Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-κB signaling pathways
Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-κB signaling pathways
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DOI：
10.1074/jbc.m607999200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Ebisu, Shigeyuki
中科院分区：
文献类型：
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作者：
Yoshitake, Fumio;Itoh, Shousaku;Ebisu, Shigeyuki
白细胞介素-6（IL-6）是由多种细胞产生的多功能细胞因子，用于调节造血、炎症、免疫应答和骨稳态。还已知IL-6调节成骨细胞和破骨细胞的分化。IL-6被认为通过诱导成骨细胞表面NF-κ B配体受体激活剂（RANKL）的表达在破骨细胞分化中发挥积极的调节作用：RANKL然后与破骨细胞祖细胞上表达的RANK相互作用，通过RANK信号通路诱导破骨细胞分化，该通路涉及NF-κ B、JNK和p38。在这份报告中，我们证明IL-6也可以直接作用于破骨细胞祖细胞，通过抑制RANK信号通路抑制其分化。IL-6特异性抑制RANK介导的I κ B降解和JNK活化。微阵列分析显示，IL-6和RANKL共刺激上调MKP 1和MKP 7的转录，其编码使JNK去磷酸化的酶，并下调与泛素途径相关的Senp 2和Cul 4A的转录。因此，IL-6直接作用于破骨细胞祖细胞并通过调节与MAPK磷酸酶和泛素途径相关的特异性基因的转录来抑制其分化。
Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cells to regulate hematopoiesis, inflammation, immune responses, and bone homeostasis. IL-6 is also known to modulate the differentiation of osteoblasts and osteoclasts. IL-6 is believed to play a positive regulatory role in osteoclast differentiation by inducing the expression of receptor activator of NF-kappa B ligand ( RANKL) on the surface of osteoblasts: RANKL then interacts with RANK expressed on osteoclast progenitors, inducing osteoclast differentiation via the RANK signaling pathway, which involves NF-kappa B, JNK, and p38. In this report, we demonstrate that IL-6 can also directly act on osteoclast progenitors to suppress their differentiation via an inhibition of RANK signaling pathways. IL-6 specifically suppressed RANK-mediated I kappa B degradation and JNK activation. Microarray analysis revealed that costimulation with IL-6 and RANKL up-regulates the transcription of MKP1 and MKP7, which encode enzymes that dephosphorylate JNK, and down-regulates the transcription of Senp2 and Cul4A, which are related to the ubiquitin pathway. Thus, IL-6 directly acts on osteoclast progenitors and suppresses their differentiation by regulating the transcription of specific genes related to MAPK phosphatases and the ubiquitin pathway.