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1.
Int J Pharm ; 416(2): 486-92, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21382458

RESUMO

UNLABELLED: Encapsulation of glucocorticoids into long-circulating liposomes provides targeting of these drugs to the inflamed synovium in experimental arthritis and thereby strongly improves their therapeutic index. The goal of this study was to evaluate the effect and mechanisms of intravenous liposomal delivery of prednisolone phosphate (Lip-PLP) on protease mediated cartilage destruction during murine antigen-induced arthritis (AIA). Mice treated with a single injection of Lip-PLP showed a pronounced suppression of synovial immune cell infiltration compared to control, PBS-treated mice. Liposomal PLP also significantly suppressed interleukin 1ß (3.6 fold) in the synovium, but not in the blood serum. Furthermore, expression of the proteases MMP-3, -9, -13 and -14 and ADAMTS-4 and -5 was suppressed by Lip-PLP in the synovium, but not within the articular cartilage of the femur and tibia, demonstrating the specific action of Lip-PLP on the synovium. Lip-PLP is phagocytosed by macrophages in vitro and suppresses their expression of IL-1ß and MMPs after LPS activation. Moreover, Lip-PLP suppresses destruction of the cartilage matrix during AIA mediated by active MMPs and ADAMTS, as assessed by immunostaining of their respective neoepitopes VDIPEN and NITEGE in various cartilage layers of the knee joint. CONCLUSION: liposomal delivery of glucocorticoids protects against cartilage matrix destruction during experimental arthritis by inhibiting protease expression and activity in the inflamed synovium.


Assuntos
Artrite Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glucocorticoides/farmacologia , Prednisolona/análogos & derivados , Proteínas ADAM/efeitos dos fármacos , Proteínas ADAM/metabolismo , Animais , Antígenos/toxicidade , Artrite Experimental/patologia , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Preparações de Ação Retardada , Glucocorticoides/administração & dosagem , Interleucina-1beta/metabolismo , Lipossomos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Prednisolona/administração & dosagem , Prednisolona/farmacologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia
2.
Arthritis Rheum ; 60(10): 2954-65, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19790077

RESUMO

OBJECTIVE: Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA). METHODS: AIA was induced in the knee joints of SR-AI/II(-/-) mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP)-mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. In synovial washouts, cytokines (interleukin-1beta [IL-1beta], IL-10, and tumor necrosis factor alpha) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay. RESULTS: Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40-75% of the cartilage surfaces. In striking contrast, in SR-AI/II(-/-) mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1beta and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable. CONCLUSION: Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA.


Assuntos
Artrite Experimental/metabolismo , Cartilagem Articular/metabolismo , Condrócitos/metabolismo , Metaloproteinases da Matriz/metabolismo , Receptores Depuradores Classe A/metabolismo , Animais , Antígenos/efeitos adversos , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Calgranulina A , Calgranulina B , Cartilagem Articular/patologia , Estudos de Casos e Controles , Morte Celular/fisiologia , Células Cultivadas , Condrócitos/patologia , Modelos Animais de Doenças , Humanos , Interleucina-1beta/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Monócitos/patologia , Receptores de IgG/metabolismo , Proteínas S100/metabolismo , Soroalbumina Bovina/efeitos adversos , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
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