Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3.
Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3.
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DOI：
10.1038/s41598-018-31853-0
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发表时间：
2018-09-10
影响因子：
4.6
通讯作者：
Komori T
中科院分区：
文献类型：
--
作者：
Kawane T;Qin X;Jiang Q;Miyazaki T;Komori H;Yoshida CA;Matsuura-Kawata VKDS;Sakane C;Matsuo Y;Nagai K;Maeno T;Date Y;Nishimura R;Komori T
Runx 2和Sp 7是成骨细胞分化所必需的转录因子。然而，成骨细胞祖细胞增殖的分子机制仍不清楚。Runx 2表达的早期发作通过Runx 2对Fgfr 1 -3的调节引起肢体缺陷。为了研究Runx 2在Fgfr 1 -3调节中的生理作用，我们比较了Sp 7 −/−和Runx 2 −/−小鼠中的成骨祖细胞。成骨细胞祖细胞在Sp 7 −/−小鼠的颅骨和下颌骨中积累并活跃增殖，但在Runx 2 −/−小鼠中没有，成骨细胞祖细胞的数量及其增殖依赖于Sp 7 −/−背景下Runx 2的基因剂量。负责成骨祖细胞增殖的Fgfr 2和Fgfr 3的表达在Runx 2 −/−颅骨中严重减少，但在Sp 7 −/−颅骨中没有。Runx 2直接调节Fgfr 2和Fgfr 3，增加成骨祖细胞的增殖，并增强FGF 2诱导的增殖。Sp 7 −/−成骨祖细胞的增殖被FGF 2增强并强烈增强，Runx 2敲低降低了FGF 2诱导的增殖。Fgfr抑制剂AZD 4547消除了所有增强的增殖。这些结果表明Runx 2是成骨祖细胞增殖所必需的，并且至少部分地通过调节Fgfr 2和Fgfr 3表达来诱导增殖。
Runx2 and Sp7 are essential transcription factors for osteoblast differentiation. However, the molecular mechanisms responsible for the proliferation of osteoblast progenitors remain unclear. The early onset of Runx2 expression caused limb defects through the Fgfr1–3 regulation by Runx2. To investigate the physiological role of Runx2 in the regulation of Fgfr1–3, we compared osteoblast progenitors in Sp7−/− and Runx2−/− mice. Osteoblast progenitors accumulated and actively proliferated in calvariae and mandibles of Sp7−/− but not of Runx2−/− mice, and the number of osteoblast progenitors and their proliferation were dependent on the gene dosage of Runx2 in Sp7−/− background. The expression of Fgfr2 and Fgfr3, which were responsible for the proliferation of osteoblast progenitors, was severely reduced in Runx2−/− but not in Sp7−/− calvariae. Runx2 directly regulated Fgfr2 and Fgfr3, increased the proliferation of osteoblast progenitors, and augmented the FGF2-induced proliferation. The proliferation of Sp7−/− osteoblast progenitors was enhanced and strongly augmented by FGF2, and Runx2 knockdown reduced the FGF2-induced proliferation. Fgfr inhibitor AZD4547 abrogated all of the enhanced proliferation. These results indicate that Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation, at least partly, by regulating Fgfr2 and Fgfr3 expression.
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