Abstract
Recent evidence indicates that the decoy receptor 3 (DcR3) of the TNF receptor superfamily, which initially though prevents cytokine responses of FasL, LIGHT and TL1A by binding and neutralization, can modulate monocyte function through reverse signaling. We show in this work that DcR3 can induce osteoclast formation from human monocytes, murine RAW264.7 macrophages, and bone marrow cells. DcR3-differentiated cells exhibit characteristics unique for osteoclasts, including polynuclear giant morphology, bone resorption, TRAP, CD51/61, and MMP-9 expression. Consistent with the abrogation of osteoclastogenic effect of DcR3 by TNFR-Fc, DcR3 treatment can induce osteoclastogenic cytokine TNF-alpha release through ERK and p38 MAPK signaling pathways. We conclude that DcR3 via coupling reverse signaling of ERK and p38 MAPK and stimulating TNF-alpha synthesis is a critical regulator of osteoclast formation. This action of DcR3 might play an important role in significant osteoclastic activity in osteolytic bone metastases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / genetics
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Acid Phosphatase / metabolism
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Animals
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Blotting, Western
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / physiology
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Bone Resorption / metabolism
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Carrier Proteins / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology*
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Cell Fusion
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Cell Line
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Cytokines / metabolism
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Cytokines / pharmacology
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Dinoprostone / metabolism
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Flow Cytometry
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Gene Expression / drug effects
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Humans
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Isoenzymes / genetics
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Isoenzymes / metabolism
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JNK Mitogen-Activated Protein Kinases / metabolism
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Lipopolysaccharides / pharmacology
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MAP Kinase Kinase 4
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Macrophages / physiology
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Matrix Metalloproteinase 9 / genetics
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Membrane Glycoproteins / pharmacology*
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Membrane Glycoproteins / physiology
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Monocytes / drug effects
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Monocytes / metabolism
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Monocytes / physiology*
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NF-kappa B / metabolism
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Nitric Oxide / metabolism
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Osteoclasts / cytology
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Osteoclasts / drug effects
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Osteoclasts / physiology*
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Protein Kinase Inhibitors / pharmacology
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RANK Ligand
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Rats
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Rats, Sprague-Dawley
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cell Surface / physiology
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 6b
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Receptors, Vitronectin / metabolism
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Tartrate-Resistant Acid Phosphatase
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Carrier Proteins
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Cytokines
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Isoenzymes
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Lipopolysaccharides
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Membrane Glycoproteins
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NF-kappa B
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Protein Kinase Inhibitors
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RANK Ligand
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Cell Surface
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 6b
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Vitronectin
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TNFRSF11A protein, human
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TNFRSF6B protein, human
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TNFSF11 protein, human
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Tumor Necrosis Factor-alpha
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Nitric Oxide
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Macrophage Colony-Stimulating Factor
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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p38 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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Acid Phosphatase
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Tartrate-Resistant Acid Phosphatase
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Matrix Metalloproteinase 9
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Dinoprostone