IL-4 inhibits bone-resorbing activity of mature osteoclasts by affecting NF-κB and Ca2+ signaling
IL-4 inhibits bone-resorbing activity of mature osteoclasts by affecting NF-κB and Ca2+ signaling
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DOI：
10.4049/jimmunol.175.2.917
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
Wani, MR
中科院分区：
文献类型：
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作者：
Mangashetti, LS;Khapli, SM;Wani, MR
IL-4是调节骨稳态的重要免疫细胞因子。我们研究了IL-4作用于骨吸收成熟破骨细胞的分子机制。使用高度纯化的成熟破骨细胞群体，我们发现IL-4剂量依赖性地抑制成熟破骨细胞的NF-κ B配体受体激活剂（RANKL）诱导的骨吸收。我们检测到成熟破骨细胞中IL-4 R mRNA的存在。IL-4在不影响破骨细胞多核性的情况下降低TRAP表达，并抑制破骨细胞肌动蛋白环的形成和迁移。有趣的是，IL-4通过阻止RANKL诱导的p65 NF-κ B亚基核转位和细胞内Ca 2（+）变化抑制骨吸收。此外，IL-4迅速降低血液中RANKL刺激的离子化Ca 2（+）水平，并使其成熟。IL-4敲除小鼠中的破骨细胞对RANKL作用敏感，从而诱导骨吸收和高钙血症。此外，IL-4抑制人成熟破骨细胞的骨吸收和肌动蛋白环形成。因此，我们揭示了IL-4直接作用于成熟的破骨细胞，并通过抑制NF-κ B和Ca 2（+）信号传导来抑制骨吸收。
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-kappa B 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-kappa B subunit, and intracellular Ca2(+) changes. Moreover, IL-4 rapidly decreases RANKL-stimulated ionized Ca2(+) 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-kappa B and Ca2(+) signaling.