IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-κB (RANK) expression in myeloid precursor cells
IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-κB (RANK) expression in myeloid precursor cells
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DOI：
10.1002/eji.200838192
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发表时间：
2008-10-01
影响因子：
5.4
通讯作者：
Aeschlimann, Daniel
中科院分区：
文献类型：
--
作者：
Chen, Li;Wei, Xiao-Qing;Aeschlimann, Daniel
炎症介导的骨丢失是包括类风湿性关节炎、骨关节炎和晚期牙周炎在内的各种骨疾病的主要特征。炎症部位破骨细胞发育或活性增强导致骨吸收。 IL-23 是一种属于 IL-6/IL-12 家族的异二聚体细胞因子，与类风湿性关节炎的发病机制有关，并被证明通过刺激 IL-17 的产生在破骨细胞生成中发挥作用。在本研究中，我们研究了 IL-23 是否有助于独立于 IL-17 途径调节破骨细胞分化。我们发现，IL-23 剂量依赖性上调原代小鼠骨髓巨噬细胞和 RAW264.7 细胞中 NF-κ B 受体激活剂的表达，从而促进骨髓前体细胞对 NF-κ B 受体激活剂配体介导的破骨细胞分化的定向。然而，IL-23 本身不足以诱导破骨细胞生成。细胞破骨细胞分化的增加与组织蛋白酶 K 表达和牙本质吸收的增强相关，表明功能性破骨细胞的形成增强。在培养物上清液中未检测到 IL-17，并且当添加到培养物中时，不会促进 RAW264.7 细胞的分化。这些结果表明，IL-23 除了间接刺激成骨细胞中 NF-κ B 配体受体激活剂的产生外，还可以直接作用于骨髓前体细胞，并解释了其在炎症介导的骨病理学中驱动破骨细胞发育的效力。
Inflammation-mediated bone loss is a major feature of various bone diseases including rheumatoid arthritis, osteoarthritis and advanced periodontitis. Enhanced osteoclast development or activity at the inflammation site results in bone resorption. IL-23 is a heterodimeric cytokine belonging to the IL-6/IL-12 family that has been implicated in the pathogenesis of rheumatoid arthritis and demonstrated to play a role in osteoclastogenesis via stimulation of IL-17 production. in this study we investigated whether IL-23 contributes to the regulation of osteoclast differentiation independent of the IL-17 pathway. We show that IL-23 dose-dependently up-regulates receptor activator of NF-kappa B expression in primary murine bone marrow macrophages and RAW264.7 cells and thereby promotes commitment of myeloid precursor cells to receptor activator of NF-kappa B ligand-mediated osteoclastic differentiation. However, IL-23 by itself is insufficient to induce osteoclastogenesis. increased osteoclastic differentiation of cells was associated with enhanced cathepsin K expression and dentine resorption indicating enhanced formation of functional osteoclasts. IL-17 was not detectable in culture supernatants and when added to cultures, did not promote differentiation of RAW264.7 cells. These results demonstrate that IL-23 can act directly on myeloid precursor cells in addition to indirectly stimulating receptor activator of NF-kappa B ligand production in osteoblasts and explains its potency in driving osteoclast development in inflammation-mediated bone pathology.