Hand2 regulates chondrogenesis in vitro and in vivo
Hand2 regulates chondrogenesis in vitro and in vivo
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DOI：
10.1016/j.bone.2009.11.022
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发表时间：
2010-05-01
期刊：
影响因子：
4.1
通讯作者：
Wakisaka, Satoshi
中科院分区：
文献类型：
--
作者：
Abe, Makoto;Michikami, Ikumi;Wakisaka, Satoshi
Hand 2是一个基本的螺旋-环-螺旋家族的转录因子，在发育过程中发挥重要作用。Hand 2在肢体发育过程中决定前后轴，也有大量证据表明Hand 2调节肢体骨骼发生。然而，关于Hand 2如何调节骨骼发生知之甚少。在这里，我们表明，在肢芽微团培养系统中，Hand 2的过度表达抑制软骨形成和软骨细胞基因，Sox 9，II型胶原蛋白和聚集蛋白聚糖的表达。此外，我们表明，Hand 2是由典型的Wnt信号，强烈抑制软骨形成的激活诱导。令人惊讶的是，Hand 2抑制软骨形成的DNA结合和二聚体形成独立的方式。为了研究Hand 2在小鼠体内的作用，我们使用来自胶原II基因的调控元件将Hand 2的表达靶向软骨。由此产生的转基因小鼠表现出侏儒表型，具有轴向、无骨和颅面骨骼畸形。Hand 2强烈抑制中轴和颅底骨骼中的软骨形成。在胸骨上。Hand 2通过延缓软骨细胞成熟抑制软骨内骨化。这些数据支持Hand 2通过至少两个步骤调节软骨内骨化的模型：（1）通过勾勒未来软骨模板的区域来确定软骨发生的位点和（2）调节软骨细胞成熟的速率。(C)2009 Elsevier Inc. All rights reserved.
Hand2 is a transcription factor of the basic helix-loop-helix family that plays essential roles during development. Hand2 determines the anterior-posterior axis during limb development and there is also substantial evidence that Hand2 regulates limb skeletogenesis. However, little is known about how Hand2 might regulate skeletogenesis. Here we show that, in a limb bud micromass culture system, over-expression of Hand2 represses chondrogenesis and the expression of chondrocytic genes, Sox9, type II collagen and aggrecan. Furthermore, we show that Hand2 is induced by the activation of canonical Wnt signaling, which strongly represses chondrogenesis. Surprisingly, Hand2 repressed chondrogenesis in a DNA binding- and dimer formation-independent manner. To examine the in vivo role of Hand2 in mice, we targeted the expression of Hand2 to the cartilage using regulatory elements from the collagen II gene. The resulting transgenic mice displayed a dwarf phenotype, with axial, appendicular and craniofacial skeletal deformities. Hand2 strongly inhibited chondrogenesis in the axial and cranial base skeleton. In the sternum. Hand2 inhibited endochondral ossification by slowing chondrocyte maturation. These data support a model of Hand2 regulating endochondral ossification via at least two steps: (1) determination of the site of chondrogenesis by outlining the region of the future cartilage template and (2) regulation of the rate of chondrocyte maturation. (C) 2009 Elsevier Inc. All rights reserved.