Bone Pseudoarthrosis Dissected through the Generation of New Mouse Models

项目摘要 骨假关节是一种骨愈合的缺陷。骨折和假关节 代表一种潜在的、局部的骨骼组织先天性疾病的副现象， 骨生长和重塑的过程，并危及机械健全的发展， 内部结构和骨修复过程。假关节的发病机制仍有待确定 以建立适应性疗法。骨愈合涉及四种主要的细胞类型：间充质干细胞 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，骨骼中缺乏Nf 1 形成细胞是NF 1（神经纤维瘤病）假关节的原因，但涉及的细胞类型仍然存在 身份不明目前的挑战是确定NF 1功能受损的细胞类型 假关节，以表征与这种细胞类型中Nf 1功能丧失相关的缺陷，并基于 根据这些知识，提出适应性策略来纠正这些缺陷。在这一建议中，我们要问， 在三种特定骨细胞类型，软骨细胞， 成骨细胞或其共同前体MSC损害骨愈合。为了解决这个问题，我们 建议使用Nf 1 +/-小鼠和缺乏Nf 1一个或两个拷贝的条件小鼠模型， 骨髓间充质干细胞、软骨细胞或成骨细胞在骨修复研究中的应用。有了这些老鼠模型， 通过以下步骤确定软骨愈伤组织的形成需要Nf 1的一个或两个拷贝 软骨细胞或骨折后成骨细胞对骨痂的钙化和重塑（特异性 目标一和二）。我们还设计了旨在描述一种新的治疗方法的研究， 骨假关节，基于我们之前的工作（R21 AR 053978 -01）和ERK抑制特性， PD 19830和洛伐他汀来纠正Nf 1-/-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的新途径和基因 重塑和修复，长期目标是更好地了解骨骼疾病， 适应性疗法我们希望我们的研究1）表征Nf 1在骨修复的特定阶段的作用， 特定的骨细胞类型，2）表征新的治疗靶点和策略，以确定最 3）提供新的小鼠模型，可用于临床前研究。 工具.

PROJECT SUMMARY 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.