Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3

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.