Control of Osteoblast Proliferation and Differentiation

描述（由申请人提供）：骨形成是一个受调节和有序的发育过程，需要成骨细胞的生物合成和代谢功能。该项目自18年前启动以来，促进了我们对调节成骨细胞增殖和分化的细胞和分子机制的理解，包括对成骨细胞表型成熟的不同阶段的表征。我们发现Runx2是成骨分化所必需的转录因子，整合了发育信号通路，是一种新的细胞命运决定的表观遗传调节剂。MicroRNAs通过改变mrna的水平和翻译潜力来控制基因表达程序。我们当前的主要发现之一是microrna在控制成骨细胞谱系承诺和成熟以及调节骨量的成骨信号通路中的关键作用（Li et al., Proc. Natl.）。学会科学。, 2008;Li et al ., [j]。化学。, 2009)。我们的初步数据表明，Runx2可能调节削弱骨形成所需的关键生物学途径的microrna的表达。因此，我们的中心假设是microrna在调节骨形成的关键发育转变中控制成骨细胞的承诺和分化，并且这些microrna的一个子集与Runx2有机制联系。因此，我们提出发育表达的microrna可以为治疗骨骼疾病提供一种新的策略。在拟议的研究中，我们将(i)表征microRNAs如何控制成骨细胞表型的发育，（ii）分析Runx2依赖性microRNAs的功能，以及（iii）表征成骨细胞中产生成熟microRNAs缺陷的小鼠的骨骼表型。我们研究的意义在于定义了microrna、成骨信号通路和Runx2在控制成骨细胞分化中的机制联系，这将为骨形成的分子基础提供创新的见解。我们鉴定的限制骨合成代谢作用的microrna的主要影响是开发基于microrna的翻译前方法的潜力，作为临床应用调节患者骨量的新维度。

DESCRIPTION (provided by applicant): Bone formation is a regulated and ordered developmental process that requires the biosynthetic and metabolic functions of osteoblasts. This program since its inception 18 years ago has advanced our understanding of cellular and molecular mechanisms that regulate osteoblast proliferation and differentiation, including the characterization of distinct stages of osteoblast phenotype maturation. We identified Runx2 as a transcription factor essential for osteogenic differentiation that integrates developmental signaling pathways and is a novel epigenetic regulator of cell fate determination. MicroRNAs control gene expression programs by altering both the levels and translational potential of mRNAs. One of our major discoveries in the current period is the critical role of microRNAs in controlling osteoblast lineage-commitment and maturation, as well as osteogenic signaling pathways that regulate bone mass (Li et al., Proc. Natl. Acad. Sci., 2008; Li et al, J. Biol. Chem., 2009). Our preliminary data indicate that Runx2 may regulate the expression of microRNAs that attenuate key biological pathways necessary for bone formation. Therefore, our central hypothesis is that microRNAs control commitment and differentiation of osteoblasts at key developmental transitions for regulating bone formation and that a subset of these miRs is mechanistically linked to Runx2. Consequently, we propose that developmentally expressed microRNAs can provide a novel strategy for treating skeletal disorders. In the proposed studies, we will (i) characterize how microRNAs control development of the osteoblast phenotype, (ii) analyze the function of Runx2 dependent microRNAs, and (iii) characterize skeletal phenotypes in mice defective in producing mature microRNAs in osteoblasts. The significance of our studies is the definition of mechanistic linkages among microRNAs, osteogenic signaling pathways and Runx2 in controlling osteoblast differentiation that will provide innovative insight into the molecular basis of bone formation. The principal impact of our identification of microRNAs that are rate-limiting for bone anabolic effects is the potential to develop microRNA-based pre-translational approaches as a novel dimension for clinical applications to modulate bone mass in patients.