Kim Jung Ha, Jin Hye Mi, Kim Kabsun, Song Insun, Youn Bang Ung, Matsuo Koichi, Kim Nacksung
National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Brain Korea 21, Chonnam National University Medical School, Gwangju, Korea.
J Immunol. 2009 Aug 1;183(3):1862-70. doi: 10.4049/jimmunol.0803007. Epub 2009 Jul 8.
IL-1 is a potent cytokine that can induce bone erosion in inflammatory sites such as rheumatoid joint regions via activation of osteoclasts. Not only is IL-1 capable of activating osteoclasts, but it is also a key cytokine involved in the differentiation, multinucleation, and survival of osteoclasts. Herein, we show that IL-1 has the potential to drive osteoclast differentiation via a receptor activator of NF-kappaB ligand (RANKL)/RANK-independent mechanism. Although IL-1 has a synergistic effect on RANKL-induced osteoclast formation, IL-1 alone cannot induce osteoclast differentiation from osteoclast precursors (bone marrow-derived macrophages (BMMs)) due to a lack of IL-1 signaling potential in these cells. However, we demonstrate that overexpression of the IL-1RI receptor in BMMs or induction of IL-1RI by c-Fos overexpression enables IL-1 alone to induce the formation of authentic osteoclasts by a RANKL/RANK-independent mechanism. The expression of IL-1RI is up-regulated by RANKL via c-Fos and NFATc1. Furthermore, the addition of IL-1 to IL-1RI overexpressing BMMs (IL-1/IL-1RI) strongly activates NF-kappaB, JNK, p38, and ERK which is a hallmark gene activation profile of osteoclastogenesis. Interestingly, IL-1/IL-1RI does not induce expression of c-Fos or NFATc1 during osteoclast differentiation, although basal levels of c-Fos and NFATc1 seem to be required. Rather, IL-1/IL-1RI strongly activates MITF, which subsequently induces osteoclast-specific genes such as osteoclast-associated receptor and tartrate-resistant acid phosphatase. Together, these results reveal that IL-1 has the potential to induce osteoclast differentiation via activation of microphthalmia transcription factor under specific microenvironmental conditions.
白细胞介素-1（IL-1）是一种强效细胞因子，可通过激活破骨细胞，在类风湿关节区域等炎症部位诱导骨侵蚀。IL-1不仅能够激活破骨细胞，还是参与破骨细胞分化、多核化和存活的关键细胞因子。在此，我们表明IL-1有潜力通过核因子κB受体活化因子配体（RANKL）/RANK非依赖机制驱动破骨细胞分化。尽管IL-1对RANKL诱导的破骨细胞形成有协同作用，但由于这些细胞中缺乏IL-1信号传导潜力，单独的IL-1不能诱导破骨细胞前体（骨髓来源的巨噬细胞（BMMs））分化为破骨细胞。然而，我们证明在BMMs中过表达IL-1RI受体或通过c-Fos过表达诱导IL-1RI，能使单独的IL-1通过RANKL/RANK非依赖机制诱导真正破骨细胞的形成。RANKL通过c-Fos和活化T细胞核因子c1（NFATc1）上调IL-1RI的表达。此外，将IL-1添加到过表达IL-1RI的BMMs（IL-1/IL-1RI）中可强烈激活核因子κB、应激活化蛋白激酶（JNK）、p38和细胞外信号调节激酶（ERK），这是破骨细胞生成的标志性基因激活谱。有趣的是，在破骨细胞分化过程中，IL-1/IL-1RI不会诱导c-Fos或NFATc1的表达，尽管似乎需要c-Fos和NFATc1的基础水平。相反，IL-1/IL-1RI强烈激活小眼畸形相关转录因子（MITF），随后诱导破骨细胞特异性基因，如破骨细胞相关受体和抗酒石酸酸性磷酸酶。总之，这些结果表明，在特定微环境条件下，IL-1有潜力通过激活小眼畸形转录因子诱导破骨细胞分化。
