Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells
Connective tissue growth factor (CTGF) is regulated by Wnt and bone morphogenetic proteins signaling in osteoblast differentiation of mesenchymal stem cells
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DOI：
10.1074/jbc.m407810200
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发表时间：
2004-12-31
影响因子：
4.8
通讯作者：
He, TC
中科院分区：
文献类型：
--
作者：
Luo, Q;Kang, Q;He, TC
间充质干细胞的成骨细胞系特异性分化是一个调控良好但知之甚少的过程。骨形态发生蛋白(BMPs)和Wnt信号都参与了成骨细胞分化和骨形成的调节。在这里，我们分析了Wnt3a和成骨BMPs刺激的间充质干细胞的表达谱，并确定结缔组织生长因子(CTGF)是Wnt和BMP信号的潜在靶点。我们证实了微阵列的结果，我们证明了CTGF在BMP-9和Wnt3a刺激的早期阶段上调，并且Wnt3a调节的CTGF的表达是β-连环蛋白依赖性的。RNA干扰介导的CTGF表达下调可显著抑制BMP-9诱导的成骨分化，但不影响Wnt3a诱导的成骨分化，提示Wnt3a也可能以非CTGF依赖的方式调节成骨细胞的分化。然而，CTGF的结构性表达显示抑制BMP-9和WNT3a诱导的成骨分化。外源性表达CTGF可促进间充质干细胞的迁移和募集。我们的研究结果表明，在成骨分化的早期，CTGF被Wnt3a和BMP-9上调，这可能调节了成骨前体细胞的增殖和募集；但随着承诺的前成骨细胞分化潜能的增加，CTGF的表达下调，强烈表明严格调控CTGF的表达可能对间充质干细胞的正常成骨分化至关重要。
Osteoblast lineage-specific differentiation of mesenchymal stem cells is a well regulated but poorly understood process. Both bone morphogenetic proteins (BMPs) and Wnt signaling are implicated in regulating osteoblast differentiation and bone formation. Here we analyzed the expression profiles of mesenchymal stem cells stimulated with Wnt3A and osteogenic BMPs, and we identified connective tissue growth factor (CTGF) as a potential target of Wnt and BMP signaling. We confirmed the microarray results, and we demonstrated that CTGF was up-regulated at the early stage of BMP-9 and Wnt3A stimulations and that Wnt3A-regulated CTGF expression was beta-catenin-dependent. RNA interference-mediated knockdown of CTGF expression significantly diminished BMP-9-induced, but not Wnt3A-induced, osteogenic differentiation, suggesting that Wnt3A may also regulate osteoblast differentiation in a CTGF-independent fashion. However, constitutive expression of CTGF was shown to inhibit both BMP-9- and Wnt3A-induced osteogenic differentiation. Exogenous expression of CTGF was shown to promote cell migration and recruitment of mesenchymal stem cells. Our findings demonstrate that CTGF is up-regulated by Wnt3A and BMP-9 at the early stage of osteogenic differentiation, which may regulate the proliferation and recruitment of osteoprogenitor cells; however, CTGF is down-regulated as the differentiation potential of committed pre-osteoblasts increases, strongly suggesting that tight regulation of CTGF expression may be essential for normal osteoblast differentiation of mesenchymal stem cells.