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首页> 外文期刊>Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research >Kruppel-like zinc finger protein Glis3 promotes osteoblast differentiation by regulating FGF18 expression.
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Kruppel-like zinc finger protein Glis3 promotes osteoblast differentiation by regulating FGF18 expression.

机译：Kruppel样锌指蛋白Glis3通过调节FGF18表达促进成骨细胞分化。

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摘要

The zinc finger protein Glis3 is highly expressed in human osteoblasts and acts synergistically with BMP2 and Shh in enhancing osteoblast differentiation in multipotent C3H10T1/2 cells. This induction of osteoblast differentiation is at least in part caused by the induction of FGF18 expression. This study supports a regulatory role for Glis3 in osteoblast differentiation. INTRODUCTION: Gli-similar 3 (Glis3) is closely related to members of the Gli subfamily of Kruppel-like zinc finger proteins, transcription factors that act downstream of sonic hedgehog (Shh). In this study, we analyzed the expression of Glis3 in human osteoblasts and mesenchymal stem cells (MSCs). Moreover, we examined the regulatory role of Glis3 in the differentiation of multipotent C3H10T1/2 cells into osteoblasts and adipocytes. MATERIALS AND METHODS: Microarray analysis was performed to identify genes regulated by Glis3 in multipotent C3H10T1/2 cells. Reporter and electrophoretic mobility shift assays were performed to analyze the regulation of fibroblast growth factor 18 (FGF18) by Glis3. RESULTS: Glis3 promotes osteoblast differentiation in C3H10T1/2 cells as indicated by the induction of alkaline phosphatase activity and increased expression of osteopontin, osteocalcin, and Runx2. In contrast, Glis3 expression inhibits adipocyte differentiation. Glis3 acts synergistically with BMP2 and Shh in inducing osteoblast differentiation. Deletion analysis indicated that the carboxyl-terminal activation function of Glis3 is needed for its stimulation of osteoblast differentiation. Glis3 is highly expressed in human osteoblasts and induced in MSCs during differentiation along the osteoblast lineage. Microarray analysis identified FGF18 as one of the genes induced by Glis3 in C3H10T1/2 cells. Promoter analysis and electrophoretic mobility shift assays indicated that a Glis3 binding site in the FGF18 promoter flanking region is important in its regulation by Glis3. CONCLUSIONS: Our study showed that Glis3 positively regulates differentiationof C3H10T1/2 cells into osteoblasts and inhibits adipocyte differentiation. Glis3 acts synergistically with BMP2 and Shh in inducing osteoblast differentiation. The promotion of osteoblast differentiation by Glis3 involves increased expression of FGF18, a positive regulator of osteogenesis. This, in conjunction with the induction of Glis3 expression during osteoblast differentiation in MSCs and its expression in osteoblasts, suggests that Glis3 is an important modulator of MSC differentiation.
机译：锌指蛋白Glis3在人成骨细胞中高表达，并与BMP2和Shh协同作用，增强多能C3H10T1 / 2细胞的成骨细胞分化。成骨细胞分化的这种诱导至少部分地由FGF18表达的诱导引起。这项研究支持Glis3在成骨细胞分化中的调节作用。简介：Gli-like 3（Glis3）与Kruppel样锌指蛋白的Gli亚家族成员密切相关，锌指蛋白是在声波刺猬（Shh）下游起作用的转录因子。在这项研究中，我们分析了人类成骨细胞和间充质干细胞（MSCs）中Glis3的表达。此外，我们检查了Glis3在将多能C3H10T1 / 2细胞分化为成骨细胞和脂肪细胞中的调节作用。材料与方法：进行了微阵列分析，以鉴定多能C3H10T1 / 2细胞中由Glis3调控的基因。进行了记者和电泳迁移率变动分析，以分析Glis3对成纤维细胞生长因子18（FGF18）的调节。结果：Glis3促进了C3H10T1 / 2细胞的成骨细胞分化，其表现为碱性磷酸酶活性的诱导和骨桥蛋白，骨钙素和Runx2表达的增加。相反，Glis3表达抑制脂肪细胞分化。 Glis3与BMP2和Shh协同作用，诱导成骨细胞分化。缺失分析表明，Glis3的羧基末端激活功能是其刺激成骨细胞分化所必需的。 Glis3在人类成骨细胞中高度表达，并在沿成骨细胞谱系分化期间在MSC中诱导。微阵列分析鉴定了FGF18是C3H10T1 / 2细胞中由Glis3诱导的基因之一。启动子分析和电泳迁移率变动分析表明，FGF18启动子侧翼区域中的Glis3结合位点在其通过Glis3调控中很重要。结论：我们的研究表明，Glis3积极调节C3H10T1 / 2细胞向成骨细胞的分化，并抑制脂肪细胞的分化。 Glis3与BMP2和Shh协同作用，诱导成骨细胞分化。 Glis3促进成骨细胞分化涉及增加FGF18（成骨作用的阳性调节剂）的表达。这与在MSC中成骨细胞分化期间诱导Glis3表达及其在成骨细胞中表达相结合，表明Glis3是MSC分化的重要调节剂。

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