Control of Osteoblast Proliferation and Differentiation

成骨细胞增殖和分化的控制

• 批准号: 8049230
• 负责人: Jane B. Lian
• 金额: $ 43.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049230
• 关键词: Ablation; Address; Apoptosis; Arthritis; Attenuated; Biological; Biological Process; Bone Development; Bone Diseases; Calvaria; Cell Lineage; Cells; Characteristics; Code; Complement; Data; Databases; Development; Developmental Process; Dicer Enzyme; Differentiation and Growth; Dimensions; Disease; Enzyme Gene; Epigenetic Process; Feedback; Fibrosis; Gene Expression; Genes; Genetic; Genomics; Individual; Lead; Link; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; MicroRNAs; Molecular; Mus; Osteoblasts; Osteogenesis; Pathway interactions; Patients; Phenotype; Physiologic calcification; Post-Transcriptional Regulation; Process; Property; Proteins; Role; Signal Pathway; Signal Transduction; Site; Staging; Validation; base; bone; bone loss; bone mass; bone quality; bone turnover; chromatin immunoprecipitation; clinical application; cohort; feeding; human DICER1 protein; in vivo; innovation; insight; mRNA Expression; molecular phenotype; novel; novel strategies; null mutation; osteoblast differentiation; osteogenic; programs; public health relevance; rRNA Genes; selective expression; skeletal; skeletal disorder; substantia spongiosa; trait; transcription factor; translational approach

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. PUBLIC HEALTH RELEVANCE: MicroRNAs have emerged as key regulators of biological cell lineage commitment and differentiation and apoptosis and are also associated with numerous disease states (cancer, fibrosis, arthritis). This recently appreciated level of post-transcriptional control has been minimally studied in relation to normal bone development and turnover. Identification of bone- related miRs and their targets for control of osteoblast growth and differentiation will lead to novel approaches for treating bone diseases.

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。该计划自18年前成立以来，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提高了我们的理解，包括表征成骨细胞表型成熟的不同阶段。我们将Runx2鉴定为成骨分化的转录因子，该转录因子整合了发育信号通路，并且是细胞命运测定的新型表观遗传调节剂。 MicroRNA通过改变mRNA的水平和翻译潜力来控制基因表达程序。我们当前时期的主要发现之一是microRNA在控制成骨细胞谱系谱系和成熟以及调节骨骼质量的成骨信号通路方面的关键作用（Li等，Proc。Natl。Acad。Sci。，2008; Li et al，2008; Li et al，J.Biol。Chem。，Chem。，2009）。我们的初步数据表明，runx2可能调节microRNA的表达，从而减弱骨形成所需的关键生物学途径。因此，我们的中心假设是microRNA控制的承诺和分化成骨细胞的关键发育过渡以调节骨形成，这些miR的子集与Runx2机械上链接在一起。 因此，我们提出，发育表达的microRNA可以为治疗骨骼疾病提供新的策略。在拟议的研究中，我们将（i）表征MicroRNAS控制成骨细胞表型的发育，（ii）分析Runx2依赖性microRNA的功能，（III）表征小鼠在产生成骨细胞成熟的MicroRNA的小鼠中的骨骼表型。我们研究的重要性是MicroRNA之间的机械链接的定义，成骨信号通路和Runx2在控制成骨细胞分化中的定义，这将为骨形成的分子基础提供创新的见解。我们对骨合成代谢效应限制速率限制的microRNA鉴定的主要影响是开发基于microRNA的翻译前方法，这是临床应用的新维度，以调节患者的骨骼质量。 公共卫生相关性：MicroRNA已成为生物细胞谱系承诺和分化和凋亡的关键调节剂，并且还与许多疾病状态（癌症，纤维化，关节炎）有关。最近对正常的骨骼发育和周转率进行了最小研究了最近对转录后控制的水平。识别骨相关的miR及其控制成骨细胞生长和分化的靶标将导致治疗骨骼疾病的新方法。