Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts
Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts
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DOI：
10.1016/s1534-5807(02)00369-6
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发表时间：
2002-12-01
影响因子：
11.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
--
作者：
Takayanagi, H;Kim, S;Taniguchi, T
RANKL 信号传导对于单核细胞/巨噬细胞最终分化为破骨细胞至关重要。 TRAF6 和 c-Fos 信号通路均在 RANKL 下游发挥重要作用。我们在此表明 RANKL 通过这两条途径选择性诱导 NFATc1 表达。 RANKL 还会引起 Call 振荡，从而导致钙调神经磷酸酶介导的 NFATc1 激活，从而在破骨细胞分化过程中触发持续的 NFATc1 依赖性转录程序。我们还表明，NFATc1 缺陷的胚胎干细胞无法响应 RANKL 刺激而分化为破骨细胞，并且 NFATc1 的异位表达导致前体细胞在没有 RANKL 信号传导的情况下进行有效分化。因此，NFATc1 可能代表调节破骨细胞终末分化的主开关，在 RANKL 下游发挥作用。
Signaling by RANKL is essential for terminal differentiation of monocytes/macrophages into osteoclasts. The TRAF6 and c-Fos signaling pathways both play important roles downstream of RANKL. We show here that RANKL selectively induces NFATc1 expression via these two pathways. RANKL also evokes Call oscillations that lead to calcineurin-mediated activation of NFATc1, and therefore triggers a sustained NFATc1 dependent transcriptional program during osteoclast differentiation. We also show that NFATc1-deficient embryonic stem cells fail to differentiate into osteoclasts in response to RANKL stimulation, and that ectopic expression of NFATc1 causes precursor cells to undergo efficient differentiation without RANKL signaling. Thus, NFATc1 may represent a master switch for regulating terminal differentiation of osteoclasts, functioning downstream of RANKL.