Abstract
Abnormal T cell immune responses induce aberrant expression of inflammatory cytokines such as TNF-alpha, leading to osteoclastmediated bone erosion and osteoporosis in autoimmune arthritis. However, the mechanism underlying enhanced osteoclastogenesis in arthritis is not completely understood. Here we show that TNF-alpha contributes to inflammatory bone loss by enhancing the osteoclastogenic potential of osteoclast precursor cells through inducing paired Ig-like receptor-A (PIR-A), a costimulatory receptor for receptor activator of NF-kappaB (RANK). In fact, bone erosion and osteoporosis, but not inflammation, caused by aberrant TNF-alpha expression were ameliorated in mice deficient in Fc receptor common gamma subunit or beta(2)-microglobulin, in which the expression of PIR-As and PIR-A ligands is impaired, respectively. These results establish the pathological role of costimulatory receptors for RANK in bone loss in arthritis and may provide a molecular basis for the future therapy of inflammatory diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / administration & dosage
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology
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Arthritis, Experimental / pathology*
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Arthritis, Experimental / therapy
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Gene Amplification / immunology
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Inflammation Mediators / immunology
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology
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Infliximab
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Mice
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Mice, Knockout
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Mice, Transgenic
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NFATC Transcription Factors / genetics
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Osteoclasts / cytology
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Osteoclasts / immunology
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Osteoclasts / pathology*
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Osteoporosis / genetics
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Osteoporosis / immunology
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Osteoporosis / pathology*
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Osteoporosis / therapy
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Receptors, Immunologic / biosynthesis
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / physiology
Substances
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Antibodies, Monoclonal
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Inflammation Mediators
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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Pira1 protein, mouse
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Pira4 protein, mouse
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Pira6 protein, mouse
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Receptors, Immunologic
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Tumor Necrosis Factor-alpha
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Infliximab