Regulation of osteoclast differentiation and function by the CaMK-CREB pathway
Regulation of osteoclast differentiation and function by the CaMK-CREB pathway
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DOI：
10.1038/nm1515
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发表时间：
2006-12-01
期刊：
影响因子：
82.9
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Sato, Kojiro;Suematsu, Ayako;Takayanagi, Hiroshi
钙（Ca 2+）信号传导对于多种细胞反应和更高的生物学功能是必不可少的。Ca 2 +/钙调蛋白依赖性激酶（CaMK）和磷酸酶钙调磷酸酶激活不同的下游途径，这些途径分别由转录因子cAMP反应元件（CRE）结合蛋白（CREB）和活化T细胞核因子（NFAT）介导（1）。钙调神经磷酸酶-NFAT途径在骨代谢中的重要性已在破骨细胞、成骨细胞和软骨细胞中得到证实（2-5）。然而，对CaMK-CREB通路的贡献知之甚少，部分原因是难以剖析同源家族成员的功能（6-8）。在这里，我们表明，CaMKIV-CREB通路是破骨细胞分化和功能的关键。CaMK的药理学抑制以及Camk 4的基因消融减少了CREB磷酸化并下调了c-Fos的表达，这是诱导NFATc 1（破骨细胞生成的主转录因子（2，3））所必需的，NFATc 1由NF-κ B配体（RANKL）的受体激活剂激活。此外，CREB与NFATc 1一起诱导分化的破骨细胞表达的特异性基因的表达。因此，CaMK-CREB通路双相作用，不仅通过增强NFATc 1的诱导，而且一旦其表达被诱导，还通过促进NFATc 1依赖性基因调控来调节骨细胞骨吸收的转录程序。这为骨疾病的新治疗策略提供了分子基础。
Calcium (Ca2+) signaling is essential for a variety of cellular responses and higher biological functions. Ca2+/calmodulin-dependent kinases (CaMKs) and the phosphatase calcineurin activate distinct downstream pathways that are mediated by the transcription factors cAMP response element (CRE)-binding protein ( CREB) and nuclear factor of activated T cells ( NFAT), respectively(1). The importance of the calcineurin-NFAT pathway in bone metabolism has been demonstrated in osteoclasts, osteoblasts and chondrocytes(2-5). However, the contribution of the CaMK-CREB pathway is poorly understood, partly because of the difficulty of dissecting the functions of homologous family members(6-8). Here we show that the CaMKIV-CREB pathway is crucial for osteoclast differentiation and function. Pharmacological inhibition of CaMKs as well as the genetic ablation of Camk4 reduced CREB phosphorylation and downregulated the expression of c-Fos, which is required for the induction of NFATc1 ( the master transcription factor for osteoclastogenesis(2,3)) that is activated by receptor activator of NF-kappa B ligand ( RANKL). Furthermore, CREB together with NFATc1 induced the expression of specific genes expressed by differentiated osteoclasts. Thus, the CaMK-CREB pathway biphasically functions to regulate the transcriptional program of osteoclastic bone resorption, by not only enhancing induction of NFATc1 but also facilitating NFATc1-dependent gene regulation once its expression is induced. This provides a molecular basis for a new therapeutic strategy for bone diseases.