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1.
Nat Med ; 17(12): 1674-9, 2011 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-22057346

RESUMO

Osteoarthritis, characterized by the breakdown of articular cartilage in synovial joints, has long been viewed as the result of 'wear and tear'. Although low-grade inflammation is detected in osteoarthritis, its role is unclear. Here we identify a central role for the inflammatory complement system in the pathogenesis of osteoarthritis. Through proteomic and transcriptomic analyses of synovial fluids and membranes from individuals with osteoarthritis, we find that expression and activation of complement is abnormally high in human osteoarthritic joints. Using mice genetically deficient in complement component 5 (C5), C6 or the complement regulatory protein CD59a, we show that complement, specifically, the membrane attack complex (MAC)-mediated arm of complement, is crucial to the development of arthritis in three different mouse models of osteoarthritis. Pharmacological modulation of complement in wild-type mice confirmed the results obtained with genetically deficient mice. Expression of inflammatory and degradative molecules was lower in chondrocytes from destabilized joints from C5-deficient mice than C5-sufficient mice, and MAC induced production of these molecules in cultured chondrocytes. Further, MAC colocalized with matrix metalloprotease 13 (MMP13) and with activated extracellular signal-regulated kinase (ERK) around chondrocytes in human osteoarthritic cartilage. Our findings indicate that dysregulation of complement in synovial joints has a key role in the pathogenesis of osteoarthritis.


Assuntos
Complemento C5/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Animais , Antígenos CD59/genética , Antígenos CD59/metabolismo , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Complemento C5/genética , Complemento C6/genética , Complemento C6/metabolismo , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Articulações/metabolismo , Articulações/patologia , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Proteômica/métodos , Líquido Sinovial/metabolismo
2.
Metallomics ; 1(2): 142-7, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21305107

RESUMO

Laser ablation inductively coupled plasma mass spectrometry (LA ICP-MS) was employed to image deposits of calcium phosphate based crystals in knee cartilage and synovial fluid from arthritic patients. A reaction/collision cell containing hydrogen minimised plasma interferences on calcium and also improved the image quality without significant sensitivity reduction. Areas of high calcium and phosphorus intensities consistent with crystal deposits were observed for both the cartilage and synovial fluid samples. These areas were also characterised by high magnesium and strontium intensities. Distribution patterns of other elements such as copper and sulfur did not correlate with the crystal deposits. Filtered and non-filtered solutions of calcium phosphate crystals grown in synthetic synovial fluid were also imaged as further evidence of crystal deposits. The crystal deposits were detected in the unfiltered solution, and were absent from the filtered solutions.


Assuntos
Fosfatos de Cálcio/química , Fosfatos de Cálcio/metabolismo , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Osteoartrite do Joelho/metabolismo , Cálcio/química , Cartilagem Articular/química , Cartilagem Articular/metabolismo , Humanos , Isótopos/química , Articulação do Joelho/química , Articulação do Joelho/metabolismo , Magnésio/química , Fósforo/química , Estrôncio/química , Líquido Sinovial/química , Líquido Sinovial/metabolismo
3.
J Immunol ; 171(5): 2287-95, 2003 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-12928373

RESUMO

The localization of receptors, signaling intermediates, and cytoskeletal components at the T cell/APC interface is thought to be a major determinant of efficient T cell activation. However, important questions remain open. What are the dynamics of the T cell cytoskeleton as a potential mediator of such localization? How are they regulated by the TCR and costimulatory receptors? Do they actually mediate receptor localization? In this study, we have addressed these questions. Even under limiting T cell activation conditions, actin accumulated immediately and transiently at the T cell/APC interface, the microtubule organizing center reoriented toward it. In contrast, sustained (>5 min) actin accumulation in highly dynamic patterns depended on an optimal T cell stimulus: high concentrations of the strong TCR ligand agonist peptide/MHC and engagement of the costimulatory receptors CD28 and LFA-1 were required in an overlapping, yet distinct, fashion. Intact sustained actin dynamics were required for interface accumulation of TCR/MHC in a central pattern and for efficient T cell proliferation, as established using a novel approach to selectively block only the sustained actin dynamics. These data suggest that control of specific elements of actin dynamics by TCR and costimulatory receptors is a mechanism to regulate the efficiency of T cell activation.


Assuntos
Actinas/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Actinas/genética , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Antígenos CD28/fisiologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Linhagem Celular Tumoral , Citoesqueleto/genética , Citoesqueleto/imunologia , Citoesqueleto/metabolismo , Proteínas de Fluorescência Verde , Antígenos de Histocompatibilidade/metabolismo , Proteínas Luminescentes/genética , Ativação Linfocitária/genética , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Antígeno-1 Associado à Função Linfocitária/fisiologia , Camundongos , Camundongos Transgênicos , Centro Organizador dos Microtúbulos/imunologia , Centro Organizador dos Microtúbulos/metabolismo , Dados de Sequência Molecular , Pseudópodes/imunologia , Pseudópodes/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tubulina (Proteína)/genética
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