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

• 批准号: 8103141
• 负责人: Florent Elefteriou
• 金额: $ 32.82万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 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/8103141
• 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; Foundations; Fracture; Fracture Healing; Future; Generations; Genes; Genetic; Goals; Hand; Health; 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; repaired; skeletal disorder; skeletal tissue; sound; therapeutic target; tool

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(申请人提供)：骨假关节是骨愈合的一种衰弱的缺陷。骨折和假关节都是一种潜在的、局限性的先天性骨骼组织紊乱的附带现象，这种疾病改变了骨生长和重塑的过程，并危及机械结构健全的内部结构的发展和骨修复的过程。假性关节病的病因仍有待确定，以建立适应的治疗方法。骨愈合涉及四种主要细胞类型：间充质干细胞(MSCs)、软骨细胞、成骨细胞和破骨细胞。到目前为止，证据表明骨形成细胞中缺乏NF1是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。目前的挑战是确定在NF1假关节中功能受损的细胞类型，描述与NF1功能丧失相关的缺陷，并在此基础上提出适当的策略来纠正这些缺陷。在这项建议中，我们询问三种特定的骨细胞类型-软骨细胞、成骨细胞或其共同的前体细胞--间充质干细胞中的NF1功能缺失或NF1功能丧失是否损害骨愈合。为了解决这个问题，我们建议在骨修复研究中使用NF1小鼠和在MSCs、软骨细胞或成骨细胞中缺乏一个或两个NF1拷贝的条件性小鼠模型。有了这些小鼠模型，就有可能确定软骨细胞形成软骨骨痂或骨折后成骨细胞对骨痂的钙化和重塑是否需要一个或两个NF1拷贝(特定目标I和II)。我们还在前期工作(R21AR053978-01)和PD19830和洛伐他汀的ERK抑制特性的基础上，设计了一种新的治疗骨假关节的方法，以纠正NF1-/-成骨细胞的缺陷(特异性目标III)。本申请中提出的研究旨在表征调节骨骼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合适的治疗方法。我们希望我们的研究1)表征NF1在特定骨细胞类型的骨修复的特定阶段中的作用，2)表征新的治疗靶点和策略，以确定针对这种综合征的最合适的治疗方法，3)提供可用作临床前工具的新的小鼠模型。公共卫生相关性：本申请中提出的研究旨在通过建立新的小鼠模型来表征NF1骨假关节的分子缺陷，并随后用作临床前模型，以测试各种药物对骨愈合的纠正作用。