Bone Cell Growth Regulation by Runx2/Cbfa1

描述(由申请人提供)：严格控制间充质细胞、骨祖细胞和未成熟成骨细胞的增殖扩张是正常骨骼发育和骨形成的关键。矿化骨骼的形成需要矮小相关的转录因子RUNX2/CBFA1，但新的证据表明，其生物学功能超出了成骨细胞成熟的范围。我们的中心假设是RUNX2/CBFA1是成骨细胞增殖的主要调节因子。这一假设将通过调查三个相关问题来解决。首先，RUNX2蛋白的失活是否在遗传上影响骨祖细胞的生长参数(目标1)？这项拟议的研究将检验RUNX2失活是否会改变RUNX2缺陷的头盖骨细胞的生长特征，以及重新引入RUNX2是否会恢复正常的细胞生长控制。第二，RUNX2的哪个转录辅助调节因子介导其成骨细胞增殖相关的生物学功能(目标2)？Runx2与调节其基因调控活性的几个不同的辅助因子相互作用。为了解决这个问题，将描述与RUNX2一起介导骨细胞生长调节的关键协同调节因子。第三，哪些受RUNX2调控的基因有助于成骨细胞的生长控制(目标3)？这个问题将通过确定RUNX2的下游靶基因来解决，这些基因与RUNX2一起调节RUNX2的增殖相关调节特性。这些研究的结果将为RUNX2依赖的分子机制和控制成骨细胞增殖的基因调控程序提供关键的见解。了解骨细胞生长受控的机制，可以控制其细胞生长潜能，用于骨科疾病、骨折和/或骨定向基因治疗的临床应用。

DESCRIPTION (provided by applicant): Stringent positive and negative control of the proliferative expansion of mesenchymal cells, osteoprogenitor cells and immature osteoblasts is critical for normal skeletal development and bone formation. Formation of a mineralized skeleton requires the runt-related transcription factor RUNX2/CBFA1, but new evidence indicates that its biological function extends beyond that in osteoblast maturation. Our central hypothesis is that RUNX2/CBFA1 is a principal regulator of osteoblast proliferation. This hypothesis will be addressed by investigating three related questions. First, does inactivation of the RUNX2 protein genetically influence cell growth parameters in osteoprogenitors (Aim 1)? The proposed studies will examine whether inactivation of RUNX2 alters cell growth characteristics of RUNX2 deficient calvarial cells, and whether re-introduction of RUNX2 restores normal cell growth control. Second, which transcriptional co-regulator of RUNX2 mediates its osteoblast proliferation-related biological functions (Aim 2)? RUNX2 interacts with several distinct co-factors that modulate its gene regulatory activity. To address this question, the critical co-regulatory factor that together with RUNX2 mediates bone cell growth regulation will be characterized. Third, which RUNX2 regulated genes contribute to growth control of osteogenic cells (Aim 3)? This question will be addressed by identifying downstream target genes of RUNX2 that together with RUNX2 mediate the proliferation-related regulatory properties of RUNX2. The results of these studies will provide key insights into the RUNX2 dependent molecular mechanisms and gene regulatory programs that control osteoblast proliferation. Understanding the mechanisms by which growth of osseous cells is controlled may permit manipulation of their cell growth potential for clinical applications in the treatment of skeletal diseases, bone fractures and/or bone-directed gene therapy.