Bone Pseudoarthrosis Dissected through the Generation of New Mouse Models

通过生成新的小鼠模型来剖析骨假关节

基本信息

批准号：
7867980
负责人：
Florent Elefteriou
金额：
$ 34.19万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7867980
关键词：
Address Amputation Biomechanics Bone Growth Bone Regeneration Bone callus Bone remodeling Cell Lineage Cells Chondrocytes Collagen Congenital Disorders Defect Development Discipline Disease Epiphysial cartilage Exhibits Figs - dietary Foundations Fracture Fracture Healing Future Generations Genes Genetic Goals Hand Histopathology Homing In Vitro Inherited Knowledge Loss of Heterozygosity Lovastatin Mesenchymal Stem Cells Modeling Molecular Molecular Target Mus Nature Neurofibromatoses Operative Surgical Procedures Osteoblasts Osteoclasts Pathway interactions Patients Pre-Clinical Model Process Property Pseudarthrosis Research Design Resolution Role Signal Transduction Site Skeleton Staging Structure Syndrome Testing Work base bone bone cell bone healing bone quality calcification cell type comparative improved in vivo leukemia loss of function mineralization mouse model neurofibroma new therapeutic target novel novel strategies novel therapeutic intervention osteoblast differentiation osteoclastogenesis palliative pre-clinical prevent public health relevance repaired skeletal disorder skeletal tissue sound therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): Bone pseudoarthrosis is a debilitating defect of bone healing. Both fracture and pseudoarthrosis represent the epiphenomena of an underlying, localized congenital disorder of skeletal tissues that alters the process of bone growth and remodeling and jeopardizes both the development of a mechanically sound internal structure and the process of bone repair. The etiopathology of pseudoarthrosis remains to be defined for the establishment of adapted therapies. Bone healing involves four main cell types: mesenchymal stem cells (MSCs), chondrocytes, osteoblasts and osteoclasts. To date, evidence suggests that lack of Nf1 in bone forming cells is responsible for NF1 (neurofibromatosis) pseudoarthrosis, but the cell types involved remain unidentified. The challenges today are to identify the cell types whose function is impaired in NF1 pseudoarthrosis, to characterize the defects associated with loss of function of Nf1 in this cell type, and based on this knowledge to propose adapted strategies to correct these defects. In this proposal, we ask whether Nf1 haplo-insufficiency or Nf1 loss of function in three specific bone cell types, chondrocytes, osteoblasts or their common precursor, MSCs, impairs bone healing. To address this question, we propose to use Nf1 mice and conditional mouse models lacking one or both copies of Nf1 specifically in MSCs, chondrocytes or osteoblasts in bone repair studies. With these mouse models in hand, it will possible to determine whether one or two copies of Nf1 is required for the formation of a cartilaginous callus by chondrocytes or for the calcification and remodeling of this callus by osteoblasts following fracture (Specific Aim I and II). We also designed studies aimed at characterizing a new therapeutic approach for treating bone pseudoarthrosis, based on our previous work (R21AR053978-01) and the ERK inhibitory property of PD19830 and lovastatin to correct the defects of Nf1-/- osteoblasts (Specific Aim III). The studies proposed in this application aim at characterizing novel pathways and genes regulating bone remodeling and repair, with the long-term goals of better understanding skeleton diseases and proposing adapted therapies. We expect our studies 1) to characterize the role of Nf1 at specific stages of bone repair in specific bone cell types, 2) to characterize novel therapeutic targets and strategies to identify the most appropriate treatment for this syndrome and 3) to provide new mouse models that can be used as pre-clinical tools. PUBLIC HEALTH RELEVANCE: The studies proposed in this application aim at characterizing the molecular defects of NF1 bone pseudoarthrosis by the generation of new mouse models, subsequently used as pre-clinical models to test the corrective effect of various pharmacological agents on bone healing.

描述（由申请人提供）：骨假关节是一种使骨愈合衰弱的缺陷。骨折和假关节都是骨骼组织潜在的局部先天性疾病的副现象，这种疾病会改变骨骼生长和重塑的过程，并危及机械健全的内部结构的发育和骨骼修复的过程。假关节的病因病理学仍有待确定，以建立适应的疗法。骨愈合涉及四种主要细胞类型：间充质干细胞（MSC）、软骨细胞、成骨细胞和破骨细胞。迄今为止，有证据表明，骨形成细胞中缺乏 Nf1 是导致 NF1（神经纤维瘤病）假关节的原因，但所涉及的细胞类型仍未确定。今天的挑战是识别 NF1 假关节中功能受损的细胞类型，表征与该细胞类型中 Nf1 功能丧失相关的缺陷，并基于这些知识提出纠正这些缺陷的适应策略。在本提案中，我们询问三种特定骨细胞类型（软骨细胞、成骨细胞或其共同前体 MSC）中 Nf1 单倍体不足或 Nf1 功能丧失是否会损害骨愈合。为了解决这个问题，我们建议在骨修复研究中使用 Nf1 小鼠和缺乏一个或两个 Nf1 拷贝的条件小鼠模型，特别是在 MSC、软骨细胞或成骨细胞中。有了这些小鼠模型，就可以确定软骨细胞形成软骨愈伤组织或骨折后成骨细胞钙化和重塑该愈伤组织是否需要一个或两个拷贝的 Nf1（具体目标 I 和 II）。基于我们之前的工作 (R21AR053978-01) 以及 PD19830 和洛伐他汀的 ERK 抑制特性，我们还设计了旨在描述治疗骨假关节的新治疗方法的研究，以纠正 Nf1-/- 成骨细胞的缺陷（具体目标 III）。本申请中提出的研究旨在表征调节骨重塑和修复的新途径和基因，长期目标是更好地了解骨骼疾病并提出适应性疗法。我们期望我们的研究 1) 表征 Nf1 在特定骨细胞类型的骨修复特定阶段的作用，2) 表征新的治疗靶点和策略，以确定针对该综合征的最合适的治疗方法，3) 提供新的小鼠模型可以用作临床前工具。公共健康相关性：本申请中提出的研究旨在通过生成新的小鼠模型来表征 NF1 骨假关节的分子缺陷，随后用作临床前模型来测试各种药物对骨愈合的纠正作用。