Cbfβ regulates Runx2 function isoform-dependently in postnatal bone development
Cbfβ regulates Runx2 function isoform-dependently in postnatal bone development
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DOI：
10.1016/j.ydbio.2006.03.039
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发表时间：
2006-08-01
影响因子：
2.7
通讯作者：
Komori, Toshihisa
中科院分区：
文献类型：
--
作者：
Kanatani, Naoko;Fujita, Takashi;Komori, Toshihisa
Runx 2和Cbf β在胚胎阶段对骨骼发育至关重要。Runx 2有两种具有不同N-末端的同种型。我们研究了Runx 2亚型和Cbf β在出生后骨发育中的功能。在荧光素酶和电泳迁移率变动测定中，Runx 2-I在不存在Cbfb的情况下活性低于Runx 2-II，但两种Runx 2亚型在存在Cbfb的情况下具有相似的活性水平。我们建立了Colla 1启动子控制下的Runx 2-I转基因小鼠和Runx 2-I/Cbfb和Runx 2-II/Cbfb双转基因小鼠。Runx 2-I转基因小鼠表现出比Runx 2-II转基因小鼠更轻的骨量减少和脆性，这是由于对成骨细胞成熟和向骨细胞转化的抑制更温和，尽管前者小鼠表现出更高的转基因表达。然而，Runx 2-I/Cbfb和Runx 2-II/Cbfb双转基因小鼠对成骨细胞成熟的抑制作用增强，导致骨质减少和脆性的严重程度相似，尽管后者小鼠的骨细胞较少。这些发现表明：（1）Runx 2-II比Runx 2-I更强烈地抑制成骨细胞成熟和向骨细胞转化;（2）Cbf β依赖性地调节Runx 2功能亚型;（3）Runx 2-I活性高度依赖于Cbf β。这些发现表明Runx 2亚型通过至少部分不同的机制发挥其功能，并且Cbf β通过依赖性地调节Runx 2功能亚型来调节骨发育。(c)2006年爱思唯尔公司All rights reserved.
Runx2 and Cbf beta are essential for skeletal development during the embryonic stage. Runx2 has two isoforms with different N-termini. We examined the functions of the Runx2 isoforms and Cbf beta in postnatal bone development. On luciferase and electrophoretic mobility shift assays, Runx2-I was less active than Runx2-II in the absence of Cbfb, but the two Runx2 isoforms had similar activity levels in the presence of Cbfb. We generated Runx2-I transgenic mice under the control of Colla1 promoter and Runx2-I/Cbfb and Runx2-II/Cbfb double transgenic mice. Runx2-I transgenic mice showed less severe osteopenia and fragility than Runx2-II transgenic mice due to milder inhibition of both osteoblast maturation and transition to osteocytes, even though the former mice showed higher transgene expression. However, Runx2-I/Cbfb and Runx2-II/Cbfb double transgenic mice had enhanced inhibition of osteoblast maturation, resulting in similar severity of osteopenia and fragility, although the latter mice had less osteocytes. These findings indicate that (1) Runx2-II more strongly inhibits osteoblast maturation and transition to osteocytes than Runx2-I;(2) Cbf beta regulates Runx2 function isoform-dependently; and (3) Runx2-I activity is highly dependent on Cbf beta. These findings demonstrate that Runx2 isoforms exert their functions through at least partly different mechanisms and Cbf beta regulates bone development by regulating Runx2 function isoform-dependently. (c) 2006 Elsevier Inc. All rights reserved.