Abstract
Rheumatoid arthritis is a prevalent example of an inflammatory angiogenic disease, which is mediated by pro-inflammatory and pro-angiogenic cytokines such as tumor necrosis factor (TNF). To evaluate the effect of the potent anti-angiogenic factor endostatin on TNF-induced inflammatory arthritis, we injected an endostatin-expressing lentiviral vector directly into the joints of human TNF-transgenic mice before the onset of disease. Histological analysis of the injected joints 8 weeks later revealed that endostatin reduced blood vessel density within the synovial tissues and an overall mean arthritis index. In vitro and in vivo examination of the potential mechanism by which endostatin inhibited the arthritis revealed that endostatin blocks TNF-induced activation of JNK and JNK-dependent pro-angiogenic gene expression. These data suggest a novel mechanism by which endostatin inhibits angiogenesis, and demonstrates the potential utility of anti-angiogenic gene therapy for treatment of inflammatory arthritis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / genetics*
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Animals
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Arthritis, Rheumatoid / pathology
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Arthritis, Rheumatoid / therapy*
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Chemokine CCL2 / metabolism
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Collagen / genetics*
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Electrophoretic Mobility Shift Assay
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Endostatins
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Endothelial Growth Factors / metabolism
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Endothelium, Vascular / metabolism
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Gene Transfer Techniques
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Genetic Therapy*
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Humans
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Immunoenzyme Techniques
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Interleukin-8 / metabolism
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JNK Mitogen-Activated Protein Kinases*
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Joints / blood supply*
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Lymphokines / metabolism
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MAP Kinase Kinase 4
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Matrix Metalloproteinases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinase Kinases / physiology
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Neovascularization, Pathologic / prevention & control*
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Peptide Fragments / genetics*
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RNA / metabolism
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Synovitis / pathology
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Synovitis / therapy*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Angiogenesis Inhibitors
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Chemokine CCL2
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Endostatins
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Endothelial Growth Factors
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Interleukin-8
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Lymphokines
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Peptide Fragments
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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RNA
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Collagen
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Matrix Metalloproteinases