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首页> 外文期刊>Cellular Signalling >MHC class II transactivator negatively regulates RANKL-mediated osteoclast differentiation by downregulating NFATc1 and OSCAR
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MHC class II transactivator negatively regulates RANKL-mediated osteoclast differentiation by downregulating NFATc1 and OSCAR

机译：MHC II类反式激活因子通过下调NFATc1和OSCAR负调控RANKL介导的破骨细胞分化

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摘要

Nuclear factor of activated T cells (NFAT) c1 plays a key role in receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast differentiation and function via induction of osteoclast-specific target genes including osteoclast-associated receptor (OSCAR), cathepsin K, and tartrate-resistant acid phosphatase. To elucidate which downstream target genes are regulated by NFATc1 during osteoclastogenesis, we used microarray analyses to examine gene expression profiles in the context of bone marrow-derived macrophages overexpressing a constitutively active form of NFATc1. Herein, we demonstrate that MHC class II transactivator (CIITA) is up-regulated downstream of NFATc1. Overexpression of CIITA in osteoclast precursors attenuates RANKL-induced osteoclast formation through down-regulation of NFATc1 and OSCAR. Epigenetic overexpression of CIITA regulates NFATc1 and OSCAR by competing with c-Fos and NFATc1 for CBP/p300 binding sites. Furthermore, silencing of CIITA by RNA interference in osteoclast precursors enhances osteoclast formation as well as NFATc1 and OSCAR expression. Taken together, our data reveal that CIITA can act as a modulator of RANKL-induced osteoclastogenesis.
机译：活化T细胞（NFAT）c1的核因子在核因子κB配体（RANKL）诱导的破骨细胞分化的受体激活剂中起关键作用，并通过诱导破骨细胞特异性靶基因（包括破骨细胞相关受体（OSCAR），组织蛋白酶K）发挥作用和抗酒石酸酸性磷酸酶。为了阐明破骨细胞形成过程中哪些下游靶基因受NFATc1调控，我们使用微阵列分析来检查在过度表达NFATc1组成型活性形式的骨髓巨噬细胞中的基因表达谱。在这里，我们证明了MHC II类反式激活因子（CIITA）在NFATc1下游被上调。破骨细胞前体中CIITA的过表达通过下调NFATc1和OSCAR来减弱RANKL诱导的破骨细胞形成。 CIITA的表观遗传过表达通过与c-Fos和NFATc1竞争CBP / p300结合位点来调节NFATc1和OSCAR。此外，通过破骨细胞前体中RNA干扰使CIITA沉默，可增强破骨细胞形成以及NFATc1和OSCAR表达。两者合计，我们的数据表明CIITA可以作为RANKL诱导的破骨细胞生成的调节剂。

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