metabolismo , Masculino , Sinovitis Pigmentada Vellonodular/enzimología , Sinovitis Pigmentada Vellonodular/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia ArribaRESUMEN
Sweet's syndrome (acute febrile neutrophilic dermatosis) was first described in 1964. The typical symptoms of Sweet's syndrome are high temperature, peripheral leucocytosis, painful cutaneous rashes (papules, plaques) and arthralgia. Sweet's syndrome has particularly been described in association with neoplastic, infectious and immunological diseases. The pathogenesis of Sweet's syndrome can be explained by a reaction to an antigenic structure with accumulation of immunological complexes and liberation of inflammatory mediators. For the first time we report on a patient with Sweet's syndrome and pigmented villonodular synovitis, which is believed to play the antigenic role in the Sweet syndrome.
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Síndrome de Sweet/etiología , Sinovitis Pigmentada Vellonodular/complicaciones , Humanos , Articulación de la Rodilla/patología , Masculino , Persona de Mediana Edad , Síndrome de Sweet/inmunología , Sinovitis Pigmentada Vellonodular/inmunologíaRESUMEN
OBJECTIVE: To elucidate the involvement of telomerase activity in the pathogenesis of rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVS). METHODS: Peripheral blood lymphocytes (PBL), synovial infiltrating lymphocytes, and synoviocytes were isolated from peripheral blood samples and synovial tissue obtained from 18 patients with RA, 9 with PVS, 12 with osteoarthritis (OA), and 10 with knee joint trauma. Cellular telomerase activity was measured by the telomeric repeat amplification protocol assay. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was assessed for correlations with histologic features in rheumatoid synovium. RESULTS: A high level of telomerase activity was detected in the PBL and synovial infiltrating lymphocytes from RA patients and in the synoviocytes from PVS patients, whereas the enzyme activity was expressed at a low-to-borderline level in the PBL and synovial lymphocytes from OA, PVS, and trauma patients and was absent in the synoviocytes from RA as well as OA and trauma patients. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was significantly correlated with the intensity of synovial lining hyperplasia, microvessel proliferation, lymphocyte infiltration, and percentage of synovial cells positive for proliferating cell nuclear antigen in rheumatoid synovium. CONCLUSION: Telomerase activation in lymphocytes may provide insights into the progression of synovitis and synovial proliferation in RA. Moreover, the enzyme may be implicated in the proliferation of synoviocytes in PVS.
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Artritis Reumatoide/patología , Membrana Sinovial/patología , Sinovitis Pigmentada Vellonodular/patología , Telomerasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Linfocitos T CD4-Positivos/inmunología , División Celular/inmunología , Sondas de ADN , Femenino , Regulación Enzimológica de la Expresión Génica/inmunología , Humanos , Hiperplasia , Masculino , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/análisis , Membrana Sinovial/citología , Membrana Sinovial/enzimología , Sinovitis Pigmentada Vellonodular/inmunología , Sinovitis Pigmentada Vellonodular/metabolismo , Telomerasa/genéticaRESUMEN
Nineteen giant cell tumors of tendon sheath (GCTTS) were studied to elucidate the origin of the proliferating cells of these tumors, using single and multiple immunostaining techniques with a labeled avidin-biotin [LAB] method in paraffin-embedded tissues. Proliferating cell nuclear antigen (PCNA) and Ki-67 (MIB-1) antigen were present in mononuclear cells (PCNA 26%; MIB-14%) but were absent in giant cells. These findings indicate that mononuclear cells, but not giant cells, participate in the proliferative compartment of GCTTS. A histiocytic marker, HAM56, was positive in many mononuclear cells (mean 81%), but was totally negative in osteoclastic giant cells. Another histiocytic antigen, CD68, was expressed in both mononuclear cells (mean 28%) and most of the giant cells (mean 89%). By triple immunostaining for PCNA, HAM56 and vimentin, 83% of PCNA-positive mononuclear cells co-expressed HAM56. Because of the frequent co-expression of PCNA and HAM56, the main portion of proliferating cells in GCTTS may represent a monocyte/macrophage lineage. However, there is a small but definite mesenchymal/fibroblastic component, characterized by PCNA+vimentin+HAM56-, relating to the proliferative compartment of GCTTS. Multiple immunostainings with MIB-1 showed similar patterns to those with PCNA. These observations indicate that the GCTTS represent bimodal proliferative lesions consisting of histiocytic and mesenchymal/fibroblastic elements.
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Biomarcadores/análisis , Sinovitis Pigmentada Vellonodular/patología , Adolescente , Adulto , Anciano , Antígenos CD/análisis , Antígenos de Diferenciación Mielomonocítica/análisis , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67 , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Proteínas Nucleares/análisis , Antígeno Nuclear de Célula en Proliferación/análisis , Sinovitis Pigmentada Vellonodular/inmunología , Vimentina/análisisRESUMEN
Pigmented villonodular synovitis (PVNS) is an uncommon proliferative disease of synovium. We report a 35-year-old male with diffuse form of PVNS of left knee, treated with intraarticular injection of 5 mCi of yttrium-90 (Y-90) silicate colloid consisting of two doses with a 3-month interval between them. During follow-up, the affected knee showed clinical improvement and was accompanied by a decrease of the levels of soluble interleukin-2 receptor in sera and synovial fluids (SF). When compared to osteoarthritis subjects, SF lymphocyte subsets of this case before Y-90 therapy showed a lower CD4:CD8 cell ratio and absence of suppressor inducer cells (CD4+ 2H4+). The Tc-99m pertechnetate knee uptake indexes correlated well with clinical improvement. Serial magnetic resonance imaging revealed significant change one year after Y-90 therapy. The findings of immunological assessment suggested that immunoregulatory dysfunction may be related to the pathogenesis of PVNS.