Department of Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan.
Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8588, Japan.
Sci Rep. 2018 Sep 10;8(1):13551. doi: 10.1038/s41598-018-31853-0.
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.
Runx2 和 Sp7 是成骨细胞分化的必需转录因子。然而，负责成骨细胞前体细胞增殖的分子机制仍不清楚。Runx2 早期表达会通过 Runx2 对 Fgfr1-3 的调节导致肢体缺陷。为了研究 Runx2 在 Fgfr1-3 调节中的生理作用，我们比较了 Sp7 和 Runx2 小鼠中的成骨细胞前体细胞。成骨细胞前体细胞在 Sp7 而不是 Runx2 小鼠的颅骨和下颌骨中积累并积极增殖，并且成骨细胞前体细胞的数量及其增殖依赖于 Sp7 背景中 Runx2 的基因剂量。负责成骨细胞前体细胞增殖的 Fgfr2 和 Fgfr3 的表达在 Runx2 中严重降低，但在 Sp7 颅骨中没有降低。Runx2 直接调节 Fgfr2 和 Fgfr3，增加成骨细胞前体细胞的增殖，并增强 FGF2 诱导的增殖。FGF2 增强了 Sp7 成骨细胞前体细胞的增殖，并强烈增强了其增殖，而 Runx2 敲低减少了 FGF2 诱导的增殖。Fgfr 抑制剂 AZD4547 阻断了所有增强的增殖。这些结果表明，Runx2 是成骨细胞前体细胞增殖所必需的，并通过调节 Fgfr2 和 Fgfr3 的表达至少部分地诱导增殖。
