Runx1 Control of Bone Resorption during Fracture Repair

Runx1 骨折修复过程中骨吸收的控制

基本信息

批准号：
8692536
负责人：
HICHAM M DRISSI
金额：
$ 33.79万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692536
关键词：
Apoptosis Bone Marrow Bone Regeneration Bone Resorption Bone callus Bone remodeling Cell Differentiation process Cells Commit Dendritic Cells Development Disease Elements Event FOS gene Flow Cytometry Fracture Fracture Healing Gene Expression Gene Fusion Genes Healed Histologic Homeostasis ITGAM gene Image Analysis In Vitro Incidence Infection Knock-out Lead MMP9 gene Mediating Molecular Mus Myelogenous Names New Agents Osteoclasts Osteolysis Osteoporosis Phenotype Population Process Prosthesis Proteins RNA Repression Role Signal Transduction Site Small Interfering RNA Staging Stem cells Subfamily lentivirinae TNFSF11 gene Tamoxifen Time Transcription Repressor/Corepressor Transgenic Mice Viral Wild Type Mouse bone mass cathepsin K effective therapy gain of function gene repression genome-wide healing in vivo inhibitor/antagonist insight laser capture microdissection loss of function macrophage monocyte novel osteoclastogenesis precursor cell progenitor public health relevance repaired research study skeletal skeletal regeneration substantia spongiosa transcription factor

项目摘要

DESCRIPTION (provided by applicant): We generated preliminary evidence showing that the number of osteoclasts in the fracture calluses of mice haploinsufficient for Runx1 is increased compared to wild type littermates. Furthermore, we found that targeted deletion of Runx1 in osteoclast precursors led to 25-30% decrease in trabecular bone mass and a 40-50% increase in bone resorption. Finally, we determined that Runx1 inhibits the expression of osteoclast specific genes in vitro. Thus, we hypothesized that Runx1 inhibits myeloid precursor cell differentiation into mature osteoclasts and in this way alters skeletal homeostasis and repair. We propose to: 1. Evaluate the role of Runx1 in regulating osteoclasts during bone remodeling and fracture repair. (Aim 1). We propose to determine whether: (i) Runx1 is a transcriptional repressor of osteoclast differentiation and function in vivo and (ii) if conditional deletion of Rux1 in precursors but not mature osteoclasts will impair fracture healing. 2. Define the mechanisms underlying Runx1-mediated inhibition of osteoclastogenesis. (Aim 2). We propose to determine whether (i) Runx1 is critical for early but not late osteoclast differentiation; (ii) examine if Rux1-mediated inhibition of osteoclastogenesis depends on inhibition of RANK-signaling; (iii) Runx1 alters osteoclast precursor lineage commitment and differentiation by regulating critical genes; (iv) Runx1 regulates myeloid precursor commitment towards various lineage fates. Our proposed experiments will provide a novel and integrated mechanistic insight into the transcriptional repression of osteoclast differentiation during skeletal regeneration and repair.

描述（由申请人提供）：我们生成的初步证据表明，与野生型同窝小鼠相比，Runx1 单倍体不足的小鼠骨折愈伤组织中破骨细胞的数量有所增加。此外，我们发现破骨细胞前体中Runx1的靶向缺失导致小梁骨量减少25-30%，骨吸收增加40-50%。最后，我们确定 Runx1 在体外抑制破骨细胞特异性基因的表达。因此，我们假设 Runx1 抑制骨髓前体细胞分化为成熟破骨细胞，并以这种方式改变骨骼稳态和修复。我们建议： 1.评估Runx1在骨重塑和骨折修复过程中调节破骨细胞的作用。（目标 1）。我们建议确定：(i) Runx1 是否是体内破骨细胞分化和功能的转录抑制因子；(ii) 在前体细胞中而不是成熟破骨细胞中条件性删除 Rux1 是否会损害骨折愈合。 2. 定义 Runx1 介导的破骨细胞生成抑制的机制。（目标 2）。我们建议确定 (i) Runx1 是否对早期但不是晚期破骨细胞分化至关重要； (ii) 检查 Rux1 介导的破骨细胞生成抑制是否依赖于 RANK 信号传导的抑制； (iii) Runx1 通过调节关键基因来改变破骨细胞前体谱系定型和分化； (iv) Runx1 调节骨髓前体对各种谱系命运的承诺。我们提出的实验将为骨骼再生和修复过程中破骨细胞分化的转录抑制提供新颖且综合的机制见解。