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首页> 外文期刊>Journal of Cellular Physiology >Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor.
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Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor.

机译：Wnt诱导软骨细胞肥大Runx2转录因子。

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摘要

We investigated the molecular mechanisms underlying canonical Wnt-mediated regulation of chondrocyte hypertrophy using chick upper sternal chondrocytes. Replication competent avian sarcoma (RCAS) viral over-expression of Wnt8c and Wnt9a, upregulated type X collagen (col10a1) and Runx2 mRNA expression thereby inducing chondrocyte hypertrophy. Wnt8c and Wnt9a strongly inhibited mRNA levels of Sox9 and type II collagen (col2a1). Wnt8c further enhanced canonical bone morphogenetic proteins (BMP-2)-induced expression of Runx2 and col10a1 while Wnt8c and Wnt9a inhibited TGF-beta-induced expression of Sox9 and col2a1. Over-expression of beta-catenin mimics the effect of Wnt8c and Wnt9a by upregulating Runx2, col10a1, and alkaline phosphatase (AP) mRNA levels while it inhibits col2a1 transcription. Western blot analysis shows that Wnt8c and beta-catenin also induces Runx2 protein levels in chondrocytes. Thus, our results indicate that activation of the canonical beta-catenin Wnt signaling pathway induces chondrocyte hypertrophy and maturation. We further investigated the effects of beta-catenin-TCF/Lef on Runx2 promoter. Co-transfection of lymphoid enhancer factor (Lef1) and beta-catenin in chicken upper sternal chondrocytes together with deletion constructs of the Runx2 promoter shows that the proximal region spanning the first 128 base pairs of this promoter is responsible for the Wnt-mediated induction of Runx2. Mutation of the TCF/Lef binding site in the -128 fragment of the Runx2 promoter resulted in loss of its responsiveness to beta-catenin. Additionally, gel-shift assay analyses determined the DNA/protein interaction of the TCF/Lef binding sites on the Runx2 promoter. Finally, our site-directed mutagenesis data demonstrated that the Runx2 site on type X collagen promoter is required for canonical Wnt induction of col10a1. Altogether we demonstrate that Wnt/beta-catenin signaling is regulated by TGF-beta and BMP-2 in chick upper sternal chondrocytes, and mediates chondrocyte hypertrophy at least partlythrough activation of Runx2 which in turn may induce col10a1 expression.
机译：我们调查的分子机制基础规范Wnt-mediated监管使用小鸡上胸骨软骨细胞肥大软骨细胞。(rca)病毒表达Wnt8c Wnt9a,调节X型胶原蛋白(col10a1)和Runx2信使rna表达从而诱导软骨细胞肥大。信使rna的Sox9和II型胶原水平(col2a1)。全身的形态形成蛋白(BMP-2)表达式Runx2和col10a1而Wnt8c和Wnt9a抑制TGF-beta-induced表达Sox9col2a1。Wnt8c和Wnt9a通过移植的效果Runx2 col10a1,碱性磷酸酶(美联社)信使rna水平虽然抑制col2a1转录。Wnt8c和β-连环蛋白诱发Runx2蛋白质在软骨细胞水平。表明的激活规范β-连环蛋白Wnt信号通路诱导软骨细胞肥大和成熟。进一步调查的影响beta-catenin-TCF / Lef Runx2启动子。Co-transfection淋巴增强剂的因素(Lef1)和β-连环蛋白在鸡肉上胸骨软骨细胞一起删除的构造Runx2子显示近端地区跨越第一个128个碱基对发起人负责Wnt-mediatedRunx2的感应。结合位点在-128 Runx2的片段启动子导致损失的响应能力β-连环蛋白。分析DNA /蛋白质相互作用决定的TCF / Lef Runx2的结合位点启动子。数据表明,Runx2网站类型X胶原蛋白启动子需要规范Wntcol10a1的感应。Wnt /β-连环蛋白的信号是由及和BMP-2小鸡上胸骨软骨细胞和软骨细胞提供中介至少超自然激活肥大Runx2反过来可能诱发col10a1表达式。

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