Osteoblast differentiation: Interactions of Wnt, Runx2 and FGF

成骨细胞分化：Wnt、Runx2 和 FGF 的相互作用

• 批准号: 7798088
• 负责人: THOMAS G BOYER
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798088
• 关键词: Affinity; Alleles; Binding; Binding Sites; Biological Assay; Biology; Bone Development; Bone Diseases; Bone Tissue; Cell Nucleus; Cells; Characteristics; Complex; Couples; Coupling; DNA; DNA Binding; DNA-Protein Interaction; Data; Development; Event; FGFR1 gene; FGFR2 gene; Felis catus; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Gene Expression Profile; Gene Mutation; Gene Targeting; Genes; Genetic Transcription; Health; Human; Human Genetics; Knock-out; Knowledge; Laboratory mice; Lead; Ligands; Link; Measures; Molecular; Molecular Profiling; Mus; Osteoblasts; Osteogenesis; Osteoporosis; Pathway interactions; Protein Binding; Proteins; RNA Interference; Receptor Signaling; Regulation; Signal Transduction; Site; Staging; Surface Plasmon Resonance; TCF Transcription Factor; Tertiary Protein Structure; Testing; Therapeutic; Thermodynamics; Translating; Uncertainty; beta catenin; bone; bone mass; fibroblast growth factor 18; gain of function; improved; mouse model; new therapeutic target; osteoblast differentiation; prevent; promoter; protein protein interaction; public health relevance; transcription factor

DESCRIPTION (provided by applicant): Studies of mouse and human genetics show that canonical Wnt signaling is required for normal bone development as well as acquisition of normal bone mass. Canonical Wnt signaling is strongly anabolic for bone. Consequently, understanding how canonical Wnt signaling induces bone will illuminate pathways that can be manipulated to increase bone mass for the treatment of osteoporosis. Because canonical Wnt signaling increases the protein levels of beta-catenin (bcat), which then moves to the nucleus and induces gene expression, we hypothesized that bcat cooperates with bone-specific transcription pathways to induce genes responsible for Wnt- induced bone formation. Significantly, in preliminary data we show that fibroblast growth factor 18 (FGF18) expression requires and is directly induced by canonical Wnt signaling. Moreover, the osteoblast-specific transcription factor, Runx2, binds to the Wnt-dependent transcription factor LEF/TCF and thereby stimulates the FGF18 promoter. Thus, FGF18 expression is directly linked to bone-specific and Wnt-dependent transcription. Given these direct links to the essential pathways of bone, we hypothesize that induction of FGF18 is required for the anabolic effects of Wnt signaling in bone. We further hypothesize that the Runx2-LEF/TCF transcription complex regulates a set of genes that induce a specific early stage of osteoblast differentiation. To test our hypotheses and advance new therapies for bone disease we will pursue the following specific aims: 1) determine the protein domains and thermodynamic parameters that govern assembly of the Runx2-LEF complex and its affinity for DNA, 2) identify osteoblast-relevant genes that are turned on (or off) by the convergence of Wnt signaling and Runx2, and 3) using mice with conditional loss and gain of function alleles for bcat define the requirement for FGFs and FGF signaling during canonical Wnt-induced osteoblast differentiation. These studies will provide an unprecedented view of the molecular events regulating osteoblast gene expression in respose to Wnt and FGF. Additionally, these studies will unravel how Wnt signaling induces formation of bone and in cooperation with other transcription factors regulates specific steps in the sequence of osteoblast differentiation. We anticipate that the completion of these studies will suggest new way to treating bone diseases like osteoporosis. PUBLIC HEALTH RELEVANCE. This application aims to improve human health by advancing our understanding of the bone and bone producing cells. The completion of these studies will reveal new therapeutic targets and ways for treating bone disease like osteoporosis.

描述（由申请人提供）：小鼠和人类遗传学的研究表明，正常骨骼发育以及正常骨骼质量的获得需要规范的Wnt信号传导。规范的Wnt信号对于骨骼来说是强烈的合成代谢。因此，理解构成的Wnt信号传导如何诱导骨头会照亮可以操纵的途径，以增加骨质量以治疗骨质疏松症。由于规范的Wnt信号会增加β-catenin（BCAT）的蛋白质水平，然后移动到核并诱导基因表达，因此我们假设BCAT与骨特异性转录途径合作，以诱导造成WNT诱导的骨骼形成的骨骼特异性转录途径。值得注意的是，在初步数据中，我们表明成纤维细胞生长因子18（FGF18）表达需要并直接由规范的Wnt信号传导诱导。此外，成骨细胞特异性转录因子runx2与Wnt依赖性转录因子LEF/TCF结合，从而刺激FGF18启动子。因此，FGF18表达直接与骨特异性和Wnt依赖性转录有关。鉴于这些与骨骼基本途径的直接联系，我们假设FGF18的诱导是Wnt信号在骨中的合成代谢作用所必需的。我们进一步假设RUNX2-LEF/TCF转录复合物调节了一组诱导成骨细胞分化的特定早期阶段的基因。为了检验我们的假设并推进骨骼疾病的新疗法，我们将追求以下特定目的：1）确定蛋白质域和热力学参数，这些蛋白质域和热力学参数控制Runx2-Lef复合物的组装及其对DNA的亲和力，其对DNA的亲和力，2）确定与整个成骨的基因（或使用Wnt and runsing and Runss signely and Runsing and runs and runs and runs signel和3）确定与骨化的基因，并确定runs and runsing and runx2＆3对于BCAT，定义了在规范WNT诱导的成骨细胞分化过程中FGF和FGF信号传导的要求。这些研究将为调节对Wnt和FGF的响应中调节成骨细胞基因表达的分子事件提供前所未有的观点。此外，这些研究将揭示Wnt信号如何诱导骨骼的形成并与其他转录因子合作，调节成骨细胞分化序列中的特定步骤。我们预计这些研究的完成将提出治疗骨质疏松等骨疾病的新方法。公共卫生相关性。该应用旨在通过促进我们对骨骼和骨产生细胞的理解来改善人类健康。这些研究的完成将揭示新的治疗靶标以及治疗骨质疏松症（如骨质疏松症）的方法。