MAP KINASE REGULATION OF OSTEOBLAST FUNCTION

成骨细胞功能的 MAP 激酶调节

• 批准号: 7903811
• 负责人: Renny Theodore Franceschi
• 金额: $ 30.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7903811
• 关键词: Adult; Age-Months; Aging; Biochemical Genetics; Biological; Bone remodeling; Calvaria; Cell Adhesion; Cell Nucleus; Cells; Cephalic; Chromatin; Complex; Consensus; DNA; Development; Dominant-Negative Mutation; Environment; Exercise; Extracellular Matrix; Extracellular Signal Regulated Kinases; FGF2 gene; Gene Expression; Gene Family; Genetic Transcription; Goals; Growth Factor; Homeostasis; Hormonal; Hormones; IGF1 gene; In Vitro; Knock-in Mouse; Laboratories; Life; Link; MAP2K1 gene; Maps; Marrow; Mechanical Stimulation; Mechanics; Mediating; Mesenchymal Differentiation; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutation; Nuclear; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Ovariectomy; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Process; Proteins; Regulation; Regulator Genes; Role; Serine; Signal Transduction; Site; Skeletal Development; Skeleton; Stimulus; Stromal Cells; Study models; Testing; Therapeutic; Tissues; Transcriptional Activation; Transgenes; Transgenic Mice; Weight-Bearing state; age related; base; bone; bone loss; expression vector; extracellular; fluid flow; in vivo; mature animal; mineralization; mutant; novel; novel therapeutic intervention; osteoblast differentiation; prevent; promoter; response; shear stress; transcription factor

The extracellular signal-regulated kinase (ERK)/MAP kinase pathway is a major control point for mesenchymal differentiation. In bone, this pathway is a major conduit for conveying information about the extracellular environment to the nucleus and has been implicated in the response of bone to a variety of signals including cell adhesion, hormone/growth factor stimulation and mechanical loading. As shown by this laboratory, ERK/MAPK signaling is necessary for osteoblast differentiation and in vivo skeletal development. Furthermore, actions of this pathway on osteoblast differentiation are mediated by phosphorylation and activation of the bone-related transcription factor, RUNX2, at 2 critical serine residues. Goals for this renewal are to understand how phosphorylation controls RUNX2 transcriptional activity and establish the physiological significance of MAPK signaling and RUNX2 phosphorylation during development and post-natal life. Aims are: 1. Establish the importance of MAPK phosphorylation to the biological activity of RUNX2 in vitro and the underlying mechanism of transcriptional activation. 2. Evaluate the role of the ERK/MAPK pathway in osteoblast/osteocyte function in adult mice. 3. Evalulate the in vivo role of RUNX2 phosphorylation in skeletal development and homeostasis. These studies will establish the significance of a novel pathway for controlling gene expression in bone. Mechanisms defined in this project have the potential to explain how bone responds to a number of primary extracellular stimuli including ECM and mechanical signals and may serve as the basis for new therapeutic approaches targeting MAPK signaling. 7. Project Narrative Bone is a dynamic tissue whose formation and breakdown are precisely controlled by mechanical, hormonal and growth factor stimulation. This laboratory discovered a novel pathway involving mitogen-activated protein kinase (MAPK) phosphorylation of a bone-specific gene regulatory factor known as RUNX2. This pathway links external signals to induction of a family of genes that are required for bone formation. This project seeks to gain a mechanistic understanding of this pathway by conducting detailed biochemical and genetic studies in mice. Therapeutic manipulation of the MAPK pathway has the potential to augment bone anabolic therapies such as weight-bearing exercise to prevent or reverse the deleterious effects of osteoporosis.

细胞外信号调节激酶（ERK）/MAP激酶途径是间充质干细胞的主要控制点。 分化在骨骼中，这条通路是传递细胞外信息的主要管道。 环境到细胞核，并已涉及骨对各种信号的反应，包括 细胞粘附、激素/生长因子刺激和机械负荷。正如这个实验室所示， ERK/MAPK信号通路是成骨细胞分化和体内骨骼发育所必需的。此外，委员会认为， 该途径对成骨细胞分化的作用是通过磷酸化和激活成骨细胞的 骨相关转录因子，RUNX 2，在2个关键的丝氨酸残基。这次更新的目标是了解 磷酸化如何控制RUNX 2的转录活性，并确定其生理意义。 MAPK信号和RUNX 2磷酸化在发育和出生后的生活。目标是： 1.建立MAPK磷酸化对RUNX 2体外生物活性的重要性， 转录激活的潜在机制。 2.评价ERK/MAPK通路在成年小鼠成骨细胞/骨细胞功能中的作用。 3.评估RUNX 2磷酸化在骨骼发育和稳态中的体内作用。 这些研究将建立一个新的途径控制基因在骨中的表达的意义。 在这个项目中定义的机制有可能解释骨如何对一些主要的 细胞外刺激，包括ECM和机械信号，并可能作为新的治疗基础， 针对MAPK信号的方法。7.项目叙述 骨是一种动态的组织，其形成和分解受到机械、激素和生物学的精确控制。 和生长因子刺激。这个实验室发现了一个新的途径， 在一些实施方案中，骨特异性激酶（MAPK）磷酸化被称为RUNX 2的骨特异性基因调节因子。这条道路连接着 外部信号诱导骨形成所需的基因家族。本项目谋求 通过进行详细的生物化学和遗传学研究， 小鼠MAPK通路的治疗操作有可能增加骨合成代谢治疗 例如负重锻炼以预防或逆转骨质疏松症的有害影响。