Genetic Control of Osteoblast Differentiation

成骨细胞分化的遗传控制

• 批准号: 6944901
• 负责人: Benoit de Crombrugghe
• 金额: $ 42.39万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944901
• 关键词: SDS polyacrylamide gel electrophoresis; binding sites; bone development; cell differentiation; cell line; chondrocytes; collagen; gel mobility shift assay; gene expression; gene induction /repression; genetically modified animals; human tissue; laboratory mouse; microarray technology; northern blottings; osteoblasts; osteocalcin; protein binding; protein structure function; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): Similarly to the formation of other organs, skeletogenesis involves two broad classes of regulatory factors. Patterning factors control the shape, size and number of skeletal element, as well as initial decisions regarding the body plan of the embryo, whereas differentiation factors control the fate of the constituent cells of the skeleton. Previous cell biological experiments suggested that osteoblast differentiation occurs along a multistep pathway. More recently, the transcription factor Cbfa1/Runx2 was shown to be needed for osteoblast differentiation. Very recently, we have discovered that a novel member of the Kruppel family of transcription factors, called Osterix (Osx), is required for bone formation and osteoblast differentiation. Osx null mice have no membranous, and no endochondral bones, although chondrocyte differentiation and cartilage formation occur normally. Furthermore, our experiments indicate that Osx acts downstream of Cbfa1/Runx2. This application proposes to characterize the mechanisms by which Osx controls osteoblast differentiation. We plan to examine the extent of the osteoblast-genetic program that is controlled by Osx and identify sequences in target genes that directly mediate the transcriptional activation by Osx of these genes in osteoblasts in vivo. Our studies will also identify the proteins that either physically or functionally interact with Osx, or control its activity. Finally, we will determine whether Osx is a negative regulator of Sox9 expression and of the chondrocyte differentiation program. Overall, these experiments should greatly improve our understanding of the molecular mechanisms of osteoblast differentiation.

描述（由申请人提供）：与其他器官的形成类似，骨骼形成涉及两大类调节因素。模式因子控制骨骼元素的形状、大小和数量，以及有关胚胎身体规划的初始决定，而分化因子控制骨骼组成细胞的命运。先前的细胞生物学实验表明，成骨细胞分化沿着多步骤途径发生。最近，转录因子 Cbfa1/Runx2 被证明是成骨细胞分化所必需的。最近，我们发现 Kruppel 转录因子家族的一个新成员，称为 Osterix (Osx)，是骨形成和成骨细胞分化所必需的。尽管软骨细胞分化和软骨形成正常发生，但Osx缺失小鼠没有膜，也没有软骨内骨。此外，我们的实验表明 Osx 作用于 Cbfa1/Runx2 的下游。该应用旨在描述 Osx 控制成骨细胞分化的机制。我们计划检查 Osx 控制的成骨细胞遗传程序的程度，并鉴定直接介导 Osx 在体内成骨细胞中这些基因转录激活的靶基因序列。我们的研究还将确定与 Osx 物理或功能相互作用或控制其活性的蛋白质。最后，我们将确定 Osx 是否是 Sox9 表达和软骨细胞分化程序的负调节因子。总的来说，这些实验应该极大地提高我们对成骨细胞分化分子机制的理解。