Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation.
Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation.
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DOI：
10.1002/jbmr.2287
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发表时间：
2014-12
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影响因子：
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通讯作者：
Javed A
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文献类型：
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作者：
Chen H;Ghori-Javed FY;Rashid H;Adhami MD;Serra R;Gutierrez SE;Javed A
软骨细胞合成软骨是软骨内骨化的必经步骤。Runx 2基因的整体缺失导致骨化过程完全失败，但其潜在的细胞和分子机制尚不完全清楚。在这里，我们阐明Runx 2的监管控制独特的软骨细胞和软骨组织产生Runx 2外显子8 floxed小鼠。软骨细胞中Runx 2的缺失导致软骨内骨化失败和出生时的死亡。Runx 2 ΔE8/ΔE8小鼠的四肢缺乏成熟的软骨细胞、脉管系统和骨髓。我们证明了Runx 2的C-末端驱动其生物活性。重要的是，Runx 2的核输入和DNA结合功能不足以进行软骨形成。分子研究表明，尽管Sox 9和PTHrP水平正常，但Runx 2 ΔE8/ΔE8小鼠的软骨细胞分化和软骨生长受到破坏。软骨细胞中Runx 2的缺失也损害了OPG-RANKL信号传导和破软骨细胞发育。Runx 2突变体中观察到的侏儒症与生长板中几乎不存在增殖区有关。最后，我们表明Runx 2直接调节一组独特的细胞周期基因Gpr 132，Sfn，c-Myb和Cyclin A1来控制软骨细胞的增殖能力。因此，Runx 2对于软骨细胞的增殖和分化都是必需的。
Synthesis of cartilage by chondrocytes is an obligatory step for endochondral ossification. Global deletion of the Runx2 gene results in complete failure of the ossification process, but the underlying cellular and molecular mechanisms are not fully known. Here, we elucidated Runx2 regulatory control distinctive to chondrocyte and cartilage tissue by generating Runx2 exon 8 floxed mice. Deletion of Runx2 in chondrocytes caused failure of endochondral ossification and lethality at birth. The limbs of Runx2ΔE8/ΔE8 mice were devoid of mature chondrocytes, vasculature, and marrow. We demonstrate that the C-terminus of Runx2 drives its biological activity. Importantly, nuclear import and DNA binding functions of Runx2 are insufficient for chondrogenesis. Molecular studies revealed that despite normal level of Sox9 and PTHrP, chondrocyte differentiation and cartilage growth is disrupted in Runx2ΔE8/ΔE8 mice. Loss of Runx2 in chondrocytes also impaired OPG-RANKL signaling and chondroclast development. Dwarfism observed in Runx2 mutants was associated with the near absence of proliferative zone in the growth plates. Finally, we show Runx2 directly regulates a unique set of cell cycle genes Gpr132, Sfn, c-Myb, and Cyclin A1 to control proliferative capacity of chondrocyte. Thus, Runx2 is obligatory for both proliferation and differentiation of chondrocytes.