Abstract
IL-4 is an important immune cytokine that regulates bone homeostasis. We investigated the molecular mechanism of IL-4 action on bone-resorbing mature osteoclasts. Using a highly purified population of mature osteoclasts, we show that IL-4 dose-dependently inhibits receptor activator of NF-kappaB ligand (RANKL)-induced bone resorption by mature osteoclasts. We detected the existence of IL-4R mRNA in mature osteoclasts. IL-4 decreases TRAP expression without affecting multinuclearity of osteoclasts, and inhibits actin ring formation and migration of osteoclasts. Interestingly, IL-4 inhibition of bone resorption occurs through prevention of RANKL-induced nuclear translocation of p65 NF-kappaB subunit, and intracellular Ca(2+) changes. Moreover, IL-4 rapidly decreases RANKL-stimulated ionized Ca(2+) levels in the blood, and mature osteoclasts in IL-4 knockout mice are sensitive to RANKL action to induce bone resorption and hypercalcemia. Furthermore, IL-4 inhibits bone resorption and actin ring formation by human mature osteoclasts. Thus, we reveal that IL-4 acts directly on mature osteoclasts and inhibits bone resorption by inhibiting NF-kappaB and Ca(2+) signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acid Phosphatase / antagonists & inhibitors
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Acid Phosphatase / biosynthesis
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Acid Phosphatase / genetics
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Actins / antagonists & inhibitors
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Actins / metabolism
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Active Transport, Cell Nucleus / genetics
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Active Transport, Cell Nucleus / immunology
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Adult
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Animals
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Bone Resorption / immunology*
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Bone Resorption / pathology
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Bone Resorption / prevention & control*
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Calcium Signaling / genetics
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Calcium Signaling / immunology*
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Carrier Proteins / administration & dosage
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / physiology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Migration Inhibition
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Glycoproteins / antagonists & inhibitors
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Glycoproteins / biosynthesis
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Glycoproteins / genetics
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Humans
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Hypercalcemia / immunology
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Hypercalcemia / metabolism
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Hypercalcemia / pathology
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Interleukin-4 / deficiency
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Interleukin-4 / genetics
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Interleukin-4 / physiology*
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Intracellular Fluid / immunology
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Intracellular Fluid / metabolism
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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Male
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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NF-kappa B / physiology*
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Osteoclasts / enzymology
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Osteoclasts / immunology*
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Osteoclasts / metabolism*
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Osteoclasts / pathology
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Osteoprotegerin
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RANK Ligand
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Calcitonin / antagonists & inhibitors
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Receptors, Calcitonin / biosynthesis
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Receptors, Calcitonin / genetics
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / biosynthesis
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Tumor Necrosis Factor / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor / biosynthesis
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Receptors, Tumor Necrosis Factor / genetics
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Tartrate-Resistant Acid Phosphatase
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Transcription Factor RelA
Substances
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Actins
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Carrier Proteins
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Glycoproteins
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Isoenzymes
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Membrane Glycoproteins
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NF-kappa B
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Osteoprotegerin
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RANK Ligand
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RNA, Messenger
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Receptor Activator of Nuclear Factor-kappa B
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Receptors, Calcitonin
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Receptors, Cytoplasmic and Nuclear
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Receptors, Tumor Necrosis Factor
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TNFRSF11A protein, human
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TNFRSF11B protein, human
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TNFSF11 protein, human
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Tnfrsf11a protein, mouse
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Tnfrsf11b protein, mouse
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Tnfsf11 protein, mouse
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Transcription Factor RelA
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Interleukin-4
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Acid Phosphatase
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Acp5 protein, mouse
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Tartrate-Resistant Acid Phosphatase